Antibiotic resistance is increasingly in the news. But what’s often missing from the headlines is that repeated short courses of antibiotics, weeks or months apart can be a gift to bacteria. Antibiotics are often prescribed at the lowest possible dose to avoid antibiotic resistance.
For UTIs, new research suggests that longer courses of higher dose antibiotics not only work to resolve infections but do not create antimicrobial resistance.
Getting the right treatment, at the right time is key. If you’re taking a course of antibiotics that’s too short it might fail to completely kill the infection. It’ll stick around, flaring up over the next few weeks, or months.
What is antibiotic resistance?
Antibiotic resistance occurs when an antibiotic has lost its ability to effectively control or kill bacterial growth; in other words, the bacteria are ‘resistant’ and continue to multiply in the presence of therapeutic levels of an antibiotic.
The antibiotic-resistant bacteria that we see today have an ancestry that dates back hundreds of millions of years. As life forms emerged from the oceans and transitioned from marine animals to land animals, they brought along bacteria that adapted to different extreme environments such as cold and starvation. As they adapted, they began to resist things in the natural environment that could kill them, eventually emerging into the bacterial microbes we see today. Thus microbial resistance is part of natural selection and shouldn’t be seen solely in relation to antibiotics.
Why do bacteria become resistant to antibiotics?
Antibiotic resistance is a natural phenomenon. When an antibiotic is used, bacteria that can resist that antibiotic have a greater chance of survival than those that are ‘susceptible.’ Susceptible bacteria are killed or inhibited by an antibiotic, resulting in a selective pressure for the survival of resistant strains of bacteria.
Some resistance occurs without human action, as bacteria can produce and use antibiotics against other bacteria, leading to a low-level of natural selection for resistance to antibiotics.
However, the current higher levels of antibiotic-resistant bacteria are attributed to the overuse and abuse of antibiotics. In some countries and over the internet, antibiotics can be purchased without a doctor’s prescription. Patients sometimes take antibiotics unnecessarily, to treat viral illnesses like the common cold. There is also the issue of the usage of antibiotics within the farming food chain and then antibiotic usage seeping into the natural environment such as water supplies.
How do bacteria become resistant to antibiotics?
Some bacteria are naturally resistant to certain types of antibiotics. Bacteria may also become resistant
- by a genetic mutation
- or by acquiring resistance from another bacterium.
Mutations, rare changes of the bacteria’s genetic material, are thought to occur in about one in one million to one in ten million cells. Different genetic mutations yield different types of resistance. Some mutations enable the bacteria to produce potent chemicals (enzymes) that inactivate antibiotics, while other mutations eliminate the cell target that the antibiotic attacks. Others close up the entry ports that allow antibiotics into the cell, and others manufacture pumping mechanisms that export the antibiotic back outside so it never reaches its target.
Bacteria can acquire antibiotic resistance genes from other bacteria in several ways. By undergoing a simple mating process called ‘conjugation,’ bacteria can transfer genetic material, including genes encoding resistance to antibiotics from one bacterium to another. Viruses are another mechanism for passing resistance traits between bacteria. The resistance traits from one bacterium are packaged into the head portion of the virus. The virus then injects the resistance traits into any new bacteria it attacks. Bacteria also have the ability to acquire naked, ‘free’ DNA from their environment.
Any bacteria that acquire resistance genes, whether by mutation or genetic exchange with other bacteria, have the ability to resist one or more antibiotics. Because bacteria can collect multiple resistance traits over time, they can become resistant to many different families of antibiotics.
Due to increased awareness and campaigns around the issue of antibiotic resistance as a result of an overprescription of antibiotics both within a clinical setting but also within the food chain, clinicians try to avoid resistance issues by using the lowest effective dose for the shortest possible time when treating bacterial infections. This is known as the Minimum Inhibitory Concentration (MIC). However understanding bacterial growth is about survival advantage and balance as we outlined above. Thus not all antibiotics or antimicrobial agents prescribed at insufficient dosage strength have adequate penetration to treat urinary tract infections especially if offered for a short period of time.
One study noted: “subinhibitory antibiotics prime uropathogens for adherence and invasion of murine urothelial tissues. These changes in initial colonization promoted the establishment of chronic infection”.
Non-lethal concentrations of antibiotics mean that the bacterial population is not eradicated as with higher levels of a drug where only pre-existing resistant mutations will survive. Instead, at sub-MIC the bacterial community will continue to grow allowing a larger effective population size and a continuing supply of possible resistance mutations. Antibiotics such as fluoroquinolones, aminoglycosides or beta-lactams have been found to increase the rate of mutations at non-lethal concentrations thereby further adding to the possible supply of resistance mutations.
Antibiotic resistance and UTI
Acute cystitis symptoms used to be relieved by a single high-dose antibiotic. The single dose was thought to get rid of the symptoms quickly but studies have shown that there are often enough bacteria left over for the infection to come back.
Now urinary tract infections (UTIs) are treated with either a three-day short course of low dose antibiotics or a longer course (five days or more). A Cochrane review published in 2005 noted “After five-day antibiotic treatment, most women didn’t have bacteria in their urine. After three-day antibiotic treatment, on the other hand, some women still had bacteria in their urine”.
This study states that most women after five days didn’t have bacteria in their urine but it still illustrates that the infection is present in a cohort of patients because of the low dose antibiotic prescribed and the infection is certainly still present after 3 days. Clinical studies have suggested that MIC antibiotic therapies and dosing strategies are risk factors for severe complication of infection, risk of breakthrough infection, and future recurrence episodes. Read the study on PubMed.gov.
Those experiencing recurrent symptoms or who have undergone investigations to understand the causes of their symptoms may have been offered a low-dose course of antibiotic known as a prophylactic dose. While prophylaxis is usually effective in reducing some symptoms, it does not alter the long-term risk of recurrence, as infection rates can return to pre-treatment levels following therapy and pathogens become more resistant to future treatment. Read more on PubMed.gov.
A better tactic may be to consider a high dose persistence of the same antibiotic or antimicrobial. Even if the bacteria utilise resources to evade the initial antimicrobial treatment, critically, the length and high dose means that the bacteria will eventually run out of adaptation resources and die. Indeed, a clinical study of 624 women suffering from chronic lower urinary symptoms over a ten year period and treated with narrow spectrum first generation antibiotics noted the following:
“The median number of antibiotics to which the isolate was resistant remained at one over all visits [interquartile range (IQR) 0–2 for visits one and two, and 0–3 for the third and subsequent visits). These differences were not significant (Kruskal–Wallis χ2 = 2.5; df = 3; p = 0.47).”
UTI Bacterial Biofilms and Antibiotic resistance
Chronic Urinary Tract infections can be attributed to the development of bacterial biofilms. Biofilms are bacterial communities encased in a polysaccharide matrix capable of adhering to and inside surfaces and tissues such as the bladder wall which are capable of expressing antibiotic resistance genes. E. coli, the most commonly attributed bacteria for urinary tract infections, is a high biofilm-producing bacterium, responsible for contributing with 62.5% of E. coli infections shown to produce biofilm.
Compared to free floating or planktonic bacteria, microbes encased in biofilms are 10-1,000 times more resistant to antibiotics (i), with 64% of biofilm-forming E. coli infections being multi-drug resistant (MDR) compared to 36% for non-biofilm forming E. coli infections (ii).
Biofilms and Intracellular multi-bacterial bacterial communities allow microbes within them the opportunity to evade host immune cells as well as infection fighting antibodies and antimicrobials such as antibiotics. They are also capable of producing enzymes which disable antibiotics. Biofilms and Intracellular bacterial communities also exhibit behaviours such as quorum sensing which is the ability for bacterial species to transfer behaviours such as antibiotic resistance between each other.
Thus early, clinical intervention in those cases of recurrent or chronic urinary tract infection is necessary to prevent the creation and development of multi-cellular bacterial communities and achieve better clinical outcomes for patients.
i. Sharma, D., Misba, L. & Khan, A.U. Antibiotics versus biofilm: an emerging battleground in microbial communities. Antimicrob Resist Infect Control 8, 76 (2019). https://doi.org/10.1186/s13756-019-0533-3
ii. Katongole, P., Nalubega, F., Florence, N.C. et al. Biofilm formation, antimicrobial susceptibility and virulence genes of Uropathogenic Escherichia coli isolated from clinical isolates in Uganda. BMC Infect Dis 20, 453 (2020). https://doi.org/10.1186/s12879-020-05186-1