Prof Li Ning
Huashan Hospital Affiliated to Fudan University – Department of Infectious Diseases

Social undertakings:
Vice-Chairman of the Youth Committee, Shanghai Branch of Clinical Epidemiology and Evidence-based Medicine
Youth Committee Member of Internal Medicine Branch, Chinese Medical Association
Member of the Hepatology Group, National Society of Tropical Diseases
Young member of the Liver Disease Committee, Shanghai Medical Association
Reviewer of the National Natural Science Foundation of China
Young Editorial Board Member of the Chinese Journal of Viral Diseases
Reviewer of the various scientific journals (Journal of Medical Virology, Cell Death & Disease and, Annual of Hepatology)

Li Ning is the executive director of the Department of Infectious Diseases, a Chief physician and supervisor of postgraduates at the Huashan Hospital Affiliated to Fudan University. Additionally, Dr. Li is a visiting scholar at the City of Hope National Medical Center, USA. His clinical specialty is the clinical management of infectious diseases, especially chronic liver diseases such as hepatitis B, liver fibrosis, cirrhosis and liver failure. He also specialises in the diagnosis and treatment of pulmonary infections, urinary tract infections, skin and soft tissue infections, sepsis, central nervous system infections, immunodeficiency infections, and unexplained fevers.

Since the first-generation quinolone, nalidixic acid, was launched in 1962, quinolones have been in clinical use for 60 years and have become one of the most valuable antimicrobial therapeutic classes in clinical practice. To better understand the therapeutic status of quinolones in the treatment of urinary tract infections, we invited Professor Li Ning from Huashan Hospital Affiliated to Fudan University to share the clinical application of quinolones in urology.

1. The clinical status of quinolones in the treatment of urinary tract infections

Urinary tract infection is a common clinical problem, the incidence of which has increased by nearly 30% in the past 30 years. One-third of nosocomial infections are urinary tract infections. The first-generation quinolones were applied in the treatment of urinary tract infections, and their efficacy remains evident after 60 years of clinical application. The purpose of antimicrobial treatment for urinary tract infection is to remove pathogenic bacteria, relieve urinary tract irritation, prevent renal damage and contain further spread of infection. Clinicians treat patients empirically based on the site and setting of infection, and the patient’s medication history. If drug sensitivity monitoring results are available, the target therapy will be administered based on drug sensitivity¹.

In principle, oral therapy is recommended for lower urinary tract infections while intravenous therapy is recommended for severe upper urinary tract infections. Apart from the severity of the disease and the site of infection, the choice of administration is also based on the local concentration of the selected drug such as the blood concentration, especially in the urinary tract.² In outpatient and emergency treatment, anti-infective therapy is offered mainly through oral administration. However, when compared with intravenous drugs, there are fewer options for oral preparations. In clinical practice, skin tests should be performed with amoxicillin and clavulanic acid. Cephalosporins have exhibited a high resistance rate, and fosfomycin tromethamine is only used for the treatment of lower urinary tract infections. Nitrofurantoin is ineffective in the treatment of upper urinary tract infections owing to low blood concentration, and it is not recommended for use in patients with renal insufficiency.

In this context, the classic quinolones, ciprofloxacin, levofloxacin, and the novel quinolone, sitafloxacin, suddenly emerged as the choice of drug for urinary tract infections. These are also commonly used as treatment in the outpatient and emergency anti-infection settings.³ Quinolones are available in both intravenous and oral preparations. Oral preparation is widely used owing to its high bioavailability and drug concentration, and good accessibility in China; additionally, skin tests are not required before using quinolones. In clinical application, there are five common quinolones, namely moxifloxacin, nefloxacin, ciprofloxacin, levofloxacin and sitafloxacin. Among the drugs, levofloxacin, ciprofloxacin and sitafloxacin are more commonly used to treat urinary tract infections, while moxifloxacin is rarely used owing to its low urinary tract concentration. There are no indications for urinary tract infections in the prescribing information for nenofloxacin.

Ciprofloxacin requires twice-daily dosing owing to its low bioavailability and short half-life; it is highly active against Pseudomonas aeruginosa.⁴ While levofloxacin has good safety profile and high bioavailability, owing to the emergence of drug resistance over the past two years, its sensitivity has reduced. Compared with levofloxacin and ciprofloxacin, sitafloxacin has higher sensitivity to Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus and more, with an oral utilisation rate of 96%, indicating great advantage in urinary tract infections.⁵

In conclusion, quinolones have comprehensive efficacy in the treatment of urinary tract infections towing to their high oral availability, broad antibacterial spectrum, and low minimal inhibitory concentration (MIC) values ​​for common pathogenic bacteria in urinary tract infections.

2. Differences and reasons of quinolone regimen selection in the treatment of urinary tract infections in China and other countries

The treatment of urinary tract infections is mainly based on initial empirical therapy. In the “Guidelines for the Diagnosis and Treatment of Urinary Tract Infections in China”, quinolones are recommended as first-line treatment normal urinary tract infections in women, and quinolones are highly recommended for complicated urinary tract infections. Fluoroquinolones are also highly recommended in the “Japanese UTI Guidelines”.⁶ However, in the “EAU Urinary Tract Infection Guidelines”, there is some variability in the recommendation for fluoroquinolone; it is recommended for use in combination, or depending on resistance rate, medication history, drug dosage form, and more. For example, in normal urinary tract infections, quinolones are not recommended for treating cystitis, while oral dosage forms of quinolones are recommended for treating pyelonephritis. The status of fluoroquinolones in the treatment of complicated urinary tract infections is nowhere near a first-line recommended regimen.⁷ The recommended regimens in the guidelines vary from country to country.

In China, quinolones are highly valued as a treatment for simple to complicated urinary tract infections. The selection of quinolones varies according to drug resistance profiles. The target treatment is critical in treating infections and therefore, drug susceptibility is very important; the breakpoint of the drug is closely related to drug susceptibility. The breakpoint is calculated based on the blood concentration, which is not conducive to the treatment of urinary tract infection in terms of clinical application. As most drugs do not have high plasma concentrations, they are often categorized as drug-resistant; but owing to their high urine concentrations, these drugs actually appear to be clinically effective. Pharmaceutical experts may be needed to further calculate the breakpoint based on the concentration at different sites, and to provide drug susceptibility reports on the sites of infection.

The quinolones recommended in the Japanese guidelines are of a very high standard owing to the advanced research and development of quinolones in Japan. Japan has a long and proven track record in the treatment of urinary tract infection. From simple urinary tract infection to complicated cystitis, to premenopausal and mild to moderate pyelonephritis, quinolones are recommended as first-line treatment. For postmenopausal acute simple cystitis, the Japanese guidelines recommend quinolones as a second-line treatment while second-generation cephalosporins such as cefaclor are recommended as a first-line treatment.

In the European guidelines for urinary tract infection, quinolones are not recommended for cystitis owing to the difference in local resistance profiles compared with China, and not because of a lacking treatment effect. In Europe, the resistance rate of nitrofurantoin and fosfomycin is low, and patients can be treated with conventional drugs without the use of quinolones.

Overall, the differences in distribution of aetiological agents, drug resistance, and access to drugs are the source of differences in the formulation of treatment regimens between the Chinese guidelines and those of other countries. In China, the prevalence of extended spectrum beta lactamase (ESBL)-producing Escherichia coli is over 50%,⁸ while the prevalence in Australia is lower. The percentage of ESBL-producing Escherichia coli also varies among different provinces in China. Therefore, empirical treatment should take the aetiological characteristics into account, and guidelines should be developed in consideration of local aetiological characteristics. In terms of drug use, although a variety of quinolones are available in the U.S., most of them have been excluded owing to adverse reactions. This demonstrates that the influence of safety profiles on drug use can never be underestimated. Differences in the intensity of antimicrobial use in different may also play a role in regional differences in guidelines.

3. Clinical application of the novel quinolone, sitafloxacin, in the treatment of urinary tract infection

Sitafloxacin has good antibacterial activity against the major pathogenic bacteria in urinary tract infection, including Escherichia coli and Enterobacteriaceae such as Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis and Enterococcus. Compared to other quinolones, the MIC90 value of sitafloxacin against common bacteria in urinary tract infection is the lowest, indicating that sitafloxacin has the strongest antibacterial activity.⁹ This advantage is owed to the optimisation of the structure of sitafloxacin; this can allow for effective inhibition of the dual targets of DNA gyrase and topoisomerase IV without developing drug resistance.¹⁰

In healthy adults, when taking sitafloxacin (50 mg or 100 mg orally) on an empty stomach in a single dose, approximately 70% of the dose will be excreted via urine as unchanged metabolite within 48 hours after administration. The urinary drug concentration after sitafloxacin administration usually remains at least 5 times higher compared with the MIC90 of Escherichia coli,¹¹ this demonstrates that urine drug concentrations of sitafloxacin are adequate for the treatment of urinary tract infection.

Owing to the broad antibacterial spectrum of sitafloxacin, which covers common causative organisms responsible for urinary tract infection, along with its strong antibacterial activity and high urine drug concentration, sitafloxacin provide a safe and effective treatment for patients with urinary tract infections despite generally high drug resistance. Sitafloxacin is not only highly effective in both outpatient and inpatient treatments, it can also be used in the sequential treatment for inpatients after discharge, which is a real benefit to patients.

References:

1. Chinese Expert Consensus on the Diagnosis and Treatment of Urinary Tract Infections. Chinese Journal of Urology, 2015, 36(4):241–244.
2. Chinese Expert Consensus on the Diagnosis and Treatment of Urinary Tract Infections. Chinese Journal of Urology, 2015, 36(4):245–248.
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9. Instruction on Sitafloxacin in China
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