Introduction
Recurrent urinary tract infections (UTIs) are defined as 2 infections in 6 months or 3 in 12 months, with at least 2 weeks of symptom-free interval. Symptoms include frequent urination, urgency, dysuria, and foul-smelling urine. Escherichia coli causes 75–90% of UTIs; other pathogens include Klebsiella, Proteus, Enterococcus, and Staphylococcus.
In women, most recurrent UTIs result from reinfection with new bacteria, though some are due to relapse with the same strain. In such cases, radiologic evaluation helps detect anatomical abnormalities. Hidden bacteria in the bladder may go undetected in urine cultures. Intracellular bacterial communities (IBCs) in bladder cells may play a role in recurrence.
Bacterial persistence
Bacterial persistence refers to identical bacteria lying dormant between two UTI episodes. Unlike antibiotic resistance, persistence is a temporary, non-growing state where a small fraction of bacteria survive antibiotic treatment without being resistant. These persistent cells resume growth once the antibiotic is removed. Though proven, bacterial persistence is still not widely considered in clinical practice.
Figure 1. A bacterial population undergoing antibiotic therapy and the emergence of a fraction of persistent cells. Panel (a) shows the bacterial population undergoing antibiotic therapy, panel (b) represents emerging dormant bacteria under the antibiotic therapy, panel (c) shows the surviving dormant bacteria before becoming active again as indicated in panel (d).
In Vitro Studies
Toxin-Antitoxin
Toxin-antitoxin (TA) systems feature stable toxin proteins that inhibit bacterial growth and labile antitoxins (protein or RNA) that neutralize them. Under antibiotic stress, this balance shifts toward toxin dominance, inducing a low-metabolic dormancy state that protects bacteria from antibiotics that typically target active cells. Eight TA system types exist, with Types I and II best characterized in E. coli and P. aeruginosa. Key persistence-related toxins include HokB, HipB, RelE, MazF, YafQ, MqsR, and DinJ. Current research explores peptides that could hyperactivate toxins under normal conditions as potential antimicrobials, though no clinical applications exist yet.
Stringent Response and SOS Response
The stringent response helps bacteria adapt to nutrient scarcity by entering dormancy while remaining prepared to utilize limited resources. Guanosine tetraphosphate (ppGpp) accumulation downregulates DNA replication and rRNA synthesis. Meanwhile, the SOS response maintains DNA repair through LexA and RecA factors during persistence. These mechanisms offer potential targets for treating persistent infections by either directly eliminating dormant cells or blocking their formation/reactivation. The natural resuscitation of bacteria post-antibiotic treatment suggests pulsed antibiotic therapy could effectively eliminate persistent cells, though optimal timing requires further research.
In Vivo Animal Studies
Escherichia coli, typically an extracellular bacterium, can act as an intracellular pathogen in urinary tract infections. Uropathogenic E. coli (UPEC) forms intracellular bacterial communities (IBCs) inside bladder cells, allowing it to hide from the immune system and resist antibiotics. This intracellular presence may be a key cause of recurrent UTIs, though most evidence comes from mouse studies, with limited data in humans.
Figure 2. Diagram of the urinary bladder with intracellular bacterial community (IBC) maturation and development.
In Vivo Human Studies
Intracellular bacterial communities (IBCs) have long been reported in the urine of patients with acute cystitis [14], but they have not yet been detected in the urine of patients in between two acute episodes of rUTIs as proof of the existence of bacterial persistence and of a pathogenetic link between subsequent UTIs. The morphology of IBCs in the urine sediment (see Figure 3 below) is well characterized as illustrated by Eirnaes K [12]: the only problem seems to be not knowing how to describe and report it. This will be possible only if, in time, specific studies are conducted to look for IBCs in the urine of asymptomatic patients suffering from rUTIs.
Figure 3. An illustration of IBCs of bacteria inside an endosome of a urothelial cell as may be found in the urinary sediment.
In Vivo Human Studies
Standard treatment for recurrent UTIs involves short-course antibiotics as per acute cystitis guidelines, though these aren’t specific to recurrence. Many patients self-medicate, leading to increased antibiotic resistance over time. Continuous low-dose antibiotic prophylaxis may reduce infections by up to 95%, but relapses often occur after stopping treatment. Postcoital antibiotics help in sexually triggered UTIs, while vaginal estrogen has shown benefit in postmenopausal women.
Non-antibiotic options like probiotics, cranberry tablets, and D-Mannose are also used, though results vary. The ideal duration and long-term success of prophylaxis remain uncertain.
Future Clinical Practice
Recurrent UTI management should address bacterial persistence and intracellular bacterial communities (IBCs), using protocols different from acute UTI treatment. Intracellular infections require antibiotics that can reach inside bladder cells, which standard UTI antibiotics often can’t
Intracellular Active Antibiotics
Some antibiotics (e.g., fluoroquinolones, tetracyclines, rifampicin) can target bacteria inside cells. Others like beta-lactams don’t work well intracellularly. However, not all intracellular-active drugs are suitable for UTIs.
Pulsed Antibiotic Therapy
To target dormant bacteria, pulsed therapy (repeating short antibiotic courses with breaks) is proposed. Though not fully studied, this could awaken bacteria for better eradication. However, this may risk antibiotic resistance.
Drug Combination
Combining antibiotics (e.g., Ciprofloxacin + Nitrofurantoin) could enhance treatment and prevent resistance. Though not yet standard for UTIs, this approach is used in other infections and holds promise.
Backbone and Ancillary Therapy
A base (backbone) antibiotic like Ciprofloxacin or Fosfomycin could be given on fixed days weekly, paired with secondary drugs (ancillary) like Nitrofurantoin to protect against resistance. These regimens must be compared with existing 6-month low-dose prophylaxis.
Back-Up Plan
If pulsed therapy with short breaks isn’t effective, longer intervals (9–11 days) may be tried. Pilot studies are being planned to evaluate this method.
Conclusions
The purpose of this review about rUTIs is to suggest a new clinical perspective based on research regarding bacterial persistence and intracellular bacterial communities. Pulsed antibiotic therapy with intracellular active preparations represents a potentially novel concept that could be tested in clinical trials; pulsed Ciprofloxacin, Cotrimoxazole or Fosfomycin associated with Pivmecillinam, Nitrofurantoin or Gentamycin could be interesting new options for the treatment for rUTI, as clinicians feel they are left without treatment options. The aim is to inspire a controlled multicenter clinical trial of pulsed antibiotic therapy for rUTIs.
Source: Sgarabotto, D.; Andretta, E.; Sgarabotto, C. Recurrent Urinary Tract Infections (UTIs): A Review and Proposal for Clinicians. Antibiotics 2025, 14, 22. https://doi.org/10.3390/antibiotics14010022
