Professor TAKAHASHI Satoshi
Department of Infection Control and Clinical Laboratory Medicine
School of Medicine, Sapporo Medical University

The prevalence of antimicrobial resistance to therapies widely prescribed for the management of urinary tract infections (UTIs) is rising globally.¹ The safety profile of antimicrobial agents is also of significant concern, particularly in the setting of long-term or recurrent infection.² As such, there is a clinical need for antimicrobial agents that may address key barriers to the management of UTIs.³

Professor Satoshi Takahashi from Japan provides insights on effective treatment strategies for both acute uncomplicated UTI (auUTI) and complicated UTI (cUTI), based on his extensive clinical experience.

Q1: Please describe the aetiology and epidemiology profile of auUTI and cUTI in Japan.

The difference between auUTI and cUTI is the absence or presence of any disease conditions in the urinary tract. Healthy individuals with normal immunity could be affected by auUTI, while cUTI accompanies the deterioration of the systemic or local immune system. In auUTIs, the prevalence rate of cystitis is very high in healthy young women, thus, auUTI is a common disease for females. The prevalence rate of auUTI in females in Japan is similar to those outside of Japan.

There are two forms of cUTI: when any exogenous materials such as catheters are inserted into the urinary tract and when a patient is prone to UTI owing to existing systemic or urinary tract disease. Therefore, cUTI can be observed regardless of the patient’s age, although it is more common in elderly people.

There is no epidemic trend for cUTI, while some studies reported that auUTI is more prevalent in summer.^4,5 In contrast, other studies reported that no remarkable seasonality for auUTI was identified, and that seasonality decreased with advancing age.^6,7 Textbooks state that Staphylococcus saprophyticus is the common pathogen for auUTI in summer; however, I feel this is not the case, and no seasonal trends for auUTI are observed in clinical practice. The epidemic trends for age and sex in Japan should be similar to those outside of Japan.

Q2: Please provide an overview of recommended treatment strategies for the management of auUTI and cUTI.

Sparing quinolone therapy is recommended globally.⁸ However, our aim is always to treat patients for better outcomes; I believe the most optimal treatment should be given to patients when necessary.

As for the treatment of auUTI, quinolones have an exceptional antimicrobial property and are effective against a broad spectrum of bacteria; thus, treatment can be completed in a short period. The target treatment cycle is 3–7 days depending on the antibiotics used. For example, effectiveness can be observed with cephalosporins in 7 days, sulfamethoxazole/trimethoprim in 3 days, and with quinolones in 3 days.

It is highly important to re-examine patients for the effectiveness of the treatment. When no effects are observed after administering antibiotics, a different diagnosis other than infection should be considered.

Fever mainly determines the appropriate treatment for cUTI. At least one week of treatment is necessary for cUTI with fever. The treatment period should be determined by various aspects, e.g., the presence or absence of urinary tract obstruction. I believe the best management for cUTI is to assess the urinary tract abnormalities in the early stage, and provide the appropriate treatment in addition to administering antibiotics. When only symptoms of UTI without fever are observed, and no other causal factors can be considered, the treatment strategy aims to shorten the one-week treatment period as much as possible.

auUTI patients are mostly outpatients, but cUTI patients may be outpatients or inpatients.

In Japan, a urine culture test should be performed as soon as UTI is suspected. There is consensus that a urine culture test should be performed prior to treatment initiation. However, if the test results are not instantly available, empiric treatment is usually initiated until the results become available.

As for whether to use quinolones in empiric therapy, it seems that not all doctors consider quinolones first-line drugs in cUTI, since some patients are using other drugs in combination. As for the course of treatment, cephalosporin antibiotics may be prescribed for 7 days, while other antibiotics may be prescribed for a shorter period, depending on the patient’s preference. Furthermore, side effects must be taken into consideration, thus, quinolones should be considered as one of the various treatment options. It is important to develop a treatment strategy based on comprehensive assessments, including patients’ symptoms, preferences, and side effects rather than following guidelines and limiting the use of certain drugs.

Q3: What is the clinical role and efficacy of sitafloxacin in the treatment of auUTI and cUTI in clinical practice in Japan? In your experience, are there advantages observed with sitafloxacin compared with other fluoroquinolones and antibiotics used in the management of auUTI and cUTI?

Sitafloxacin has significant antimicrobial properties. The antimicrobial activities of quinolones against pathogens of UTIs are very high, thus quinolones could replace injectable antibiotics. For example, if a patient has been hospitalised for 3 days with drip infusion and wants to be discharged because he/she wants to return to work when another 4 days of treatment is required, sitafloxacin can be a very good treatment option. Sitafloxacin can penetrate well into the tissue in the urinary system, and has significant antimicrobial activities. Furthermore, owing to the broad-spectrum antibiotic activity of sitafloxacin, susceptibility of antimicrobial-resistant bacteria is high. Another advantage of sitafloxacin is that it can be prescribed for patients who cannot be hospitalised when antimicrobial-resistant bacteria are suspected as pathogens.

Q4:  What is the safety and tolerability profile of sitafloxacin? In your experience, are there advantages observed with sitafloxacin compared with other fluoroquinolones and antibiotics used in the management of auUTI and cUTI?

I would say sitafloxacin is extremely safe. In my experience, I have not found any issues after prescribing sitafloxacin in clinical practice. I had observed various kinds of side effects with older quinolones, in particular, seizures and photosensitivity reactions.

As for the tolerability, we have not found any issues after prescribing sitafloxacin 100 mg twice daily for non-gonococcal urethritis. Therefore, the safety and tolerability of sitafloxacin are both highly favourable compared with old quinolones. Also, I believe sitafloxacin can be prescribed with no safety issues, even when compared with new quinolones.⁹

In Japan, sitafloxacin is the first-line drug for the treatment of urethritis caused by Mycoplasma genitalium, as it is covered by medical health insurance. Other antibiotics, except for sitafloxacin, are not very effective against M. genitalium, thus, no treatment options are available if bacterial resistance is identified to sitafloxacin. Hence, appropriate use of antibiotics is critical for the long-term availability of sitafloxacin.

Q5: Please describe the antibiotic resistance trends/patterns among UTI pathogens in Japan – particularly fluoroquinolone resistance among UTI pathogens.

The majority of auUTI are caused by Escherichia coli (E. coli), and other bacteria such as Klebsiella pneumoniae and S. saprophyticus can cause a small number of auUTI. A Japanese surveillance study that took place between 2009 and 2010 reported that approximately 10% of fluoroquinolone-resistant E. coli (1%–2% when limited to sitafloxacin-resistant E. coli) were isolated from pre- or postmenopausal women with auUTI.¹⁰ However, the rate of fluoroquinolone-resistant E. coli has been increasing recently.

There are regional differences in quinolone resistance against bacteria, particularly in patients with auUTI. For example, as quinolone-resistant bacteria are barely observed in Sapporo, Hokkaido, we usually do not have any difficulty in treating patients in clinical practice. In contrast, quinolone resistance can be higher in other regions.

Like auUTI, the main pathogens for cUTI are E. coli; the proportion of E. coli should be 40%–50% at most. Gram-positive bacteria can cause cUTI in patients with catheters. The rate of quinolone-resistant E. coli and extended-spectrum beta-lactamase (ESBL)-producing bacteria are increasing in cUTI. Therefore, appropriate use of antibiotics is highly important, particularly in the early stage of cUTI.

Although the proportions of E. coli causing auUTI and cUTI are different, targeting E. coli is crucial for the treatment strategy. Other than E. coli, K. pneumoniae in the urinary tract has hardly shown antimicrobial resistance, but cephalosporins are becoming less effective against S. saprophyticus. Therefore, the use of quinolones should be considered when Gram staining is positive.

Antimicrobial-resistant E. coli is likely developed by exposure to antibiotics. E. coli can be a pathogen for cystitis but is also a normal inhabitant; hence, one cannot be infected by E. coli, unlike sexually transmitted diseases. Uropathogenic E. coli, which can cause infection in the urinary tract and bladder, can cause cystitis. However, even if uropathogenic E. coli are eliminated by antibiotics, many reservoirs of the same bacteria are already present in the body as normal inhabitants. Maintaining the viability of these normal bacteria (as reservoirs) under exposure to antibiotics may result in antimicrobial resistance. Antibiotics are not used only for cystitis treatment but also for many kinds of infectious diseases. In this case, a certain percentage of ‘good’ microbiomes are constantly exposed to antibiotics. Antimicrobial resistance can be developed as a result of the survival strategy of normal microorganisms from antibiotic exposure.

Q6: How has the emergence of fluoroquinolone-resistant pathogens affected the way clinicians approach patients with auUTI and cUTI?

We spend time with patients during consultations and obtain detailed information such as past history of UTI, use of medications, outcomes, and any side effects. It is important to consider using other types of antibiotics if a patient has been taking certain antibiotics many times, as bacteria that are resistant to the antibiotics may be pathogens responsible for the UTI. I believe the management for the appropriate use of antibiotics is highly important and should be implemented in clinical practice so that patients get relief from pain and recover more quickly from abnormal sensations upon urination.

Severity is a key factor in the treatment of cUTI with fever. Patients who are not severe and who are able to take fluids orally can be treated with oral quinolones. In patients with severe cUTI who need to be hospitalised, cUTI may be caused by quinolone-resistant or ESBL-producing bacteria. Hence, antibiotics that can address these bacteria should be used until quinolone susceptibility is confirmed. Once pathogens are identified, we would replace the antibiotics with the appropriate one; we would neither increase the dose of injectable antibiotics nor recommend a combination of antibiotics unnecessarily.

Q7: What is the role of sitafloxacin in the emergence of such resistance?

There is no doubt that sitafloxacin is an extremely valuable drug, and it is no exaggeration to say that sitafloxacin is the ultimate weapon. I think sitafloxacin is on a par with carbapenem, in the sense that these must not become inviable. Given how valuable sitafloxacin is, we hope that it will remain viable for a long time. Many antibiotics have become unusable due to antimicrobial resistance. I hope that healthcare professionals recognise the appropriate use of sitafloxacin and only use it when necessary, so that sitafloxacin may always remain viable.

References

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3. Li Y, Yin Y, Peng X, et al. A randomized, active-controlled, multicentre clinical trial to evaluate the efficacy and safety of oral sitafloxacin versus levofloxacin in Chinese adults with acute uncomplicated or complicated urinary tract infection. Ann Med. 2021;53(1):217-226.
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6. Rosello A, Pouwels KB, Domenech DECM, et al. Seasonality of urinary tract infections in the United Kingdom in different age groups: longitudinal analysis of The Health Improvement Network (THIN). Epidemiol Infect. 2018;146(1):37-45.
7. Simmering J, Tang F, Cavanaugh J, Polgreen L, Polgreen PM. Trends and Seasonal Effects in Hospitalizations for Urinary Tract Infection Differ by Age and Sex. Open Forum Infectious Diseases. 2015;2(suppl_1).
8. Chao YS FK. Fluoroquinolones for the Treatment of Urinary Tract Infection: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines [Internet]. Canadian Agency for Drugs and Technologies in Health. https://www.ncbi.nlm.nih.gov/books/NBK543513/. Published 2019. Accessed 12/06/2022.
9. Chen CK, Cheng IL, Chen YH, Lai CC. Efficacy and Safety of Sitafloxacin in the Treatment of Acute Bacterial Infection: A Meta-analysis of Randomized Controlled Trials. Antibiotics (Basel). 2020;9(3).
10. Hayami H, Takahashi S, Ishikawa K, et al. Nationwide surveillance of bacterial pathogens from patients with acute uncomplicated cystitis conducted by the Japanese surveillance committee during 2009 and 2010: antimicrobial susceptibility of Escherichia coli and Staphylococcus saprophyticus. J Infect Chemother. 2013;19(3):393-403.