Understand the science behind UTIs and related cancers

Urinary tract infection (UTI) is one of the most common infectious diseases and the leading cause of community-acquired and healthcare-associated infections acquired while receiving healthcare that was not present during the admission.

UTIs annually affect 30 million people and are responsible for the single-greatest use of antibiotics outside a hospital setting in the United States [134].

Women are disproportionately affected, with 60% of women in the U.S. acquiring a UTI in their lifetime, as compared with 14% of men [33]. However, these data points are underestimated. In fact, about 50% of UTIs do not come to medical attention.

In women, the urethra is close to the vagina and rectum, which can lead to unintentional introduction of colonies of pathogenic bacteria, like Escherichia coli (the most common pathogen associated with acute and recurrent UTIs in women) traveling from the rectum to the genital area, or vagina and ascending the urethra and entering the bladder. Infections that travel to the kidneys or enter the bloodstream are more challenging to treat and more dangerous.

Lower urinary tract symptoms include cystitis and prostatitis, and upper UTIs include pyelonephritis. In otherwise healthy, sexually active women >18 years, UTIs occur approximately every other year [34] and are simple or uncomplicated. The prevalence of UTIs increases with age due to functional and anatomical problems [32]. Up to 90% of men aged 50 to 80 in the U.S. may suffer from troublesome lower urinary tract symptoms [83]. A population-based study of community-onset UTI among 31,000 residents of Calgary showed that the incidence of UTI among women initially peaked in the twenties (30 per 1,000), decreased slightly during the later reproductive years, then steadily increased with every decade of life starting in late middle age, reaching a maximum of 125/1,000 at and above age 80 [35].

Recurrent UTIs are defined as the occurrence of 2 or more UTIs within 6 months or 3 or more UTIs within 12 months. They differ from one-off UTIs and are often resistant to one or more antibiotics. People with weakened immune systems or chronic medical conditions are usually the most vulnerable to antibiotic-resistant infections [39, 73]. For example, beta-lactam antibiotics, such as penicillins, cephalosporins, monobactams, and carbapenems, once a standard treatment, have less efficacy in eradicating vaginal colonization with E. coli, and clinically, these agents are associated with rapid recurrence of UTI after antibiotic therapy compared with other agents [68, 69].

The intestinal microbiota is the ultimate source of bacterial strains associated with protecting the mucosa of various organs, and when disrupted, it is associated with pathogenesis and recurrence of UTIs [41]. Shifts in the intestinal microbiota increase the colonization of the vagina and urethra with pathogens, followed by their ascension to the bladder and sometimes the kidneys to cause infection [41, 42, 43]. Repeated antibiotic use lowers the bacterial diversity, alters the inflammatory process, and enables pathogens, such as Proteus [24], Staphylococcus, Pseudomonas, Providencia, Escherichia coli, Enterococcus, Enterobacter, Ureaplasma [25], and Klebsiella [26], to multiply. Pathogens increase the production of proinflammatory proteins (specifically cytokines) and suppress anti-inflammatory proteins [67], which, in turn, interfere with iron homeostasis and hemoglobin and red blood cell synthesis. Decreased concentration of oxygen to tissues accelerates cell death and increases the delivery of iron to pathogenic bacteria (essential for their growth) [77-81]. Pathogens also rob the body of citrate, a substance that helps prevent kidney and bladder stones and keep existing stones from growing [135]. Urease and other enzymes produced by pathogens release ammonia, carbon dioxide, uric acid, and free radicals that allow bacteria to form crystalline biofilms and ensure their survival in hostile conditions, such as antibiotics and starvation from glucose, iron, and oxygen (essential for their growth) [29]. Pathogens modulate the inflammatory process, which, in turn, damages the structure and function of the GI and GU tracts [89, 90] and causes a variety of urogenital disease conditions, including bacterial vaginosis, HIV infection, Neisseria gonorrhoeae urethritis, kidney and bladder stone formation and retention, acute and recurrent UTIs [5-9, 27-31, 55-60]. Surgical stone extraction with antibiotics given before and after treatment does not completely eradicate infection risk [28].

Recurrent UTIs are highly correlated with increased incidence of acute urinary retention and genital organ, bladder, kidney, male colorectal, prostate, and female liver cancer [Source, 27-31]. Acute urinary retention is characterized by a sudden, painful inability to void [84, 85]. The incidence of this condition in men is 2.2 to 8.8 per 1000 men per year, and it increases substantially with age [86]. An estimated 10 percent of men in their 70s and 30 percent in their 80s will develop acute urinary retention [87]. The incidence in women to men is estimated as a 1:13 ratio [88]. The antibiotic dosage and length (days) of use also correlate with the severity of infection and an increased risk for cancer than those without a UTI and antibiotic treatment. For example, a significant increase in bladder cancer in men was observed after antibiotic treatment for more than 7 days [Source]. Women after UTI have a higher liver cancer risk, especially approximately 30 months after infection. These results contradict many prior research studies hypothesizing that most antibiotics, such as cephalosporins, quinolones, and ampicillin, are considered cancer treatment drugs rather than carcinogens [91-93].

A 2018 Denmark study of 5.8 million residents examining all hospital admissions, emergency department, and outpatient specialty clinic visits between January 1995 and December 2017 demonstrated that the absolute risk of urinary tract cancer in patients aged 50 years and older was 1.3 percent at three months, 1.8 percent at one year, and 2.5 percent at five years after a first diagnosis of acute non-surgical induced urinary retention [Source]. Within three months after a first diagnosis of acute urinary retention in men, the observed number of invasive bladder cancer was 372 versus 19 expected, and the observed number of non-invasive bladder cancers was 383 versus 18 expected, corresponding to 25 and 26 excess cancers per 1000 person-years, respectively. In women, the observed number of invasive bladder cancers was 62 versus 1 expected, and the observed number of non-invasive bladder cancers was 30 versus 1 expected, corresponding to 20 and 9 excess cancers per 1000 person-years, respectively. During this same timeframe, the observed number of genital cancers was 80 versus 5 expected in women, corresponding to 24 excess cases per 1000 person-years. Of these, 46 percent were ovarian cancers, and 29 percent were endometrial cancers. Prostate cancer accounted for most genital cancers in men. The total number of colorectal cancers was 273 versus 63 expected. Of these, 244 were detected in men and 29 in women, corresponding to 13 and seven excess colorectal cancers per 1000 person-years, respectively. Of these 273 cancers, 35 percent were localized, and 43 percent had spread locally or metastasized. The number of neurological cancers was 46 versus 10 expected, corresponding to 2 excess neurological cancers per 1000 person-years. From three months and beyond, no excess risk of genital cancers in women or colorectal and neurological cancers were detected. After three months of follow-up, absolute risks of genital cancers in women and colorectal and neurological cancers were low (less than one percent).

The conventional medical standard of care for treating and preventing UTIs has led to 53 percent of females with their first UTI experiencing a second UTI within 6 to 12 months [94]. Men are less likely to get a recurrent UTI, but if they do, it is because pathogens tend to hide inside the prostate. The choice of the specific antibiotic may vary based on the individual’s history and the bacteria found. The last published estimate in 2010 estimated that the annual U.S. domestic cost for UTI treatment exceeded two billion dollars [36, 37, 38]. Given the exponential increase in antibiotic resistance worldwide over the past few decades, antibiotics as first-line therapy for UTIs have become less attractive and responsible for the high rate of antibiotic-resistant UTIs and a variety of urogenital conditions and cancers [40]. Most of the world’s biggest pharmaceutical companies, unable to profit from antibiotics, have long since stopped investing in alternative ways to treat UTIs.