Colorectal cancer is one of the most common cancers worldwide.1 In the United States, 147,000 individuals received a diagnosis of the disease in 2020, and 53,200 died from it.2 Most patients with colorectal cancer are older than 50 years of age at diagnosis.2 Men have a higher risk than do women and are on average 5 to 10 years younger than women when they receive the diagnosis.3,4
Most colorectal cancers develop from benign polyps (adenomas and serrated polyps) through a series of genetic and epigenetic changes that take 10 to 15 years.5-8 Colorectal polyps are very common; about half of individuals 50 years of age and older have polyps.9,10 Hence, almost all colorectal cancers develop from polyps, but only a small proportion of polyps develop into cancer.11,12
Detection and removal of colorectal polyps by colonoscopy hinders progression to colorectal cancer. Because only individuals who get a disease can die from it, the reduction of colorectal cancer incidence by adenoma detection and removal through screening leads to reduced mortality associated with colorectal cancer.13,14 In addition, screening may detect cancers at an early stage and thereby reduce mortality.
Colorectal cancer development through precursor stages (polyps) over a period of many years and the availability of procedures to detect and remove polyps with little patient harm make colorectal cancer an attractive target for prevention and early detection by population screening.
Screening
Screening means “to sift by passing through a screen.”15 The verb “to sift” derives from an old Dutch word zeef (sieve) for a “utensil used to separate coarser from finer particles of loose material,”15 which illuminates the main idea behind screening: separating the sick from the healthy.
A General Framework for the Benefits, Burdens, and Harms of Screening.
In contrast to care for symptomatic patients, screening targets presumptively healthy individuals with no clinical signs or symptoms of disease. Because screening targets healthy people, it is especially important that its benefits outweigh its harms. A general framework for the benefits, burdens, and harms of screening should be considered before recommending any screening (Table 1).
The Colorectal Cancer Screening Process in Practice.
Cancer screening is usually a process that includes several steps (Fig. 1). Screening involves performing the initial testing, following up with patients with positive results with other tests or procedures to confirm the suspected diagnosis, and treating the diagnosed disease or precursor. Individuals with negative screening results often need to be rescreened at regular intervals to maintain the screening effect, such as yearly or every other year for mammography for breast cancer screening or fecal testing for colorectal cancer screening (Fig. 1). The performance of cancer screening programs includes initial tests and downstream assessment and treatment.16
Main Characteristics of and Tools for Preventive and Early-Detection Screening.
Cancer screening can be divided into two different concepts: preventive screening and early-detection screening (Fig. 2). Both have distinctively different modes of action and different performance abilities. Preventive screening tests aim to detect still-benign cancer precursors. Early-detection screening tests cannot reliably detect benign cancer precursors but aim to detect invasive cancer at an early stage.17
PREVENTIVE SCREENING
The identification and removal of benign cancer precursors prevents invasive cancer. Examples of preventive screening tests are colonoscopy and sigmoidoscopy for colorectal cancer screening and the Pap smear for cervical cancer.
The main effect of preventive screening programs is to prevent cancer from developing. Thus, these programs work by reducing cancer incidence. In preventive screening, a reduction in the mortality associated with cancer is mainly a consequence of a reduction in cancer incidence, although most preventive screening tools also provide an opportunity for early cancer detection. Preventive screening can be performed with long time intervals between test rounds, because of the long duration of development from a benign precursor to invasive cancer, which is significantly longer than the growth time from early- to late-stage invasive cancer.
EARLY-DETECTION SCREENING
Most cancers do not have known precursors, or there are currently no tests available to detect them. Thus, preventive screening is not available for most cancers. Breast and prostate cancer screening with mammography and prostate-specific antigen (PSA), respectively, are examples of early-detection screening.
The prerequisite for early detection to reduce mortality is cancer detection at an earlier stage with screening in comparison with no screening. Early detection cannot reduce cancer incidence. In fact, mammography and PSA screening increase cancer incidence by finding small cancers that would not grow further and lead to symptoms or cause death. This is a harm of screening and is called “overdiagnosis.”
Colorectal Cancer Screening Tests
Screening Effect on the Incidence of Colorectal Cancer and its Associated Mortality.
A variety of tests are available for colorectal cancer screening. To date, only the guaiac-based fecal occult blood test (gFOBT) and sigmoidoscopy have been shown to reduce the incidence of colorectal cancer and its associated mortality in randomized trials (Table 2). However, the most commonly applied tests today are the fecal immunochemical test (FIT) and colonoscopy.18,19
Large-scale randomized trials are ongoing to compare FIT and colonoscopy or colonoscopy with no screening. Results are expected in 2022.20 Meanwhile, we rely on results from observational studies and models suggesting that FIT and colonoscopy reduce the incidence of colorectal cancer and its associated mortality.21 The main concern with observational studies and models is the nonrandom assignment of screening. In brief, the incidence of colorectal cancer and its associated mortality are compared in individuals who have chosen to undergo screening and those who have chosen not to undergo screening. It is well known that attenders and nonattenders usually differ substantially in the risk of cancer and its associated mortality, comorbidities, and socioeconomic status, which causes self-selection bias in nonrandomized screening studies.22,23 Although the estimates of effectiveness of FIT and colonoscopy on the basis of observational studies and modeling are uncertain, it is reasonable to infer that they should be at least as good as the closely related tests gFOBT and sigmoidoscopy.21
Other emerging technologies for colorectal cancer screening — such as computed tomography (CT) colonography, capsule endoscopy, or, most recently, genetic biomarkers in feces or blood — may play a role in future screening, but most are not used commonly worldwide.
FECAL SCREENING
Fecal testing is a stepwise screening strategy that needs to be repeated at regular intervals. All positive fecal tests need to be followed by colonoscopy to confirm the diagnosis and remove detected polyps (Fig. 1).
Fecal occult blood testing is primarily an early-detection screening test. The theory is that early colorectal cancers bleed and that small traces of blood can be detected in the stool before symptoms develop. Since many cancers bleed intermittently, the sensitivity of a fecal test is limited. Thus, fecal testing needs to be repeated. The optimal interval between fecal screening rounds and the number of tests in each round, as well as the age of screening start and end, are debated.24 Most current guidelines recommend repeating fecal testing yearly or every other year.18,19,25
There are several reasons why fecal tests may be positive, such as bleeding polyps, inflammation, peptic ulcers, or hemorrhoids. Although fecal testing works primarily through the early detection of cancer, it may also prevent some cancers, owing to the coincidental finding and removal of polyps in people undergoing colonoscopy because of a positive fecal test.
Previously, fecal testing was performed with gFOBT, but this test has been replaced with the FIT, providing more specific detection of colorectal disease (because there are no false-positive results from dietary sources and upper gastrointestinal causes of bleeding such as peptic ulcer disease) and allowing quantitative measurement of the amount of hemoglobin in feces (in micrograms of hemoglobin per gram of feces).26,27 FITs can be adjusted for the desired threshold of fecal hemoglobin for a positive test, thus allowing adjustment of the sensitivity and specificity of colorectal cancers and adenomas in screening programs.28
Different FIT screening programs apply different cutoffs depending on the priorities of benefits, harms, capacity, and costs. For example, the colorectal cancer screening program in England uses a FIT positivity threshold of 20 μg Hb/g, whereas the Scottish program applies a positivity threshold of 80 μg Hb/g.29 It is unknown whether screening benefits and harms in the incidence of colorectal cancer and its associated mortality differ between programs with different thresholds.28,30,31
ENDOSCOPIC SCREENING
Endoscopic screening may be performed with sigmoidoscopy (examining the distal part of the colon) or colonoscopy (examining the whole colon). Colonoscopy is currently the predominant endoscopic screening test.
Endoscopic screening aims to detect and remove adenomas and serrated polyps, and thus prevent colorectal cancer. In addition, cancers may be detected early at endoscopic screening. The expected reduction in mortality associated with colorectal cancer is mainly attributable to the reduction of cancer incidence by the removal of polyps and, to a lesser degree, to early detection and treatment of early cancer.32
Sigmoidoscopy is a less invasive procedure than colonoscopy and can be performed without sedation, with bowel preparation limited to an enema. Colonoscopy requires more cumbersome oral bowel preparation, is more time consuming, and is most often performed with conscious sedation or general anesthesia.33 In addition to being used as a primary screening test, colonoscopy is the common follow-up procedure for individuals who have a positive test result on any other colorectal cancer screening test (Fig. 1).
EMERGING SCREENING TESTS
One fecal biomarker panel test is currently recommended by some U.S. guidelines but not in other parts of the world, owing to the high costs and limited evidence of benefits in the incidence of colorectal cancer and its associated mortality.26,34
Many commercial entities and academic institutions are currently investigating novel blood-based screening tests using genetic, epigenetic, or proteomic markers for colorectal cancer or polyps, but no test is currently at the approval stage for use in screening programs.
CT colonography is recommended as a second-tier screening test in some U.S. guidelines. However, because of its high costs, radiation exposure, and need for follow-up colonoscopy of all CT positive results, CT colonography is not currently used in population screening.
Postscreening Surveillance
Patients who had polyps removed at screening are classified as having a high or low risk for future development of colorectal cancer, dependent on the size, number, and histologic features of the removed polyps. Most individuals with removed polyps receive surveillance colonoscopy — for example, every 3, 5, or 10 years, depending on the polyp characteristics (Fig. 1). Guidelines for surveillance after polyp removal vary in different parts of the world, with more surveillance and shorter intervals in the United States and less surveillance for fewer people in Europe.35-37
There is a lack of high-quality studies guiding recommendations for surveillance after colorectal cancer screening. Thus, all current recommendations are based on low-quality evidence using surrogate end points such as recurrent adenomas and expert opinion. Currently, a 20,000-patient European randomized trial comparing different polyp surveillance strategies for patients with removed polyps is ongoing, and a U.S. National Institutes of Health–sponsored sister trial is about to begin.38,39
Benefits and Harms
Table 2 shows the relative and absolute benefits of sigmoidoscopy and gFOBT, the colorectal cancer screening strategies that have been tested in randomized trials. The certainty of the evidence is high, because we have included randomized trials only — with the exception of colorectal cancer incidence with yearly gFOBT, where we have graded the certainty as moderate owing to imprecision in the effect estimate. For colonoscopy and FIT, the results from randomized trials are not yet available. We assume a relative effect of colonoscopy and FIT similar to that observed in the randomized trials of sigmoidoscopy and gFOBT. Because sigmoidoscopy does not reach the full colon, we have assumed the effect of colonoscopy to be similar to the effect of sigmoidoscopy in the distal colon (Table 2).
Serious Bleeds and Bowel Perforations per 1000 Endoscopies.
As shown, the benefits and harms of screening depend on the screening test, with a larger effect of colonoscopy (Fig. 2; Tables 2 and 3) compared with sigmoidoscopy and FIT/gFOBT. However, the magnitude of effect is more dependent on the individual risk of cancer than on which tests are used. Screening individuals with a 2% risk of colorectal cancer may prevent 0 to 7 cancers and hinder 1 to 3 deaths from colorectal cancer per 1000 individuals screened (Fig. 2). Screening individuals with a 4% risk of colorectal cancer may prevent 1 to 13 cancers and hinder 2 to 7 colorectal cancer deaths per 1000 individuals screened.
All tests have some adverse effects; bleeding and perforations are the most common adverse events for endoscopy (Table 3). The number of adverse events is dependent on the number of endoscopies, performed either as a primary screening test, as a follow-up to a positive sigmoidoscopy or fecal test, or for surveillance (Fig. 1). In FIT screening programs, the number of adverse events increases with a lower cutoff for FIT positivity.40 The number of adverse events also increases with increased age, the number of comorbidities, and in colonoscopies with polypectomies.41
There is considerable heterogeneity in the reports on screening-related harms; the indications for colonoscopy differ, there is no standard nomenclature for all harms, sources of information vary, and often it is unclear how adverse events are captured.14,42 Mostly, harms related to surveillance colonoscopies are not included in the harm of screening in population-based studies, so the present estimates of burdens and harms are highly uncertain.25,43
OVERDIAGNOSIS
Overdiagnosis in cancer screening is defined as the detection of a lesion (e.g., a polyp or cancer) that would not have caused symptoms or death (or polyps that would not have progressed to cancer) in the remaining lifetime of the individual who received the diagnosis. Of note, overdiagnosis is not the same as a false-positive test result.
Overdiagnosis is inherently associated with patient harm. However, it is not possible to disentangle whether an individual patient has received an overdiagnosis, because overdiagnosed disease cannot be distinguished from nonoverdiagnosed disease with the currently available screening tests. The risk of overdiagnosis with screening must be estimated on a population level. The precise risk of overdiagnosis with colorectal cancer screening is currently unknown44,45 but is believed to be smaller than for prostate cancer screening.
Overdiagnosis is harmful because it leads to unnecessary treatment, labels individuals as diseased who would not have negative consequences if they had not been screened, causes psychosocial harm such as anxiety, and has economic consequences related to health care costs or insurance premiums.46-48 Furthermore, screening may lead to unnecessary medical consequences, such as surveillance and follow-up, with the risk of more overdiagnosis and exposure to harms.
Both preventive and early-detection colorectal cancer screening entail different risks of overdiagnosis. Overdiagnosis of colorectal cancer is more severe than overdiagnosis of polyps, because cancer treatment is more excessive and harmful than polyp treatment. However, because there are many more patients with polyps than with cancer, the harm of population screening even for polyp overdiagnosis in preventive screening deserves consideration by policymakers and screening providers. The prevalence of adenomas in an average screening population of individuals 60 years of age was 32%49 and the lifetime risk of colorectal cancer in the United States is about 4.2%.50 Consequently, most adenomas will not progress to cancer.
QUALITY VERSUS OVERDIAGNOSIS
The success of preventive screening tests for colorectal cancer relies on their reliable detection of premalignant polyps. During the past 10 years, there has been increasing recognition of a large variation in the endoscopist’s ability to adequately detect and remove polyps.10,51,52 Individuals who have their colonoscopy performed by an endoscopist with high adenoma detection rates (ADRs) have a significantly lower risk for colorectal cancer than those examined by an endoscopist with low detection rates. Consequently, rigorous quality assurance programs including training, supervision, and auditing have been introduced in many colorectal cancer screening programs.
However, the exact relationship between ADRs and future cancer prevention is still unknown. Some propose a linear relationship,10 whereas others have suggested a threshold effect; for example, an additional ADR increase over a specific threshold such as 20% ADR may have little or no benefit in cancer prevention but may increase polyp overdiagnosis and overtreatment.52 If there is a threshold between ADR and colorectal cancer prevention, the risk of causing harm to patients as a result of unnecessary polyp removal will increase with increasing the ADR above the threshold, and it will result in additional cost and burden for patients and health systems without significant additional benefit.44,53
Artificial intelligence (AI)–based polyp detection tools during colonoscopy have recently been introduced to increase polyp detection. Preliminary studies suggest that AI-based polyp detection aids during colonoscopy increase the average ADR of endoscopists from 25 to 37%.54 The AI aids did not increase the detection of larger and advanced polyps, those with the highest risk for malignant transformation55; in addition, it is unknown whether AI benefits for small polyp detection lead to better cancer prevention in colorectal cancer screening.
Although there is benefit of increased ADR to an unknown threshold, AI aids and other measures to increase ADR will inevitably increase the screening burden as a result of the intensive surveillance recommended for more patients.
Guidelines
Examples of Ethical Challenges with Clinical Practice Guidelines
Clinical practice guidelines have become important tools to facilitate evidence-based clinical practice, but they may also have negative effects and pose ethical challenges (Table 4). Many national and international clinical practice guidelines exist for colorectal cancer screening. Most recommend screening for average-risk individuals between 50 and 79 years of age.18,19 Recently, some U.S. guidelines such as those from the U.S. Preventive Services Task Force25 and the American Cancer Society56 have changed the recommended starting age for screening to 45 years.
Because of the lack of data from randomized controlled trials for commonly applied colorectal cancer screening tests such as FIT and colonoscopy, several guidelines base their recommendations on estimates of benefits and harms of screening from microsimulation modeling.25,43,56 Models rely on several assumptions, including the unknown natural history of colorectal cancer, and the validity of the modeled outputs is uncertain.57,58 It is important to acknowledge the uncertainty when recommendations are based on modeling.43
Screening leads to a large clinical benefit for some, but it exposes many to burden and potential harm. Colorectal cancer screening is not a one-time event; rather, it results in follow-up colonoscopy and surveillance for many individuals (Fig. 1). People may value the potential benefits and harms differently, and some may reasonably decline screening.43,59 There is currently no established threshold of what magnitude of benefit people would want to undergo screening, given its harms and burdens.
Most previous colorectal cancer screening programs recommend screening to everyone older than a certain age and do not consider individual cancer risk. A more recent colorectal screening guideline proposes the introduction of risk and benefit thresholds for recommending for or against screening.43 The proposed threshold is based on the balance of absolute benefits and harms and used an expert and patient panel to provide guidance on what most people would choose.60 On the basis of such a benefit threshold, the panel recommended screening (weak recommendation) for individuals with a 15-year risk of colorectal cancer of 3% or higher and no screening when it is below 3%. Calculators have been developed for individuals to ascertain their personal risk.43
There is an urgent global need for new strategies and drugs to control and treat multidrug-resistant bacterial infections. In 2017, the World Health Organization (WHO) released a list of 12 antibiotic-resistant priority pathogens and began to critically analyze the antibacterial clinical pipeline. This review analyzes “traditional” and “nontraditional” antibacterial agents and modulators in clinical development current on 30 June 2021 with activity against the WHO priority pathogens mycobacteria and Clostridioides difficile. Since 2017, 12 new antibacterial drugs have been approved globally, but only vaborbactam belongs to a new antibacterial class. Also innovative is the cephalosporin derivative cefiderocol, which incorporates an iron-chelating siderophore that facilitates Gram-negative bacteria cell entry. Overall, there were 76 antibacterial agents in clinical development (45 traditional and 31 nontraditional), with 28 in phase 1, 32 in phase 2, 12 in phase 3, and 4 under regulatory evaluation. Forty-one out of 76 (54%) targeted WHO priority pathogens, 16 (21%) were against mycobacteria, 15 (20%) were against C. difficile, and 4 (5%) were nontraditional agents with broad-spectrum effects. Nineteen of the 76 antibacterial agents have new pharmacophores, and 4 of these have new modes of actions not previously exploited by marketed antibacterial drugs. Despite there being 76 antibacterial clinical candidates, this analysis indicated that there were still relatively few clinically differentiated antibacterial agents in late-stage clinical development, especially against critical-priority pathogens. We believe that future antibacterial research and development (R&D) should focus on the development of innovative and clinically differentiated candidates that have clear and feasible progression pathways to the market.
INTRODUCTION
The need for new antibacterial drugs to treat multidrug-resistant (MDR) bacterial infections is a critical global health issue, which has been recognized by many governmental, nongovernmental, and intergovernmental organizations (1, 2), including the World Health Organization (WHO). In February 2017, the WHO released a list of 12 antibiotic-resistant priority pathogens (Fig. 1), which are still among the most important bacterial infectious threats to human health (3–5). The WHO has also been critically analyzing the antibacterial pipeline since 2017, along with The Pew Charitable Trusts (6), which has resulted in the publication of four reports in 2017 (7), 2018 (8), 2019 (9), and 2021 (10). These pipeline reports and the WHO bacterial priority pathogen list have been used by policy makers, funders/sponsors, researchers, and developers to help guide the discovery and development of new antibacterial treatments. The U.S. Centers for Disease Control and Prevention (CDC) also released important pathogen (bacteria and fungi) threat lists in 2019 (11) and 2013 (12). While the WHO and CDC lists mostly overlap, there are some differences: the WHO list has ampicillin-resistant Haemophilus influenzae as a medium-priority pathogen, while the CDC list has Clostridioides difficile as an urgent threat, erythromycin-resistant group A Streptococcus and clindamycin-resistant group B Streptococcus as concerning threats, and drug-resistant Mycoplasma genitalium and Bordetella pertussis on a watch list. In March 2021, India released its own priority pathogen list (13), which included two pathogens, coagulase-negative staphylococci (CoNS) and Neisseria meningitidis (meningococcal disease), that are not in the WHO and CDC lists. The WHO is planning to update their priority pathogen list in 2022.
FIG 1
FIG 1 List of the WHO’s critical-, high-, and medium-priority pathogens (3, 4) and mycobacteria. *, Enterobacteriaceae (Escherichia coli, Enterobacter spp., and Klebsiella pneumoniae) and Enterobacterales (Morganella spp., Proteus spp., Providencia spp., and Serratia spp.).
The discovery of new antibacterial drugs with activity against MDR bacteria is very challenging due to difficulties in designing products with suitable physicochemical properties (leading to desirable pharmacokinetics/pharmacodynamics properties) and acceptable toxicity profiles. Another major challenge is the lack of a suitable economic model that can provide long-term support for biotech and small companies developing new antibacterial agents (14–17). Factors underlying the lack of support include (i) the fact that antibacterial treatments are available for most bacterial infections, with most available as inexpensive generics, (ii) the typical short treatment duration of acute bacterial infections (18), (iii) the time and cost associated with traditional research and development (R&D) models, (iv) stewardship measures that—aiming at preserving new antibiotics efficacy—appropriately encourage prescribers to reserve new antibiotics and place them in the bottom of clinical guidelines as last-resort treatments, and (v) a lack of funding for phase 2 and 3 trials (19). All these elements have led to a market environment that is only marginally, if at all, profitable for most antibacterial drug developers. For example, the highest revenue for a patent protected antimicrobial in the United States in 2018 was US$138 million for the cephalosporin ceftaroline (17). The top 10 antimicrobials by sales in the United States in 2018, which included nine antibacterial drugs and the antifungal isavuconazole, had a total revenue of US$644 million. This drops down even further for the antibacterial drugs ranked 6 to 10 in sales (total sales revenues US$136 million, average $27.2 million). This is in stark contrast to the top-selling 2018 drug, adalimumab (therapeutic area: rheumatology), which had a total U.S. revenue of US$13.680 billion; even the revenue from the 10th highest selling drug in 2018, the anticoagulant apixaban, had US$3.76 billion revenue. This significant discrepancy in revenue helps to explain why most of the large pharmaceutical companies have either stopped or reduced their antibacterial R&D programs (19).
The WHO has published an economic model that demonstrates these financial challenges (20). To address this issue, several “push” and “pull” development incentives are being proposed and implemented in several countries (21–25). Push-funding policies aim to reduce early development costs of developers by providing funding (e.g., grant support, contract funding, tax incentives, and private/public partnerships), while pull-funding policies aim to optimize the late stage of drug development and create viable market demand for sponsors (e.g., market entry rewards, extended exclusivity period, tradable market voucher, and higher reimbursement) (26). For example, the United Kingdom’s antibiotic subscription pilot is the first ever fully delinked antibiotic pull incentive (27, 28). In the United States, the PASTEUR Act is a bipartisan bill that, if passed into law, would similarly create a delinked reward model for novel and clinically needed new antimicrobials (29, 30).
In the last few years, there has been an increase in so-called “nontraditional” approaches to antibacterial therapy, developing drugs that have different modes of action compared to the “traditional” direct-acting antibacterial agents (31, 32). These nontraditional antibacterial agents can prevent or treat bacterial infections through several modes of action, including directly or indirectly inhibiting bacterial growth, inhibiting virulence, ameliorating resistance, restoring the gut microbiome, or boosting the immune system to clear infections (Table 1). However, most of these candidates are being clinically evaluated (33) as adjuvant therapies in combination with “standard of care” antibiotics. To date, there have been only three nontraditional antibacterial agents approved, all of which are monoclonal antibodies (MAb). Bezlotoxumab (approved by the FDA in 2016) binds and neutralizes Clostridioides difficile toxin B and was approved after the completion of two phase 3 clinical trials (NCT01241552 and NCT01513239) (34). Raxibacumab was authorized for the treatment of inhalational anthrax in adults and children (approved 2012 by the FDA) (35). Obiltoxaximab (US FDA, 2016; EMA, 2020) (36), like raxibacumab, has been approved to control the symptoms of inhaled anthrax toxins; while the safety profiles of raxibacumab and obiltoxaximab have been investigated in healthy volunteers, fortunately they have not yet been used clinically (37).
TABLE 1TABLE 1 The five classification categories of nontraditional antibacterial agents
Nontraditional classification
Definition
Antibodies
A protein component of the immune system (or synthetic equivalent) that circulates in the blood and recognizes foreign substances like bacteria and viruses
Bacteriophages and phage-derived enzymes
Substances that directly cause pathogen lysis that are phage-derived recombinant enzymes or phages (including those engineered as nano-delivery vehicles)
Microbiome-modulating agents
Approaches that seek to modify the microbiome to eliminate or prevent carriage of resistant or pathogenic bacteria manipulating the metabolism of microbiota
Immunomodulating agents
Compounds that augment, stimulate, or suppress host immune responses that modify the course of infection
Miscellaneous agents
Group of strategies that seek to (i) inhibit the production or the activity of virulence factors such as toxins, (ii) impede bacterial adhesion to host cells and biofilm formation, (iii) interrupt or inhibit bacterial communication, and (iv) inhibit resistance mechanisms
In this review, we discuss traditional and nontraditional antibacterial agents that were being evaluated in clinical trials on 30 June 2021 for the treatment of infections caused by the WHO priority pathogens Mycobacterium tuberculosis (38) and nontuberculosis mycobacteria (NTM) (39) and C. difficile, which is not a WHO priority pathogen but is considered by the CDC to be an urgent threat (11). A brief overview of the drug development process and drug regulatory agencies are provided in the supplemental information. Data for this review were based on the WHO’s antibacterial agents in clinical development reports published in 2021 (10), 2018 (8), 2019 (9), and 2017 (7), as well as WHO’s preclinical pipeline analyses (10, 40). First, we examined antibacterial drugs that had been approved anywhere in the world between 1 July 2017 and 30 June 2021 (Table 2, Fig. 2). Next, we analyzed the traditional and nontraditional antibacterial agents being evaluated in phase 1 to 3 clinical trials or those having a new drug application (NDA)/market authorization application (MAA) submitted to a regulatory body with a cutoff date of 30 June 2021 that had not previously been granted market authorization for human use anywhere in the world (Tables 3 to 8). The traditional and nontraditional antibacterial drug candidates were then analyzed by development phase (Fig. 3), target organism type (Fig. 4), and new pharmacophore types (Fig. 5).
TABLE 2TABLE 2 Antibacterial drugs that gained market authorization between July 2017 and June 2021a
Abbreviations: ABSSSI, acute bacterial skin and skin structure infections; AwaRe, Access Watch Reserve; CAP, community-acquired pneumonia; CC, new chemical class; cIAI, complicated interabdominal infection; CRAB, carbapenem-resistant Acinetobacter baumannii; CRE, carbapenem-resistant Enterobacterales; CRPA, carbapenem-resistant P. aeruginosa; CDSCO, Central Drugs Standard Control Organization of the Government of India; cSSTI, complicated skin and soft tissue infections; cUTI, complicated urinary tract infection; EMA, European Medicines Agency; EML, essential medicines list; FDA, Food and Drug Administration (USA); HAP, hospital-acquired pneumonia; i.v., intravenous; KPC, K. pneumoniae carbapenemase; MBL, metallo-β-lactamase; OPP, other priority pathogens; MoA, new mode of action; NCR, no cross-resistance to other antibiotic classes; NMPA, China National Medical Products Administration; PDMA, Pharmaceuticals and Medical Devices Agency (Japan); T, new target; VAP, ventilator-acquired pneumonia; XDR, extensively drug-resistant.
b
Pathogen activity: ●, active; ?, possibly active; ○, not or insufficiently active; NA, activity not assessed, as the antibiotic is focused and developed for only either Gram-positive cocci or Gram-negative rods. Agents not active against critical-priority pathogens were assessed for activity against other priority pathogens (OPP), which includes the high and medium WHO priority pathogens.
Pathogen activity: ●, active; ?, possibly active; ○, not or insufficiently active; NA, activity not assessed, as the antibiotic is focused and developed for only either Gram-positive cocci or Gram-negative rods. Agents not active against critical-priority pathogens were assessed for activity against OPP, which includes the high and medium WHO priority pathogens.
b
Innovation assessment: ✓, criterion fulfilled; ?, inconclusive data; —, criterion not fulfilled. CC, chemical class; MOA, new mode of action; NCR, no cross-resistance; T, new target.
c
Solithromycin NDA for otorhinolaryngological infections submitted in Japan in April 2019.
d
OPP target pathogens: solithromycin, S. pneumoniae; nafithromycin, S. aureus and S. pneumoniae; gepotidacin, N. gonorrhoeae and E. coli; zoliflodacin, N. gonorrhoeae.
e
Sulopenem etzadroxil NDA submitted in USA for uncomplicated UTI (uUTI) in November 2020.
f
Active against ESBL-producing cephalosporin-resistant but not carbapenem-resistant Enterobacterales.
g
Active against ESBL-producing cephalosporin-resistant and some KPC-producing CRE.
h
Gepotidacin is being tested in two distinct phase 3 programs: gonorrhea (NCR ✓) and uUTI (NCR ?).
TABLE 4TABLE 4 Traditional antibacterial agents and combinations in phase 1 and 2 clinical development against WHO priority pathogens
Pathogen activity: ●, active; ?, possibly active; ○, not or insufficiently active; NA, activity not assessed, as the antibiotic is focused and developed for only either Gram-positive cocci or Gram-negative rods. Agents not active against critical-priority pathogens were assessed for activity against OPP, which includes the high and medium WHO priority pathogens.
b
Innovation assessment: ✓, criterion fulfilled; ?, inconclusive data; —, criterion not fulfilled. CC, chemical class; MOA, new mode of action; NCR, no cross-resistance; T, new target.
c
OPP target pathogens: TNP-2198, H. pylori; afabicin, TNP-2092, KBP-7072, TXA-109, and PLG0206, S. aureus.
d
A phase 3 trial for zidebactam + cefepime was registered in July 2021 for cUTI or acute pyelonephritis (NCT04979806).
e
The DBO-BLIs zidebactam, nacubactam, and ETX0282 also have some antibacterial activity and have been classified as β-lactam enhancers (BLE) (97–99).
f
Previously used as an antibacterial treatment in animals.
g
Activity against AmpC-producing and KPC-producing CRPA. Active against KPC- but not MBL-producing Enterobacteriaceae.
h
The original developer, Arixa Pharmaceuticals, was acquired by Pfizer in October 2020.
i
PLG0206 was evaluated in phase 1 using i.v. administration, but development is currently focused on use as an irrigation solution for prosthetic joint infections.
j
Peptilogics recently reported that coagulase-negative staphylococci, E. coli, Enterobacter cloacae, Citrobacter freundii, P. aeruginosa, and A. baumannii (100).
k
QPX7728 is being evaluated with two separate β-lactams, QPX-2014 and QPX2015.
TABLE 5TABLE 5 Traditional antibacterial agents in clinical development for the treatment of TB and nontuberculous mycobacteria (NTM)
Institute of Materia Medica/TB Alliance/Chinese Academy of Medical Sciences/Peking Union Medical College
—
—
—
—
OPC-167832
1/2
3,4-Dihydrocarbostyril (DprE1 inhibitor)
Oral
Otsuka
✓
✓
✓
✓
BTZ-043
1/2
Benzothiazinone (DprE1 inhibitor)
Oral
University of Munich/Hans Knöll Institute, Jena/German Center for Infection Research
✓
✓
✓
✓
Macozinone (PBTZ-169)
1
Benzothiazinone (DprE1 inhibitor)
Oral
Innovative Medicines for Tuberculosis Foundation/Nearmedic Plus
✓
✓
✓
✓
TBI-223
1
Oxazolidinone
Oral
TB Alliance/Institute of Materia Medica
—
—
—
—
TBAJ-876
1
Diarylquinoline
Oral
TB Alliance
—
—
—
—
TBAJ-587
1
Diarylquinoline
Oral
TB Alliance
—
—
—
—
GSK 2556286 (GSK-286)
1
Undisclosed
Oral
GSK/TB Drug Accelerator/Bill & Melinda Gates Foundation
?
✓
✓
?
a
Innovation assessment: ✓, criterion fulfilled; ?, inconclusive data; —, criterion not fulfilled. CC, chemical class; MOA, new mode of action; NCR, no cross-resistance; T, new target.
b
This phase 2a trial (NCT04553406) was on FDA clinical hold, but this was lifted in January 2022.
c
This is not considered to be a new mode of action, as the GyrB/ParE inhibitor novobiocin was once marketed but is no longer in clinical use.
d
The lead drug clofazimine is approved to treat leprosy and has been used off-label for TB treatment.
TABLE 6TABLE 6 Traditional antibacterial agents in clinical development for the treatment of C. difficile infections
Innovation assessment: ✓, criterion fulfilled; ?, inconclusive data; —, criterion not fulfilled. CC, chemical class; MOA, new mode of action; NCR, no cross-resistance; T, new target. These agents are being developed for C. difficile infections, and their activity against WHO priority pathogens was not assessed.
TABLE 7
TABLE 7 Nontraditional antibacterial agents in phase 3 clinical development
TABLE 8
TABLE 8 Nontraditional antibacterial agents in phase 1 and 2 clinical development for WHO priority pathogens, mycobacteria, and C. difficile
FIG 2
FIG 2 Structures of antibacterial drugs approved worldwide since 2017 and their approved indications and targeted priority pathogens with country and year of first approval.
FIG 3
FIG 3 Number of traditional and nontraditional antibacterials by (A) development phase and (B) development against WHO priority pathogens, TB and NTM, C. difficile, and G+ve/G−ve.
FIG 4
FIG 4 Traditional and nontraditional antibacterials categorized by development phase and activity against WHO critical pathogens, WHO high- and medium-priority pathogens TB and NTM, C. difficile, and nontraditional nonspecific G+ve/G−ve activity.
FIG 5
FIG 5 Antibacterials with new pharmacophores not previously found in human antibacterial drugs by target class, target, antibacterial name (current development phase), and antibacterial class. Abbreviations: TB, tuberculosis; Sa, S. aureus; Cd, C. difficile, Ec, E. coli; Ng, N. gonorrhoeae; NTM, nontuberculosis mycobacteria; G−, Gram-negative bacteria.
METHODOLOGY
Scope and inclusion/exclusion criteria.
This review details the antibacterial drugs that have been approved for the treatment of WHO priority pathogens anywhere in the world between 1 July 2017 and 30 June 2021. Also included in this analysis are traditional and nontraditional antibacterial agents administered by intravenous (i.v.), intramuscular (i.m.), oral, inhalation, enema, and colonoscopy administration routes that are currently being evaluated in phase 1 to 3 clinical trials or have NDA/MAA applications under consideration that have not previously been granted market authorization for human use anywhere in the world. Antibacterial agents were restricted to those being developed or that have the potential to treat bacterial infections caused by the WHO priority pathogens (Fig. 1), mycobacteria, or C. difficile and are included only if they are new chemical entities (NCEs) (traditional or nontraditional) or new biological entities (NBEs) (nontraditional) not already accorded market authorization for human use anywhere in the world. Antibacterial agents whose development programs have been terminated, are no longer listed on a company’s development pipeline, or have not had any development update for three or more years have been excluded in this analysis and are listed in the supplemental information (Table S1). This review does not include new formulations of approved antibacterial drugs, vaccines, topical decolonizing agents, nonspecific inorganic substances, and antibacterial agents developed only for topical applications such as creams, ointments, or eye drops. Fixed-dose combinations of potentiators and antibacterial agents are included if they contain an NCE or an NBE.
Search strategy.
Data from the 2020 WHO antibacterial pipeline report (10) were used as a starting point for this updated analysis. Recent antibacterial pipeline reviews (41–43), previous WHO reports (7, 9), and The Pew Charitable Trusts’ antibiotic development pipeline reviews (6) were also consulted. Additional references were identified using searches of antibacterial compound names and their synonyms from PubMed (https://pubmed.ncbi.nlm.nih.gov/), Google Scholar (https://scholar.google.com.au/), and conference abstracts and posters. The U.S. NIH (https://clinicaltrials.gov/) and WHO International Clinical Trials Registry Platform (ICTRP) clinical trial databases (https://www.who.int/clinical-trials-registry-platform), the commercial database AdisInsight (https://adisinsight.springer.com/), and the Access to Medicine Foundation’s Antimicrobial Resistance Benchmark 2020 Antibacterials data (44) were searched. The websites of pharmaceutical companies active in antibacterial R&D and antibacterial development funders and foundations were also searched.
ANALYSIS AND DISCUSSION
Antibacterial drugs approved since 2017.
Twelve new antibacterial drugs (Table 2, Fig. 2) have been approved since the WHO’s first analysis of the clinical antibacterial pipeline in 2017 (7). The most recent approval was in China in June 2021 for the oxazolidinone contezolid as a treatment for complicated skin and soft tissue infections (cSSTI) caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) (45).
Only 1 of the 12 approved antibacterial drugs, the boronate β-lactamase inhibitor (BLI) vaborbactam, which is used in combination with meropenem, has a new antibacterial drug-related pharmacophore. Also, the cephalosporin cefiderocol (46, 47) is noteworthy, as it is the first marketed β-lactam (cephalosporin) that has an iron-chelating siderophore incorporated into the structure, which facilitates Gram-negative bacteria outer membrane entry. The other 10 are members of previously approved antibacterial classes: three fluoroquinolones (delafloxacin, lascufloxacin, and levonadifloxacin), two tetracyclines (eravacycline and omadacycline), one aminoglycoside (plazomicin), one pleuromutilin (lefamulin), one nitroimidazole (pretomanid), one diazabicyclooctane (DBO) BLI (relebactam), and one oxazolidinone (contezolid). Of the 12 new antibacterial drugs, 6 target carbapenem-resistant Enterobacterales (CRE), 5 target other WHO priority pathogens (high and medium priority), and 1 was approved to treat MDR/extensively drug-resistant tuberculosis (XDR-TB) in combination with two other drugs, bedaquiline and linezolid. However, it is noted that lefamulin (48) is the first systemically administered pleuromutilin approved for human use (retapamulin was approved for human topical use and valnemulin and tiamulin for veterinary medicine).
Traditional antibacterial agents in phase 3 clinical trials or with NDAs submitted against WHO priority pathogens.
We identified two compounds, solithromycin and sulopenem, that have had NDAs submitted to the Japanese PMDA and U.S. FDA, respectively. Although after this review’s cutoff date, in late July 2021, the FDA indicated that sulopenem will require further clinical trials to be undertaken (49). Three BLI/β-lactam combinations (durlobactam/sulbactam, taniborbactam/cefepime, and enmetazobactam/cefepime) and two compounds being developed to treat Neisseria gonorrhoeae infections (zoliflodacin and gepotidacin) are currently in phase 3 trials (Table 3). Gepotidacin is also being evaluated in a phase 3 trial to treat urinary tract infections (UTIs). Updating the 2020 WHO report (10), nafithromycin is now being evaluated in a phase 3 trial (CTRI/2019/11/021964) for treatment of community-associated pneumonia (CAP) in India, and the phase 2/3 trial (NCT04505683) of benapenem in China has been completed for complicated urinary tract infections (cUTI), including acute pyelonephritis.
Other phase 3 agents of interest: ATM-AVI and tebipenem pivoxil.
There are two antibacterial agents in phase 3 development that did not meet this review’s inclusion criteria (see “Scope and inclusion/exclusion criteria”) that are noteworthy. The first is the aztreonam (monobactam-type β-lactam) and avibactam (BLI) combination (ATM-AVI), which was not included, as both components are previously approved drugs. ATM-AVI is being studied by Pfizer in a phase 3 trial (NCT03580044) to treat serious infection due to metallo-β-lactamase (MBL)-producing Gram-negative bacteria (50, 51) with support from the Biomedical Advanced Research and Development Authority (BARDA), Innovative Medicines Initiative (IMI), and AbbVie, through their 2020 acquisition of Allergan. The second is the carbapenem prodrug tebipenem pivoxil (52, 53), which was first approved for pediatric use in Japan in 2009 but has not been used elsewhere. Spero Therapeutics recently completed a phase 3 trial (NCT03788967) for tebipenem pivoxil (SPR994) as an oral treatment for Gram-negative cUTI and acute pyelonephritis infections. Clinically, the oral administration of tebipenem pivoxil could provide an alternative to i.v. administered carbapenems.
Traditional antibacterial agents in phase 1 and 2 clinical trials being developed against WHO priority pathogens.
We identified 2 compounds in phase 2, 1 in phase 1/2a, and 14 in phase 1 development (Table 4). Since the 1 September 2020 cutoff date of the 2020 WHO pipeline report (10), two new polymyxin derivatives, MRX-8 (54, 55) (NCT04649541) and QPX-9003 (56, 57) (NCT04808414), started phase 1 trials in November 2020 and June 2021, respectively, as potential treatments for MDR Gram-negative pathogens. XNW-4107 is a BLI being that is developed in combination with imipenem and cilastatin that started a phase 1 in June 2021 (NCT04801043). The developer, Sinovent, has indicated that the XNW-4107 combination will be developed to treat patients with CRE, CRAB, and drug-resistant Pseudomonas aeruginosa (58). The structures of MRX-8, QPX-9003, and XNW-4107 have not been publicly disclosed. Finally, the rifamycin-quinolizinone hybrid TNP-2198 has moved into a Helicobacter pylori phase 1/2a trial (59).
Traditional antibacterial agents against M. tuberculosis and nontuberculosis mycobacteria.
There are currently 14 traditional antibacterial agents being evaluated in clinical trials against mycobacteria: 7 in phase 2, 2 in phase 1/2a, and 6 in phase 1. There also are two nontraditional antibacterial agents, CYT107 (NTM) and BVL-GSK098 (M. tuberculosis), under clinical investigation. In addition to these trials, there are also approximately 20 ongoing phase 3 trials (60) investigating new combinations and dosing regimens of previously approved TB drugs, which were not included in this review due to the selection criteria. Thirteen of the traditional antibacterial candidates target M. tuberculosis, and only one, SPR720, is in development for lung infections caused by the NTMs, Mycobacterium avium complex, and Mycobacterium abscessus (Table 5). Eight of the 14 traditional antibacterial agents belong to new classes, and 9 have new antibacterial pharmacophores (see below).
Since the 2020 WHO report (10) was released, two new compounds, TBAJ-587 (NCT04890535) and GSK 2556286 (NCT04472897), have entered phase 1 trials. TBAJ-587 is a bedaquiline analog with enhanced in vitro potency and a projected reduced cardiovascular liability (61, 62). GSK 2556286 (GSK-286) acts directly on M. tuberculosis, and its mode of action has not been disclosed but has been proposed to involve cholesterol catabolism (63, 64). In addition, TBI-166 (pyrifazimine) has moved to phase 2 (NCT04670120) and BTZ-043 has started a new phase 1/2 trial (NCT04044001).
Traditional antibacterial agents being developed against C. difficile.
There are currently five traditional antibacterial agents (Table 6), one in phase 3 (ridinilazole) and four in phase 2 (DNV-3837, MGB-BP-3, ibezapolstat, and CRS3123), being developed to treat C. difficile. Antibacterial drugs used to treat C. difficile infections (CDI) are usually administered orally and absorbed poorly, as the infection is localized in the colon. This has encouraged the development of four new antibacterial classes and modes of action (ridinilazole, MGB-BP-3, ibezapolstat, and CRS3123; Fig. 5), while DNV-3837 is differentiated through its administration via i.v. infusion and is being targeted for use in patients who are unable to receive oral administration. Since the 2020 WHO report (10) was published, CRS3123 has started a phase 2 trial (NCT04781387).
Nontraditional antibacterial agents in phase 3 clinical trials.
We found two nontraditional antibacterial agents in the NDA/MAA phase and four in phase 3 development (Table 7). Three are being developed to treat S. aureus infections: tosatoxumab is an MAb (65), exebacase is a phage-derived recombinant protein (66), and reltecimod is an immune modulator (CD28 T-lymphocyte receptor mimetic) (67). Three are being developed to treat C. difficile infections: SER-109 consists of purified Firmicutes spores (68), RBX2660 is a liquid suspension of screened donor fecal microbiota (69, 70), and BB128 is a lyophilized donor fecal microbiota product. SER-109 has already successfully completed one phase 3 trial (NCT03183128) (71).
Since the publication of the 2020 WHO pipeline report (10), a phase 3 trial (NCT03931941) has started to evaluate RBX2660 as a treatment of C. difficile, while BiomeBank has submitted an MAA to the Australian Therapeutic Goods Association (TGA) for BB128 as a potential treatment of recurrent C. difficile and ulcerative colitis (72). BiomeBank already has provisional approval for its use in Australia as a class 2 biologic. In addition, Atox Bio applied for an NDA in December 2020 for reltecimod as a potential supportive treatment for necrotizing soft tissue infections (NSTI) (73).
Nontraditional antibacterial agents in phases 1 and 2.
There are 10 nontraditional antibacterial agents in phase 2, 6 in phase 1/2a, 8 in phase 1 clinical trials, and 1 not disclosed by clinical phase (Table 8). Combined with the 4 in phase 3 and 2 at the NDA/MAA stage, there are 31 nontraditional agents overall in clinical development.
There are seven nontraditional antibacterial agents not detailed in the 2020 WHO report (10): CYT107, TRL1068, BVL-GSK098, and four bacteriophage products. CYT107 is a glycosylated recombinant human interleukin (IL-7) that is being tested in a phase 2 trial (NCT04154826) to evaluate its immunotherapeutic response in patients with NTM lung disease. CYT107 has been evaluated in other clinical trials, including a phase 2b trial (NCT02640807) that reported a 3- to 4-fold increase in the absolute lymphocyte count and in circulating CD4+ and CD8+ T cells with CYT107 in sepsis patients (predominantly secondary to pneumonia and abdominal infections) (74). TRL1068 is an MAb that binds to a DNABII epitope conserved across both Gram-positive and Gram-negative bacteria, which leads to bacterial biofilm disintegration, and is being evaluated in a phase 1 trial (NCT04763759) for prosthetic joint infections (75, 76). BVL-GSK098 recently entered phase 1 (NCT04654143) and works through inactivation of a TetR-like repressor, EthR2, thereby enhancing ethionamide activation (77). BVL-GSK098 is intended to be used clinically in combination with ethionamide or prothionamide (78). Adaptive Phage Therapeutics are undertaking a phase 1/2 trial (APT.UTI.001, NCT04287478) to evaluate its PhageBank therapy in patients with UTI. There are also three other phage products, AP-PA02 (NCT04596319), YPT-01 (NCT04684641), and BX004-A (NCT05010577), being evaluated in phase 1/2 trials with cystic fibrosis patients with P. aeruginosa infections. For the phage-derived endolysin tonabacase (N-Rephasin SAL200), a new phase 1 trial has been initiated and it has been renamed LSVT-1701 (79, 80).
Antibacterial candidates in clinical trials with new pharmacophores.
Although there have been significant efforts to identify antibacterial agents with new modes of action, most marketed antibacterial drugs still fall into four overarching mechanistic classes: inhibition of cell envelope biogenesis, DNA homeostasis, RNA homeostasis, and protein synthesis (81). A pharmacophore describes the part of a molecular structure that is responsible for a particular biological or pharmacological activity and is a key component, along with antibacterial activity differences, to decide whether an antibacterial agent belongs to a new class or subclass of antibiotics. It is possible to have antibacterial drugs and clinical candidates with the same mode of action but with different pharmacophores, which can have significant effects on biological activity, metabolism, and pharmacokinetics. For example, there are four compounds in clinical development that inhibit the M. tuberculosis cell wall synthesis enzyme decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1) that have three distinct pharmacophores: benzothiazinone (BTZ), azaindole, and 3,4-dicarbostyril (Fig. 5, Fig. S2).
There are 19 antibacterial agents with 18 new pharmacophores (macozinone and BTZ-043 are both BTZs) with seven inhibiting cell envelope synthesis, two acting at the protein synthesis level and five affecting DNA synthesis (Fig. 5, structures in supplemental information Fig. S1 to S3). Telacebec inhibits the mycobacterial respiratory system (82, 83), which was first targeted by bedaquiline, via inhibition of the respiratory complex bc1 (84). Half of the 18 new pharmacophores target mycobacteria, and 4 target C. difficile.
Four of 19 antibacterial agents have new overarching modes of actions not previously exploited by marketed antibacterial drugs. Two target virulence: fluorothyazinon (phase 2, NCT03638830) and GSK 3882347 (phase 1, NCT04488770). Ftortiazinon inhibits the Gram-negative type III secretion system (85) and is being evaluated in a trial in combination with cefepime, and GSK 3882347 functions as an antagonist of the Gram-negative type 1 pilus adhesin (FimH) (86). BVL-GSK098 (phase 1, NCT04654143) (77) directly inhibits ethionamide-acquired resistance, while GSK 2556286 (phase 1 trial, NCT04472897) is proposed to involve M. tuberculosis cholesterol catabolism (63, 64).
Antibacterial agents that have halted or stopped clinical development.
Drug development is inherently risky, and it is not uncommon for clinical development programs to be terminated or halted. The most common reasons for stopping development include lack of clinical efficacy, off-target toxicity, and commercial considerations (87). While antibacterial agents can drop out of the pipeline due to efficacy and resistance issues, it is more common to be due to toxicity and commercial concerns (16, 41, 88). A list of antibacterial compounds and nontraditional moieties whose development has been terminated or halted are listed in the supplemental information (Table S1).
Current pipeline analysis.
There are 76 antibacterial agents in clinical development using this review’s inclusion criteria, which are divided into 45 traditional and 31 nontraditional antibacterial agents (Fig. 3). Seventy-nine percent (60/76) of the antibacterial drug candidates are in phase 1 (28) and phase 2 (32), but as expected, this number falls away for late-stage development agents (12 in phase 3 and 4 NDA/MAA). This relatively low number of candidates in the later stages of drug development generally reflects the usual level of attrition in the pipeline, which is caused by several factors, including lack of efficacy, unacceptable toxicity, and market factors (87, 88). The number of early development candidates is encouraging and reinforces research efforts and recent funding that have been invested into discovery and preclinical development. For example, CARB-X has funded 92 early-stage R&D drug and diagnostics projects since its inception 5 years ago (89), while GARDP (90) has signed license and codevelopment agreements with the companies that are developing two innovative products, zoliflodacin (target: gonorrhea) and cefepime-taniborbactam (target: cUTI). In addition, the AMR Action Fund plans to help support late-stage development of 3 to 4 new antibacterial candidates by 2030, which could help increase the number of new approvals (17, 91).
The fact that there are 76 antibacterial candidates currently being evaluated in clinical trials is promising, but it needs to be asked whether these agents will address future clinical needs. To evaluate this, pipeline agents are analyzed here for activity versus each of the major pathogen categories.
The potential impact of nontraditional antibacterial agents.
Nontraditional antibacterial agents have the potential to improve the clinical outcomes using alternative mechanisms to traditional antibacterial drugs. Although the number of nontraditional antibacterial agents entering clinical trials continues to increase, only one has been approved that successfully completed phase 3 trials: bezlotoxumab (34), which is a C. difficile toxin B-binding MAb. One of the main issues facing nontraditional agent developers has been clinical trial design (32, 33), except for adjunctive agents that are being developed in combination with standard of care drugs.
WHO priority pathogens.
A total of 26/76 (34%) and 16/76 (21%) antibacterial agents are being developed to target the critical- and high/medium-priority WHO priority pathogens, respectively. This represents 55% of the total pipeline, and it is encouraging to observe product development being directed against the key pathogens. For the traditional antibacterial agents, only two compounds, gepotidacin and zoliflodacin, which are both new chemical classes, target priority pathogens (E. coli critical and N. gonorrhoeae high). β-Lactams, with and without BLI inhibitors, account for a majority of the other antibacterial agents in development against critical-priority pathogens.
Although there are six nontraditional agents in late-stage clinical development (Table 7), only three of these target the high-priority pathogen S. aureus; although there is need for innovative drugs to treat S. aureus infection, there are already several treatment options currently available to clinicians. There are nine agents in phase 1 and 2 trials being developed against critical WHO priority pathogens: four bacteriophages, one CRISP-Cas3 enhanced phage (LBP-EC01), two antivirulence (ftortiazinon and GSK-3882347), MAb-like recombinant protein (LMN-01), and an alginate oligosaccharide fragment (OligoG). Antibacterial developers and funders need to continue to develop pathways that allow the most promising of these antibacterial agents to rapidly progress through to late-stage clinical trials and beyond.
TB and NTM.
There are 16/76 (21%) candidates being developed to treat mycobacterial infections (14 TB and 2 NTM), which includes nine small molecules with new pharmacophores (Fig. 5, Fig. S2). Despite the considerable challenges associated with TB drug development (92), progress has been accelerated from sustained funding and guidance by organizations such as the TB Alliance and the Gates Foundation (93). The next challenge will be to move the most promising candidates through the pipeline and select and clinically evaluate the optimal drug regimens.
C. difficile.
There are also 15/76 (20%) agents in development to treat C. difficile infections, with 10 of these being nontraditional and 5 traditional antibacterial agents. Four of the five traditional antibacterial agents would be new classes if approved (Fig. S3). Of the 10 nontraditional agents, 7 are biotherapeutic products, 1 is an MAb (IM-01), and 2 are antibiotic inactivators (ribaxamase and DAV132). There are already several C. difficile drugs on the market, and it will be interesting to monitor the impact of any new approvals of small molecular antibacterial drugs and nontraditional biotherapeutic products and the effect that these will have on clinical practice and the market.
Broad-spectrum agents active against Gram-negative and Gram-positive bacteria.
Four of the 76 (5%) are nontraditional antibacterial agents with broad-spectrum antibacterial effects, which was achieved through a variety of mechanisms: a recombinant gelsolin protein Rhu-pGSN boosts the immune system, the MAb TRL1068 disrupts biofilms, the synthetic glycan KB109 modulates the gut microbiome composition and metabolic output, and the liposomal agent CAL02 captures and neutralizes bacterial toxins.
CONCLUSION
Since its release in 2017, the WHO’s priority pathogen list (Fig. 1) has become a focus for antibacterial R&D and stewardship initiatives. The WHO also started analyzing the antibacterial pipeline in 2017, and since then, only vaborbactam (boronate BLI) of the 12 approved antibacterial drugs (Table 2, Fig. 2) is not a derivative of a previously approved class. Importantly, vaborbactam is used in combination with meropenem to treat Enterobacterales infections, which are critical-priority pathogens. The cephalosporin derivative cefiderocol is also noteworthy, as it displays activity against all three critical-priority pathogens, CRAB, CRPA, and CRE, regardless of the carbapenemase mechanism, and is the first marketed antibacterial drug that incorporates an iron-chelating siderophore.
Renewed focus to identify new antibacterial drugs against MDR bacteria, combined with several recent financing mechanisms, has helped to increase the number of traditional and nontraditional antibacterial agents moving through the preclinical (94) and clinical development pipelines (41, 90, 95, 96). Despite a total of 76 antibacterial candidates (45 traditional and 31 nontraditional) being evaluated in clinical trials on 30 June 2021, our analysis indicated that there were still relatively few clinically differentiated antibacterial agents in late-stage clinical development, especially against critical-priority pathogens. In addition, we identified 18 new antibacterial pharmacophores, but only 2 had activity against priority pathogens with most targeted mycobacteria and C. difficile. It is important to try to keep on identifying and developing antibacterial agents with new modes of action to try to slow down antibacterial drug resistance. Furthermore, we believe that future antibacterial R&D should focus on the development of innovative and clinically differentiated candidates that have clear and feasible progression pathways right through development and onto the market. There needs to be a development focus on quality over quantity, especially with limited development resources, ever-increasing numbers of MDR infections, and potential return-on-investment issues associated with development, manufacture, regulatory compliance, and distribution costs.
Formidable challenges that we believe remain that still need further attention are as follows:
•
Difficulty in discovering novel antibacterial leads with selective activity against MDR bacteria that are nontoxic and have suitable pharmacokinetic and pharmacodynamic properties, especially with new modes of action
•
Current unmet medical need for new drugs to treat drug-resistant A. baumannii (e.g. CRAB) and P. aeruginosa (e.g. CRPA) infections
•
Development of antibacterial agents for use in neonates and children
•
Development of efficient progression pathways for nontraditional antibacterial candidates through the manufacturing, clinical trials, and approval processes
•
Difficulties in optimal trial design and selection of relevant intended target population
•
Sustained advocacy for strong and sustainable political support and governmental commitments to promote R&D and help developers overcome economic, scientific, and technical barriers
•
Implementation of business models that improve the current market dynamics with a focus on developing and securing approval of truly innovative and clinically differentiated antibacterial treatments
ACKNOWLEDGMENTS
Funding for the WHO report was kindly provided by the Governments of Austria and Germany (Ministry of Education and Science). We acknowledge François Franceschi (GARDP, Switzerland), Jennie Hood (Global AMR R&D Hub, Germany), and Mike Sharland (Chair of the WHO Antibiotic Working Group of the EML/EMLc, and St George’s University London, UK), who were observers at the November 2020 WHO antibacterial pipeline meeting, as well as Haileyesus Getahun (WHO, Antimicrobial Resistance Division), for supporting this work.
This contribution has been prepared strictly in a personal capacity and reflects the view of the authors. The views expressed must not be attributed to the WHO, its Secretariat, or its Member States.
Excess belly fat can be more dangerous than we ever thought it was. As we grow older or more sedentary, the risk of us adding this ‘killer fat’ to our waistline goes up. Studies suggest that excess belly fat or visceral fat is very harmful considering it surrounds our internal organs and puts us at great risk of developing numerous health problems – diabetes, heart disease, liver problem among others.
The stubborn fat accumulates around the abdominal area and requires quite an effort to shed it. The trick is to slow and steay and make some permanent lifestyle changes. Developing some good habits like exercising regularly, avoiding refined, process and sugar foods, and being active in general can lead to an effective fat loss around your belly area.
There are some foods that could help you achieve your goal of losing belly fat. Protein, citrus fruits, green vegetables are some of the foods that can help you in your mission to stay disease-free for as long as you can. Dietician Garima Goyal suggests you to add these five foods to your daily diet for belly fat loss.
1. Eggs
Contrary to the popular belief, 1 whole egg can actually help you lose excess fat. Eggs are high in protein, and even contain the essential amino acid leucine which catalyses the fat burning mechanism. The presence of choline in egg yolk is known to turn off the fat gain genes.
Yoghurt contains the beneficial bacterial strain lactobacillus which reduces the fat deposition.
3. Citrus Fruits.
Citrus fruits like lime, oranges are loaded with potassium- a mineral important for regulating the water balance in our body and hence can combat bloating and fight inflammation involved in fat storage.
4. Green tea
Green tea contains flavonoids and polyphenol, which helps in controlling the cholesterol level. It is advised to consume at least one cup of green tea everyday to keep the cholesterol level in check.
Green tea is rich in caffeine and a flavonoid called Catechin. Both these compounds help in breakdown of excess fat in the body.
5. Green veggies
Green vegetables: Green leafy and seasonal vegetables are good for your immunity as they are high on fibre and are packed with anti-oxidants. They have many nutrients like vitamin A, vitamin C, folate, vitamin K, magnesium, etc. Vegetables like spinach, kale, and broccoli have anti-cancer and anti-inflammatory properties.
Green Leafy Vegetables like spinach, lettuce and broccoli are not only packed with vitamins and minerals, but also are low in calories and loaded with fibre. The fibre content would help you eat less and feel fuller for longer durations.
Rectal bleeding, or hematochezia, is a frequently encountered problem in the outpatient setting. It can herald a pathology in the proximal lower gastrointestinal tract, but it can also be from diseases specific to the rectal region such as hemorrhoids, fissures, proctitis, and anorectal malignancy. This activity reviews the evaluation and treatment of rectal bleeding and highlights the role of the interprofessional team in the care of patients with this condition.
Objectives:
Identify the etiology of rectal bleeding.
Review the appropriate evaluation of rectal bleeding.
Outline the management options available for rectal bleeding.
Summarize interprofessional team strategies for improving care coordination and communication to advance the care of rectal bleeding and improve outcomes.
Introduction
Rectal bleeding, or hematochezia, is a frequently encountered problem in the outpatient setting. It can herald a pathology in the proximal lower gastrointestinal tract, but it can also be from diseases specific to the rectal region such as hemorrhoids, fissures, proctitis, and anorectal malignancy. Unfortunately, it has been reported that less than half the patients with rectal bleeding will ever seek medical help for their symptoms.[1][2]
Rectal bleeding presents as frank red blood exiting from the anus. The presentation may range from mild to severe, depending on the etiology of the bleeding. Mild cases may appear as red blood streaking the patient’s stool or toilet paper after wiping, and severe cases may present as a large volume, brisk bleed. The following review will discuss rectal bleeding with more focus on hemorrhoids as it is the most common cause of rectal bleeding in the middle-aged and elderly populations.
Gastrointestinal bleeding is divided into upper and lower gastrointestinal tract (GIT) bleeding based on whether the bleeding originates from above or below the ligament of Treitz (suspensory ligament of the duodenum). Rectal bleeding is mainly caused by pathology from the lower GI tract, which includes the small intestine beyond the duodenum, the colon, rectum, or anal canal.
Colon cancer: The proliferating cancer cells form pathological vasculature to supply itself for growth. This pathologic vasculature is extremely friable, which may lead to rectal bleeding, especially as the cancer progresses. Although it is not a major contributor to the overall incidence of rectal bleeding, representing only approximately 3.4% of the cases, it is one of the more serious causes that should be ruled out, especially in older patients.[3]
Inflammatory bowel disease: Chronic inflammation in the digestive tract, such as in ulcerative colitis and Crohn’s disease, may present with rectal bleeding. This is often associated with diarrhea and abdominal pain.
Diverticular diseases: Diverticula are small pouches in the wall of the colon, which usually occur at weak points where the vasa recta penetrate the muscular layer. Over time, the blood vessels in the wall of these pouches become friable, making them susceptible to rupture, which can cause bleeding.
Hemorrhoids: Hemorrhoids are cushions of tissues found in the submucosa of the anal canal. They are found in the left lateral, right anterior, and right posterior positions. They are comprised of submucosal vessels and muscle fibers arising from the internal sphincter and the conjoined longitudinal muscle. It is a weakness in the muscle fibers that make the hemorrhoids symptomatic. The terminal branches of the superior hemorrhoidal artery are the primary blood supply, whereas the superior, middle, and inferior hemorrhoidal veins are responsible for the venous outflow. Hemorrhoids are further classified into internal (above the dentate line), external (below the dentate line), and mixed (both above and below the dentate line). Internal hemorrhoids cause ‘painless bleeding.’[4] Goligher’s classification is the most commonly used classification system and divides the hemorrhoids into 4 grades. Grade 1 hemorrhoids bleed but don’t prolapse. Grade 2 hemorrhoids prolapse through the anus on straining but reduce spontaneously. Grade 3 hemorrhoids protrude and require digital reduction. Grade 4 hemorrhoids are irreducible after prolapse.[5]
Anal fissures: a tear in the epithelial lining of the anal canal, which commonly occurs with constipation and the passage of hard stools (posterior anal fissures) or with childbirth (anterior anal fissures). It is associated with painful defecation with blood-streaked stools.
Upper GIT bleeding:Upper GI bleeding can present with black tarry stools. As the blood passes through the GIT, gastric and duodenal secretions convert hemoglobin into acid hematin giving the stool its dark reddish-brown color. Hematochezia may result from upper GI bleeding if the bleeding is of large enough volume that the gastric and intestinal secretions are not sufficient to convert hemoglobin into acid hematin. Blood also acts as a cathartic, decreasing intestinal transit time and providing less time for the enzyme reaction to take place. If a patient is experiencing hematemesis associated with hematochezia, this would further suggest that the source of the bleed is coming from the upper GI tract, especially if these symptoms are associated with hemodynamic instability or shock. Examples of upper GI bleedings that may cause hematochezia include a Mallory Weiss tear, bleeding esophageal varices, or a perforated gastroduodenal artery. It’s worth mentioning that in patients with insufficient secretion of gastric HCl, as in achlorhydria, an upper GI bleed may present with hematochezia as well. General causes of bleeding: When evaluating an individual for GI bleed, it is also important to consider other underlying factors that may be contributing to the acute presentation. This includes bleeding diatheses such as vitamin K deficiency, hemophilia, thrombocytopenia, or anti-coagulant toxicity.
There is a dearth of population-based studies to suggest the true incidence of rectal bleeding. However, many community-based studies have shown the prevalence of rectal bleeding to be between 13% to 34%.[6][7][8] There has been conflicting data regarding the incidence of rectal bleeding between genders. As per Eslick et al., no significant difference in incidence was found between men and women. Women had higher rates of rectal bleeding in the age groups of 18 to 39, and above 60 years, whereas men had a higher incidence of bleeding in the age group of 40 to 49 years.[6][7]
It has also been noted that only 40% of patients with rectal bleeding seek medical care.[9] The most likely reason for those who did not seek medical consultation was that they thought the rectal bleeding wasn’t serious enough to require medical attention. Moreover, most of these patients hail from the age group of more than 60 years.[1]
Detailed history taking and a thorough physical exam are essential to rule out the different causes of rectal bleeding such as anal fissure, rectal prolapse, fistulas, inflammatory bowel disease, and neoplasia.[10] Direct questions regarding onset, duration, amount, frequency, and passage of clots should be foremost during the consultation. Differentiation between fresh (bright red) and old blood (maroon or tarry) is also an important distinction to make. Associated symptoms of abdominal pain, weight loss, change in bowel habits, and a previous history of any recent pelvic surgery or abdominal-pelvic radiation should be included as well.
A comprehensive review of the patients’ comorbidities and medications is warranted. Special attention should be given to comorbidities that may contribute to bleeding tendencies or those that require the patient to take anticoagulants such as an artificial heart valve or atrial fibrillation. With regards to medications, special attention should be given to NSAIDs, anticoagulants, and antiplatelet agents as possible contributing factors to the rectal bleeding.
Anal pain associated with defecation may suggest anal fissures. A change in bowel habits, as well as significant weight loss in older patients, may hint at a malignancy.
The most common cause of rectal bleeding in the middle-aged and elderly population is hemorrhoids, which are often asymptomatic. They may be described as soft, painless protrusions in the anal canal. In essence, there is a downward displacement of the hemorrhoidal cushions, which cause venous dilatation and, hence, symptoms.[11] Some of the common symptoms include bleeding with or without defecation, swelling, and mild discomfort or irritation. Other symptoms may include mucous discharge, pruritis, difficulties with hygiene, and a sense of incomplete evacuation. Internal hemorrhoids are only painful if they have thrombosed, have prolapsed with edema, and/or are strangulated. External hemorrhoids only cause pain when they become thrombosed.[5]
Physical Exam
The physical exam should begin with an assessment of hemodynamic status via the measurement of vital signs. Attention should be paid to low blood pressure, tachycardia, and/or a high respiratory rate as these may indicate hemodynamic instability and necessitate rapid escalation of care.
A focused exam for lower GI bleeding should include an abdominal exam with assessment for pain, masses, distention, and signs of cirrhosis, which might hint towards rectal varices. Perineum inspection should be carried out with the patient lying in the left lateral decubitus position under a light source to evaluate for old blood, thrombosed vessels, prolapsing hemorrhoids, fissures, or protruding masses.
The rectal exam should follow inspection of the anus for any skin tags protruding, sentinel piles, fissures, protruding piles, or any other apparent abnormalities that could be causing the bleed. A rectal exam can be uncomfortable and painful for patients, particularly in the case of acute fissures. In this case, inspection, while gently spreading the buttocks, helps in visualizing most anal fissures and is sufficient for diagnosis. A digital rectal exam should be done to assess for masses and internal hemorrhoids and to obtain stool for a fecal occult blood test (FOBT). Gross blood may also be visible after the exam. The digital rectal exam is contraindicated in immunocompromised patients, given the possibility of introducing pathogens, which could potentially cause life-threatening infections.[12]
A complete blood count (CBC) should be ordered with any complaint of bleeding to assess the severity and help direct the management. Other important lab tests to obtain are the international normalized ratio (INR) and the partial thromboplastin time (PTT), which will help to assess for any bleeding tendencies. A cross-match test may be needed in order to reserve blood for transfusion in cases of severe bleeding to maintain the hemoglobin level above 7gm/dL. Endoscopies are the gold standard for investigating rectal bleeding, which should be performed in patients who are older than 40 years of age regardless of other clinical symptoms.[13] An anoscope or rigid procto-sigmoidoscope can be used to evaluate for a distal source of bleeding, such as from internal hemorrhoids, proctitis, rectal ulcers, malignancies, or varices. A colonoscopy should be done if there is a concern for proximal lower GIT pathology.
CT angiography may be pursued if there is large volume bleeding or if the patient is too unstable to undergo anesthesia for endoscopic intervention. If there is a large volume of blood in the gut, it may be difficult to isolate the specific site of where the blood is coming from.
Tagged red blood cell scintigraphies are an accurate investigation for localizing the bleeding vessels and identifying the site into which they bleed. It can be utilized in recurrent and persistent rectal bleeding of an unknown cause.
Acute, severe rectal bleeding requires initial hemodynamic assessment and the initiation of hemostatic resuscitation if needed to control the patient’s vital signs. This may be achieved with IV fluids or vasopressors in more severe cases. Rectal bleeding severe enough to compromise the hemodynamic system is rare and is usually due to severe upper GI bleeding such as bleeding varices, perforated ulcer, or an aortoenteric fistula, and may mandate an upper GI endoscopy. If the patient undergoes endoscopy, bleeding can be controlled by certain procedures such as endoscopic cauterization, ligation, or direct injection to the bleeding site with either epinephrine or sclerosing agents.
Cauterization involves thermally ablating the site of bleeding with a unipolar or bipolar electrical cautery. Sclerosing agents are tissue irritants that cause vascular thrombosis and thus can be injected during hemostatic endoscopy. The most commonly used agents are ethanolamine oleate and sodium tetradecyl sulfate. If the patient undergoes an angiography, arterial embolization may be performed, especially if the bleeding vessels have been previously clipped as this makes them easily identifiable in imaging. If the patient is hemodynamically stable, they can be investigated and treated on an outpatient basis.[14] Below are some of the main causes of rectal bleeding and their specific treatments. Hemorrhoids
Management of hemorrhoids can be divided into conservative, office-based, and surgical categories. Conservative management revolves around the incorporation of high fiber options in the diet to minimize the risk of constipation and hence straining while defecating. Daily consumption of 25 grams of fiber for women and 38 grams of fiber for men is advised.[15] It can take up to 6 weeks for fiber therapy to improve the hemorrhoids.[16] Increased fluid intake is also important to prevent constipation.[17] Stool softeners and hyperosmolar supplements, such as glycerin and sorbitol, which can be given as rectal suppositories, or oral milk of magnesia and polyethylene glycol 3350, can be used as adjuncts to a high fiber diet. Sitz baths help to decrease pain, burning, and itching following a bowel movement for active, symptomatic hemorrhoids.[18] Symptom relief can also be achieved by the use of various topical local anesthetics, corticosteroids, and anti-inflammatory drugs. One of the most commonly used drugs is 0.2% glyceryl trinitrate (GTN) rectal ointment (mostly in grade 1 or 2 hemorrhoids), which relieves symptoms of hemorrhoids associated with high resting anal canal pressures. The efficacy of topical steroids is currently unproven.[12]
Office-based management mainly involves rubber band ligation, and it is the most widely used office technique for internal hemorrhoids. The procedure involves the application of a rubber band at the apex of internal hemorrhoids. This will cause the fixation of hemorrhoids in the anal canal, correcting the prolapse, with the additional benefit of decreasing blood flow resulting in a decrease in size.[19] It is beneficial for grade 1-3 hemorrhoids and is considered the most effective non- excisional treatment in the literature.[20] However, 18% to 32% of patients will have recurrence requiring repeated treatment.[21]
Infrared coagulation is one of the most commonly used energy ablation methods for treating internal hemorrhoids. The heat generated from the infrared radiation causes protein coagulation and local inflammation. Each hemorrhoidal complex is exposed to the radiation at 4 different locations, with the depth of the penetration being around 3 mm. This process causes tissue necrosis, eventually leading to fibrosis and scarring.[12] It is most effective for the treatment of first and second-degree hemorrhoids but is less effective for prolapsed hemorrhoids.[22] Another treatment option is injection sclerotherapy, which requires the injection of a sclerosing agent at the base of the internal hemorrhoidal complex. This causes scarring, fibrosis, and ultimately fixation of the hemorrhoidal complex.[12] Sclerotherapy is not as successful as rubber band ligation for grade 3 hemorrhoids.[23] Arterial embolization procedures of the superior and inferior rectal arteries have also proven effective in controlling severe and persistent bleeding.[16]
Operative management is reserved for patients who fail medical management, continue to have symptoms despite undergoing office-based procedures, present with extensive thrombosed hemorrhoids, or have other manifestations of advanced disease. Moreover, strangulated or gangrenous hemorrhoids will require immediate operative intervention as well. Closed excisional hemorrhoidectomy is the most commonly performed operation for this problem in the United States.[24] An elliptical incision is made around the hemorrhoidal tissue, and it is dissected off the underlying muscle sphincter fibers. After complete dissection of the underlying tissue, it is ligated at its base. The defect is then closed with absorbable suture.[25] The Milligan-Morgan technique involves a similar dissection of the hemorrhoidal tissue. However, it does not require the closure of the defect as in the Ferguson technique.[12]
Stapled hemorrhoidectomy is another alternative to second and third-degree hemorrhoids. This technique involves placing a purse-string suture in a circumferential fashion into the submucosa above the transition zone. The tissue above the suture is then excised with the help of the transplant stapler. In women, a vaginal exam should be done before firing the stapler to ensure the purse-string suture has not incorporated the posterior vaginal wall.[12] Trans-arterial hemorrhoidal de-arterialization involves the use of a doppler to search for arterial inflow to the hemorrhoid above the dentate line and then ligating it.[4] Thrombosed external hemorrhoids, if present in the early phase, can be treated with enucleation.[26]
Complications after hemorrhoidectomy include pain, urinary retention, hemorrhage, anal stenosis, infection, and fecal incontinence. Topical agents such as nitroglycerin and metronidazole have been shown to decrease post hemorrhoidectomy pain.[27][28] Urinary retention is another common complication that can increase morbidity in patients undergoing hemorrhoidectomy. Severe hemorrhoidal disease, the number of quadrants excised, and high analgesia requirements increase the risk of these complications.[29] Bleeding may occur as a complication after hemorrhoidectomy, either in the immediate postoperative period (primary hemorrhage) or 7 to 10 days after surgery (secondary hemorrhage).[30] Anal stenosis can occur if excessive anoderm is removed at the time of the procedure.[31] Postoperative infections are very rare after a hemorrhoidectomy. However, if cellulitis or an abscess develops, there is a need for antibiotics and drainage.[32]
Anal Fissures
Conservative treatment includes stool softeners, nitroglycerine to loosen the anal sphincter, and warm baths. Surgical management may be an option in chronic or resistant cases where a sphincterotomy is performed.[24]Diverticular Bleeding
Diverticular bleeding may cause severe rectal bleeding. The bleeding is controlled by endoscopic procedures such as epinephrine injection, clip placement, or ligation. In severe cases where diverticula cause significant, persistent bleeding that can’t be controlled with endoscopic procedures, partial colectomy may be performed.[33]
Colon Cancer
Management is based on removing the tumor and the associated part of the colon. Depending on the stage of the tumor, radical excision, which involves removing the affected part of the colon, the associated mesocolon, and local lymph nodes, may be required. The treatment plan may also involve adjuvant chemotherapy and radiotherapy.[34][35]
The differential diagnosis of rectal bleeding should include consideration for more proximal sources of bleeding, especially the colon. Consideration should be given to colon cancer, angiodysplasia, adenomas, inflammatory bowel disease, infectious, and ischemic colitis. Once the colonic causes have been ruled out, other important etiologies to consider include hemorrhoids, anal fissures, rectal carcinoma, and radiation-induced proctitis.
The prognosis depends on the cause of rectal bleeding, the severity, and the patient’s underlying health. Approximately 95% of rectal bleeding cases will regress spontaneously.
It is important for patients to seek medical consultation in cases of rectal bleeding, especially in middle and older aged individuals, as the risk of malignancy is higher in these groups.
Patients should be educated to seek medical assistance immediately if they experience vomiting or coughing up blood associated with rectal bleeding. This may indicate a potentially life-threatening upper gastrointestinal bleed or the presence of a bleeding tendency such as thrombocytopenia or anti-coagulant toxicity.
The complete blood count and, more specifically, the hemoglobin and hematocrit values may not immediately reflect the severity of an acute bleed. Patients with previous cardiac conditions taking low dose aspirin as secondary prevention should not stop taking it.
In the outpatient setting, haematochezia, or rectal bleeding, is a common concern. It can indicate a problem in the proximal lower gastrointestinal tract, but it can also indicate rectal disorders, such as haemorrhoids, anal fissures, proctitis, and anorectal cancer.
Haematochezia appears as a flow of frank red blood from the anus. Depending on the aetiology of the bleeding, the symptoms might range from mild to severe. Mild cases can be identified by red blood streaking the patient’s stool or toilet paper after wiping, whereas severe cases can be identified by a large volume, brisk bleeding.
Clinical manifestations:
Bleeding with or without defecation
Swelling
Mild discomfort or irritation
Pruritis
Mucous discharge
Hygiene difficulties
A sense of incomplete evacuation
Internal haemorrhoids are painful if they become thrombosed, prolapsed with oedema, and/or are strangulated.
External haemorrhoids are painful when they become thrombosed.
Differential diagnosis:
Proximal sources of bleeding, especially the colon
Colon cancer
Angiodysplasia
Adenomas
Inflammatory bowel disease (IBD)
Infectious and ischaemic colitis
Once the colonic causes have been excluded, other major aetiologies, such as haemorrhoids, anal fissures, rectal carcinoma, and radiation-induced proctitis, should be considered.[
When it comes to dietary supplements, all products are not created equal. A label can identify the presence of a specific ingredient without indicating if it’s from a natural, bioavailable and biocompatible source, or from a synthetic, inorganic source. This is despite the fact that our bodies may not recognize these synthetic ingredients as food.
When a supplement contains an ingredient that is not bioavailable, the body either will not absorb or utilize it correctly. The best one can hope for is that the substance will pass, inert, through the body. But with certain ingredients, the material from which they are extracted is highly toxic, rendering a substance that can do more bodily harm than good.
Industrial waste products such as fluoride (a byproduct of aluminum manufacturing and known neurotoxin), and cobalt-60, a radioactive waste material culled from nuclear reactors, have been used for decades in broad-reaching applications to make our water “healthier” and our food “safer.”
With FDA-approval and cherry-picked, manufacturer-sponsored studies as “proof”, the unsuspecting public is lulled into a sense of safety regarding these practices. And these aren’t the only such hoaxes being perpetrated on the American people.
Hidden in Plain Sight
As with most things in our modern world, understanding this logic requires you to follow the money trail. The economics are simple: chemical byproducts and industrial waste are environmentally hazardous and in abundant supply. This makes them both difficult and costly to dispose of properly. Selling these waste products as cheap, raw materials is a BIG win for manufacturers. And repackaging them as health supplements can be extremely profitable.
One of the most popular health supplements by category is the multivitamin. Consumed by adults and children alike, multivitamins are sold as veritable health insurance. If you don’t get enough of the recommended daily allowance of essential vitamins and minerals, taking a quality multivitamin can fill this dietary gap.
But not all vitamins on supermarket shelves are actually good for you. Some manufacturers source “healthy nutrients” that are toxic to the body, even in small quantities. This confounding trend is not limited to off-brand manufacturers looking to produce cheap knock-offs of “the good stuff”. Some of the most trusted name brands use ingredients that show up on global watch lists of hazardous substances we’ve been instructed to avoid for health and safety.
Disguised as healthy nutrients, the following toxic imposters are listed on the labels of popular multivitamins Centrum, One-A-Day, and Flintstones for Kids. As you will see, some of the biggest dangers to consumers are hidden in plain sight!
Sodium selenate/Sodium selenite
Sodium selenate, a byproduct of copper metal refining, is four times more toxic than the known killing drug, cyanide. Yet, it is proudly listed as a “nutrient” in many common health products.
Based on animal studies, we know that a mere 100 milligrams of the stuff are a fatal dose to most humans. The amount found in Centrum is 55 micrograms (mcg); that’s 5 mcg more than the EPA allows in a liter of drinking water before declaring it unsafe for human consumption!
Organically-bound selenium is the vital human nutrient that sodium selenate can not replace. Selenium is found in foods like nuts, seeds, and organic produce grown in selenium-rich soil. This naturally-occurring trace mineral is very different than the unbound, synthetic form being put into some multivitamins.
Organic selenium is known for its ability to boost the immune system, improve thyroid function, protect against heart disease, and even prevent cancer. Sodium selenite/selenate, on the other hand, has been shown to cause DNA damage associated with cancer and birth defects.
This mass market vitamin reveals a litany of toxic chemicals sold as “nutrients’
Cupric oxide
Cupric oxide is one of several derivative forms of “dietary copper”, a micronutrient needed to ensure proper growth and development of bones and connective tissues, as well as for maintaining the health of vital organs such as the brain and heart.
Organically, copper is found in a variety of foods, including dark leafy greens, organ meats, beans, nuts, dried fruits, nutritional yeast, as well as oysters and shellfish. The synthetic derivations found in many multivitamins are an entirely different kettle of fish!
For decades, cupric oxide was the principal source of dietary copper in supplements sold for livestock and companion animals. But an array of studies conducted as far back as the 1980’s on the bioavailability of cupric oxide determined it was not fit for animal consumption. This hasn’t stopped it from being fed to humans!
A summary of these studies published by The American Society for Nutritional Sciences ascertained that cupric oxide is not bioavailable due to it’s inability to permeate the gut wall. The fact that this form of copper is still being used in human health supplements and even baby formula, is particularly troubling since an estimated 61% of people in the U.S., U.K., and Canada have dietary deficits of this essential nutrient. Copper deficits are linked to heart disease, osteoporosis, and poor blood sugar metabolism, among other troubling disorders.
The dangers of this supplement go beyond the nutritional deficits caused by this deceptive masquerade. Cupric oxide is listed on the European Union’s Dangerous Substance Directive as a hazardous substance, for humans and the environment. Not surprising, considering its use as a chemical in industrial applications such as the production of rayon fabric and dry cell batteries.
Ferrous fumarate (aka iron)
With a list of side effects a mile long including nausea, vomiting, gastrointestinal discomfort, constipation, diarrhea, blackened stools, tooth discoloration, and anorexia, it should come as no surprise that this is the one ingredient in Flintstones vitamins to precipitate the warning on the label:
Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately.
However, it might surprise you to learn that the amount of ferrous fumarate in one Centrum vitamin is six times higher than the maximum EPA allowed limit for 1 liter of drinking water!
Another tip-off that this isn’t the iron Popeye was getting from spinach, is the fact that it is impossible to die from too much iron obtained from food. But ferrous fumarate is so toxic that accidental overdose is “a leading cause of fatal poisoning in children under 6.”
Ferrous fumarate is an industrial mineral that is not found in nature as food. A byproduct of iron mining, ferrous fumarate has drawn even more criticism as a supplement due to its interaction with vitamin C leading to ulceration of the GI tract, chronic inflammatory diseases, and cancer.
Adding to these concerns are the high doses present in many health supplements. Studies found high concentrations of iron to be associated with several pathologies, including cancer, diabetes, liver and heart disease.
Dishonorable Mention
In addition to the offenders already mentioned, the following common multivitamin ingredients have disturbing toxic rap sheets, and are found in dangerously high concentrations in most multivitamins.
Stannous chloride (tin)
In a 1983 study, it was determined that stannous chloride was “readily taken up by white blood cells and can cause damage to DNA.”
In small doses, it’s known to cause side effects such as skin irritation, headache, nausea, vomiting, and fatigue. In larger doses, severe growth retardation and cancer. While the EPA says a mere 4 mcg is the high-end limit for one liter of water to become undrinkable, you will find 10 mcg in one dose of Centrum.
Manganese sulfate
Manganese sulfate is often promoted as a supplement to prevent bone loss and anemia. The organic form of this essential nutrient helps with blood clotting, the formation of bones and connective tissues, as well as hormone regulation. Found in nuts, beans, seeds, and leafy greens, manganese is considered an essential nutrient. Manganese sulfate’s other claim to fame is its pervasive use as a chemical pesticide.
Even low doses of this chemical present significant neurological risk over time, as evidenced by reports of workplace exposure. Affected field workers showed loss of coordination and balance, along with an increase in reporting mild symptoms such as forgetfulness, anxiety, or insomnia.
In high concentrations, this supplement becomes a neurotoxin, presenting with Parkinson’s disease-like symptoms, including tremors and permanent memory loss. So why is the standard dose in a single Centrum more than four times the EPA safe consumption limit?
It should be noted that even if there aren’t extraordinary large amounts of these metals and toxicants in the vitamins you are taking, the age old justification that small amounts of chemicals or heavy metals won’t hurt you, i.e. “the dose makes the poison,” is now an outdated and disproved toxicological risk model. For instance, recent discoveries indicate that exceedingly small amounts of the following metals: “aluminium, antimony, arsenite, barium, cadmium, chromium (Cr(II)), cobalt, copper, lead, mercury, nickel, selenite, tin and vanadate,” exhibit estrogen receptor binding and stimulating properties, which has lead to them being described as ‘metalloestrogens’ with the capability to induce hormone reponse related carcinogenicity. This concept that, in some cases, the lower the dose concentration, or the lower the energy state, the higher the damage, has also been demonstrated with x-ray mammography, toxicants like glyphosate, and nanoparticles, to name but a few examples.
Who is Minding the Store?
It may seem unfathomable that these harmful, toxic chemicals could be allowed into our food and drug supply. The truth is, no one is minding the store. Loopholes abound, allowable limits are questionable, and even our organic food supply is not safe from subterfuge. Even organic infant formula can skirt regulatory oversight thanks to the numbers game.
According to the USDA’s National Organic Program guidelines, any multi-ingredient product that contains 95% or more organic ingredients may be labeled organic. That means even the copper sulfate in Similac’s Advance Organic formula falls within the “contains less than 2%” ingredient list guideline, giving this noxious chemical a free pass.
The public has a right to expect that any substance that is suspected of being harmful will be held to a high-level of scrutiny before it is approved for mass consumption. This basic, precautionary principle would minimize public risk until all known toxicological data has been thoroughly examined. Only when a determination that no serious health risks are present can be made, should a substance be allowed into mass-market products.
However, it is essentially the reverse of this model that is in effect today. Only when a substance has repeatedly demonstrated harm in already exposed populations, is it subject to the level of scrutiny that can precipitate its removal from FDA-approved products on store shelves. This means lobbying and corporate interests often prevail through the off-loading of harmful substances that are considered “innocent until proven guilty.” Guilt, in this instance, means acute or large-scale sickness suffered by the public.
Currently, no law forbids the use of any of these questionable substances in dietary supplements, despite copious laboratory research demonstrating their toxicity in animals, and significant clinical data demonstrating their actual or potential toxicity in humans. Don’t wait for the fallout to affect you before you act. Look for high-quality, organic supplements with food-grade sources, and a proven supply chain. Also consider using whole food concentrates and focusing on improving the quality of your food instead of focusing on taking supplements to try to counterbalance a deficient diet.
Adults with type 2 diabetes and a higher BMI may have an increased risk for diabetic kidney disease, according to study findings published in TheJournal of Clinical Endocrinology & Metabolism.
In findings from a generalized summary Mendelian randomization using 56 BMI-associated single nucleotide polymorphisms instrument variables, increasing BMI was linked to an increased risk for diabetic nephropathy and a lower estimated glomerular filtration rate, with the effects most pronounced among women.
The risk for diabetic nephropathy rises with each 1 kg/m2 increase in BMI, with women having a more pronounced increased risk than men. Data were derived from Lu J, et al. J Clin Endocrinol Metab. 2022;doi:10.1210/clinem/dgac057.
“Our research highlights how obesity contributes to the incidence and progression of diabetic nephropathy in people with type 2 diabetes, especially for women,” Zhihong Liu, MD, director of the National Clinical Research Center of Kidney Disease at Jinling Hospital and Nanjing University School of Medicine in Nanjing, China, said in a press release. “Managing your blood pressure and blood sugar may not be enough to slow the progression to end-stage renal disease, and our study shows how important it is for people with diabetes to also manage their weight.”
Researchers conducted a Mendelian randomization analysis to evaluate the causal effect of BMI on diabetes nephropathy risk and kidney traits. Fifty-six BMI-associated genetic variants from the BioBank Japan GWAS Mendelian randomization analyses to serve as instrumental variables. The study cohort included 1,347 adults with type 2 diabetes and biopsy-proven diabetic nephropathy, and 2,716 adults with diabetes for more than 10 years and no kidney disease. Mendelian randomization was conducted with all participants to analyze the causal effect on BMI on diabetic nephropathy, eGFR and proteinuria. Subgroup analysis stratifying participants by sex was also conducted using 27 genetic variants associated with BMI in men and 16 variants associated with BMI in women.
In the Mendelian randomization analysis, each 1 kg/m2 increase in BMI was associated with a higher risk for diabetic nephropathy (OR = 3.76; 95% CI, 1.88-7.53; P < .001) and lower levels of eGFR (OR = 0.71; 95% CI, 0.59-0.86; P < .001). There was no association between BMI and proteinuria level.
In subgroup analyses, each 1 kg/m2 increase in BMI increased the risk for diabetic nephropathy for men and women. However, the increased risk was much higher among women (OR = 14.81; 95% CI, 2.67-82.05; P = .002) than men (OR = 3.48; 95% CI, 1.18-10.27; P = .02).
“The increase in BMI level had a more significant influence on the risk of diabetic nephropathy in women,” the researchers wrote. “These results provide a theoretical basis for the potential therapeutic benefits of reducing BMI to prevent the occurrence and progression of diabetic nephropathy.”
Liu said the findings confirm the importance of screening for kidney complications for adults with diabetes and obesity.
“People with diabetes and obesity should have their kidneys checked more often, as they are at high risk, and while chronic kidney disease has no cure, early detection and obesity treatment could slow the progression to end-stage kidney disease,” Liu said in a press release.
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