Individualized Traditional Chinese Medicine treatment vs antibiotics for recurrent urinary tract infections: a multicenter, randomized controlled study

Abstract

OBJECTIVE:

To systematically assess the effects of individualized Chinese medicines on recurrent urinary tract infections (rUTIs).

METHODS:

This study recruited 230 adult female patients in the remission phase of rUTIs from five hospitals in China. The patients were randomly allocated to two groups: an individualized Chinese medicine group (n = 114) and a control group (n = 116). Patients in the Chinese medicine group received individualized Chinese herbs, which were evaluated for syndrome differentiation. Patients in the control group received antibiotic treatment combined with a Chinese medicine placebo. The duration of treatment was three courses of four weeks each, with a three-month subsequent follow-up. UTI recurrence rate, Traditional Chinese Medicine (TCM) syndrome scores, 36-item Short Form Survey (SF-36) score, and urine secretory immunoglobulin A (SIgA) were measured and analyzed before and after treatment in each group.

RESULTS:

Patients from the Chinese medicine group exhibited significant decreases in both short- and long-term UTI recurrence rates compared with the control group (P < 0.05). The changes in TCM syndrome scores between the Chinese medicine and control groups were significant (P < 0.05). The changes in the average SF-36 quality-of-life scores in the Chinese medicine group were also significantly higher than those in the control group after treatment (P < 0.05). The Chinese medicine group also demonstrated a significant increase in urine SIgA expression.

CONCLUSION:

Taken together, compared to the often-used long-term antimicrobial prophylaxis during the remission stage of rUTIs, treating patients with an individualized Chinese medicine decoction by syndrome differentiation could effectively reduce the recurrence rate, improve the patients' TCM syndrome scores and quality of life, and enhance immunity, which in turn helps to prevent antibiotic resistance.

1. INTRODUCTION

Urinary tract infections (UTIs) are common in women, especially during the perimenopausal and post-menopausal stages of life, and are associated with considerable morbidity and healthcare use. The annual incidence of a single UTI is 3%,¹ with up to 44%² of these women experiencing recurrence within one year. Recurrent UTIs (rUTIs) are associated with high economic costs owing to their high incidence.³ rUTIs also have a negative impact on the quality of life of women.⁴ Antibiotics are regarded as the first-line treatment. However, owing to antibiotic resistance, it is increasingly challenging to treat rUTIs. In contrast, Traditional Chinese Medicine (TCM) has unique roles in treating rUTIs, especially in improving patients' quality of life.⁵ In traditional Chinese medical theories, rUTIs are categorized as "Lao Lin," "a deficiency of kidney and bladder heat," "a deficiency of kidney Yin," and “a deficiency of kidney Yang” which are regarded as the pathogenesis of rUTIs.

Our previous studies have suggested the potential effectiveness of Chinese medicine decoctions in relieving symptoms and reducing the recurrence rates in patients with UTI. The mechanisms mainly involve enhanced systemic and mucosal immunity.⁵ According to the fundamental principles of TCM, treatment should be tailored to the individual clinical manifestations of the patient. Thus, this clinical study used a randomized controlled trial to objectively assess the effects of individualized Chinese medicine on rUTIs based on syndrome differentiation. This study will help establish the integration of TCM and modern medical treatment methods to demonstrate their effectiveness against rUTIs.

2. MATERIALS AND METHODS

This was a randomized controlled trial evaluating the efficacy of TCM in rUTIs. This trial was registered on the China Clinical Trial Registration Center website (registration number ChiCTR-TRC-14004739). Ethical approval to conduct this study was obtained from the ethics committee at Yueyang hospital on January 22, 2014. All participants gave informed consent to participate in the study.

2.1. Research patients

A total of 300 eligible patients from the inpatient and outpatient departments of Yueyang Hospital, Longhua Hospital, Shuguang Hospital, Shanghai Municipal TCM Hospital, and Shanghai No. 6 Renmin Hospital were enrolled in this clinical trial between August 2014 and June 2016. A randomized block design was used to recruit patients who met the inclusion criteria and provided informed consent. Patients underwent blind randomization in a 1:1 ratio as the control and Chinese medicine groups. Syndromes were determined after allocation, and the patients were given a TCM decoction or placebo during the treatment period.

2.2. Diagnostic criteria

2.2.1 rUTI diagnostic criteria

The criteria were based on 2018 European Association of Urology guidelines on urological infections for rUTIs: recurrent UTIs (rUTIs) are recurrences of uncomplicated and/or complicated UTIs, with a frequency of at least three UTIs/year or two UTIs in the last six months. Diagnosis of rUTI should be confirmed by urine culture.

2.2.2. Chinese medicine diagnostic criteria

The Chinese medicine diagnostic criteria were fixed according to Chinese internal medicine, Chinese medicine clinical diagnoses, and treatment terminology as follows:

Chinese medicine diagnosis standard (refer to national higher education) 15 national planning teaching material "Chinese medicine internal medicine" in "Lao Lin"): the course of the disease is long, urination pain, but dripping, sour and soft waist and knees, weak pulse.

2.2.3. Inclusion criteria

(a) Consistent with the diagnostic standards of rUTIs; (b) Female aged 18-75 years.

2.2.4. Exclusion criteria

(a) Experienced acute pyelonephritis or first-episode acute UTI; (b) Urinary tract malformation, stone, or hydronephrosis; (c) Overactive bladder; (d) Chronic renal failure with serum creatinine level greater than 442 μmol/L; (e) Pregnant or lactating women; (f) Allergic to the two control medications in this trial; (g) Severely damaged heart, liver, or kidney functions, or other serious underlying diseases such as diabetes mellitus; (h) Severe central nervous system disease; (i) Adjacent organ infection; (j) Surgical history of adjacent organs; (k) Perimenopausal with no record of urine analysis; (l) Neurogenic bladder of any cause.

2.3. Trial treatment

2.3.1. Initial treatment

If diagnosed during a flare-up period of rUTIs, full dosages of antibiotics were utilized to treat the UTI based on experience or urine culture results. After remission, patients were enrolled in the clinical trial and randomized into subgroups.

2.3.2. Subgroup treatment

2.3.2.1. Control group treatment

Levofloxacin (0.1 g) was orally administered (once a night) for four weeks, furadantin (50 mg/pill, 100 mg, once a night, orally) for four weeks, and combination sulfamethoxazole/trimethoprim (1 pill, once a night, orally, each tablet contained sulfisoxazole 400 mg and trimethoprim 80 mg) for four weeks. If the patient was allergic to the aforementioned medication, we chose another single-dose antibiotic and replaced it for every course of treatment. A placebo of TCM (1/10 dose of an essential TCM in granules, processed and produced by Tianjiang Chinese medicine granules) was also used to treat the control group.

2.3.2.2. Individualized Chinese medicine treatment based on syndrome differentiation

Patients took one dose of a Chinese medicine decoction every day. Patients with partial kidney-Yang deficiency were given the Er ding er xian decoction: Xianmao (Rhizoma Curculiginis) 15 g, Yinyanghuo (Herba Epimedii Brevicornus) 15 g, Danggui (Radix Angelicae Sinensis) 15 g, Huangbai (Cortex Phellodendri Amurensis) 15 g, Zhimu (Rhizoma Anemarrhenae) 15 g, Pugongying (Herba Taraxaci Mongolici) 30 g, Zihuadiding (Herba Violae Philippicae) 30 g, and Daxueteng (Caulis Sargentodoxae) composition 30 g.

Patients with partial kidney Yin deficiency were given the nourishing kidney Yin decoction: Taizishen (Radix Pseudostellariae) 15 g, Dihuang (Radix Rehmanniae) 15 g, Niuxi (Radix Achyranthis Bidentatae) 15 g, Yiyiren (Semen Coicis) 15 g, Zhimu (Rhizoma Anemarrhenae) 15 g, Pugongying (Herba Taraxaci Mongolici) 30 g, Zihuadiding (Herba Violae Philippicae) 30 g, and Daxueteng (Caulis Sargentodoxae) composition 30 g.

Based on the syndromes mentioned above, Chinese herbs were added according to the patients’ symptoms.

The treatment duration consisted of a total of three treatment courses of four weeks each.

All drugs were consistent with national quality standards. There were no obvious differences in appearance or odor among the TCM decoctions and placebo groups.

2.4. Outcome

2.4.1. Primary outcome

2.4.1.1. Primary endpoint event

(a) Recurrence of recurrent UTIs (including recurrence or reinfection)

Recurrence was defined as follows: the symptoms disappeared after treatment, bacteriuria reappeared within six weeks after the urinalysis became negative, and the bacteria were the same as the previous infection (same bacteria, same serotype).

Reinfection was defined as follows: the symptoms disappeared after treatment; the urinalysis was negative for bacteria, although bacteriuria reappeared six weeks after the drug was discontinued; and the strain was different from the previous infection.

We checked the patients’ urine routinely every two weeks and urine cultures every four weeks. If the white blood cell count was > 10/high power field or the number of bacterial colonies in the urine culture was >10⁵, it was considered a recurrence.

(b) We considered recurrence rates within three months of the treatment period (recurrent recurrence rate) and recurrence rate (long-term recurrence rate) within three months of outpatient or telephone follow-up after treatment for patients without recurrence within three months.

2.4.2. Secondary outcome

2.4.2.1. Assessment of TCM syndrome scores

The TCM syndrome evaluation involved a questionnaire based on internal Chinese medicine, Chinese medicine clinical diagnoses, and treatment terminologies.

2.4.2.2. Quality-of-life survey

The medical outcome 36-item Short Form Survey (SF-36) was used to analyze seven areas of quality of life: overall health self-assessment; health change; physiological function; and the effect of physical function on role function, mental function, social function, and physical pain. Each score on the quality-of-life scale and the total score on the scale were investigated before and after treatment.

2.4.2.3. Urine secretory immunoglobulin A (SIgA)

SIgA concentration was measured with an enzyme-linked immunoassay kit (MIBO).

2.4.3. Safety measurement

Clinical observations of adverse reactions were recorded in detail and treated in time, including electrocardiogram; routine blood, urine, and stool analysis; fecal occult blood; and liver (alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase levels), and kidney function tests (blood urea nitrogen and serum creatinine levels). A safety check was also performed before and after the treatment.

2.5. Statistical methods

Statistical analyses were performed using SPSS 18.0 (SPSS Inc., Chicago, IL, USA). All statistical tests were two-sided, and a P value < 0.05 was considered statistically significant. In the balance analysis of the essential value, we used the t-test, χ² test, and rank sum test to compare demographic data and other basic value indicators to measure the balance between the two groups. A paired t-test was used to compare the groups before and after treatment. The Wilcoxon rank-sum test was used for normal distribution, and the Mann-Whitney U test was used for the analysis of the curative effect grade data of the two groups.

3. RESULTS

3.1. Demographic and clinical characteristics

A total of 230 subjects, comprising 114 and 116 subjects in the two groups, respectively, completed this study. The details are shown in the trial flow chart in Figure 1. The demographics of the UTI patients are shown in Table 1. The average age and disease duration were not significantly different between the two groups.

Figure 1. CONSORT flow diagram.

Table 1.

Demographics of Chinese medicine group compared to controls (P25, P75)

Group	n	Age (years)	Disease course (months)
Chinese medicine	114	61.00 (55.50, 64.00)	54.00 (33.00, 125.00)
Control	116	60.00 (56.00, 66.00)	45.00 (25.00, 121.00)
P value		0.956	0.437

Notes: Chinese medicine group: Chinese medicine decoction treatment combined with antibiotics for a total of three treatment courses of four weeks each. Control group: antibiotics with placebo Chinese herb granules for a total of three treatment courses for four weeks each. Data were presented as median (Q25, Q75).

3.2. Comparison of 12-week short-term recurrence rates

The 12-week short-term recurrence rate was first observed between the two groups. As a result, the Chinese medicine group had significantly fewer cases of rUTI, with a 15.79% recurrence rate (18 out of 114 patients) versus 26.72% (31 out of 116 patients) in the control group.

3.3. Comparison of 3-month long-term recurrence rates

After 12 weeks of treatment, the patients refrained from any more treatments for another three months. The results showed that the 3-month long-term recurrence rate in the Chinese medicine group was significantly lower than in the control group (11.46% vs 42.35%).

3.4. Complete remission rate of UTIs

We also calculated the complete remission rate of patients after twelve weeks of treatment and three months of follow-up. We found that 85 patients in the Chinese medicine group and 49 patients without a UTI diagnosis in the control group no longer developed rUTIs within this six-month period (Table 2).

Table 2.

Complete remission rate of UTI

Group	n	No recurrent cases (n)	Recurrent cases within 12 weeks (n)	Recurrent cases during follow-up (n)	CR rate (%)
Chinese medicine	114	85	18	11	74.56a
Control	116	49	31	36	42.24

Notes: Chinese medicine group: Chinese medicine decoction treatment combined with antibiotics for a total of three treatment courses of four weeks each. Control group: antibiotics with placebo Chinese herb granules for a total of three treatment courses for four weeks each. UTI: Urinary tract infection. CR: Complete remission. ^aP < 0.05 Chinese medicine group vs Control group (χ ² test).

3.5. Changes in baseline TCM syndrome scores

We also assessed the TCM syndrome scores of patients before and after the twelve-week treatment period. The TCM syndrome scores were comparable at baseline, and after treatment, the TCM syndrome scores in both groups decreased significantly. Furthermore, the changes in the TCM syndrome scores between the two groups were statistically significant (P < 0.05) (Table 3).

Table 3.

Changes in TCM syndrome scores from baseline ($\overline{\mathrm{x}} \pm s$)

Group	n	Scores before	Scores after	Changes in TCM syndrome score
Chinese medicine	96	10.4±3.8	3.6±2.6a	6.8±2.9b
Control	85	9.7±3.3	5.5±3.6a	4.2±2.4

Notes: Chinese medicine group: Chinese medicine decoction treatment combined with antibiotics for a total of three treatment courses of four weeks each. Control group: antibiotics with placebo Chinese herb granules for a total of three treatment courses for four weeks each. TCM: Traditional Chinese Medicine. Data were presented as mean ± standard deviation. ^aP < 0.05 after treatment vs before treatment; ^bP < 0.05 Chinese medicine group vs Control group (paired sample t-test or two independent sample t-test).

3.6. Changes in SF-36 scores

Furthermore, we also analyzed the SF-36 quality-of-life scores of patients with rUTIs before and after treatment. The SF-36 scores were also comparable at baseline in both groups. Consistent with a previous study, the SF-36 scores in both groups increased significantly after treatment compared with before treatment. We also observed that the Chinese medicine group had significant increases in changes in SF-36 scores compared with the control group (Table 4).

Table 4.

SF-36 score before and after treatment ($\overline{\mathrm{x}} \pm s$)

Groups	n	Scores before	Scores after	Changes in SF-36 score
Chinese medicine	96	59.6±4.7	63.6±2.3a	4.0±4.1b
Control	85	59.4±4.3	61.3±3.6a	1.9±3.9

Notes: Chinese medicine group: Chinese medicine decoction treatment combined with antibiotics for a total of three treatment courses of four weeks each. Control group: antibiotics with placebo Chinese herb granules for a total of three treatment courses for four weeks each. SF-36: 36-item Short Form Survey. Data were presented as mean ± standard deviation. ^aP < 0.05 after treatment vs before treatment; ^bP < 0.05 Chinese medicine group vs Control group (paired sample t-test or two independent sample t-test).

3.7. Urine SIgA level before and after treatment

To understand whether the Chinese medicine decoction could enhance the immunity of rUTI patients, we assessed urine SIgA expression in both groups before and after treatment. The results showed that both groups exhibited significant increases in SIgA expression after treatment compared with before treatment. The SIgA expression level was remarkably elevated in the Chinese medicine group compared with the control group after treatment. These results indicate that Chinese medicine may play an important role in immune regulation (Table 5).

Table 5.

Urine SIgA before and after treatment (ng/mL)

Group	n	Before treatment	After treatment
Chinese medicine	40	0.54±0.24	1.12±0.35a
Control	34	0.62±0.32	0.87±0.48a

Notes: Chinese medicine group: Chinese medicine decoction treatment combined with antibiotics for a total of three treatment courses of four weeks each. Control group: antibiotics with placebo Chinese herb granules for a total of three treatment courses for four weeks each. SIgA: secretory immunoglobulin A. Data were presented as mean ± standard deviation ^aP < 0.05 after treatment vs before treatment (paired sample t-test).

4. DISCUSSION

UTIs are one of the most common types of bacterial infections secondary to respiratory infections.⁶ Due to anatomical and physical defects, the UTI incidence rate in women is remarkably higher than that in men. It is estimated that at least half of all adult women may experience at least one UTI during their lifetime, especially during the sexually active, gestational, or postmenopausal periods.^7,⇓-9 Furthermore, more than one-third of older women may develop rUTIs.¹⁰ However, clinicians often regard UTIs as a minor issue because of their high recovery rates. From the patients’ perspective, symptomatic rUTIs greatly impact their quality of life. Using the SF-36 health survey, studies have also confirmed that patients with recurrent acute uncomplicated UTIs had significantly lower quality of life scores in seven of eight SF-36 domains than those of healthy individuals.¹¹

Currently, guidelines strongly recommend long-term, low-dose antibiotics for the treatment of rUTIs in adult women.¹² Although antibiotics are reasonably effective, the long-term and repeated use of antibiotics inevitably results in strong bacterial resistance, and withdrawal of antimicrobial prophylaxis causes relapse of UTIs.¹³ This has led clinicians to explore non-antibiotic options for rUTI prevention. Thus, some alternative approaches have been used to manage rUTIs, including intake of cranberry supplements and oral immunostimulation with OM-89 (bacterial extracts of E. coli). Previous evidence supports the use of cranberry supplements as a treatment option for rUTIs in women. However, recent studies have failed to identify the protective values.

Chinese medicine treatment strategies for UTIs are promising.¹⁴ In TCM theories, rUTIs could be categorized as "Lao Lin," "a deficiency of kidney and bladder heat," "a deficiency of kidney Yin," and “a deficiency of kidney Yang” which are regarded as the pathogenesis of rUTIs. Some studies have shown that acupuncture may be useful in preventing rUTIs.¹⁵ A Meta-analysis comprising seven randomized controlled trials of Chinese medicine treatment comprising 542 women, showed that active Chinese medicine treatments formulated explicitly for rUTIs were more effective in reducing infection incidence than generic Chinese herbal medicine treatments that were more commonly used for acute UTIs (relative risk: 0.40, 95% confidence interval: 0.21-0.77.¹⁶ In our study, we used syndrome differentiation to treat patients with a Chinese medicine decoction for individualized precise treatment. The results showed that the recurrence rate of UTIs decreased significantly in the Chinese medicine group compared with the control group. We also focused on patients’ quality of life. Using the SF-36, we found that Chinese medicine treatment greatly improved the quality of life of patients with rUTI. To further understand the possible mechanism, we used urine SIgA expression as a marker to assess the immunity of patients. Increased secretion of SIgA plays an essential role in the resistance of pathogens in the urinary tract.¹⁷ We found that SIgA expression was significantly elevated in the Chinese medicine group compared to that in the control group. Administration of a Chinese medicine decoction may increase SIgA secretion, indicating the role of Chinese medicine in enhancing systemic immunity. In vivo studies¹⁸ have demonstrated that Chinese medicine decoctions may prevent and reduce UTI occurrence through the inhibition of toll-like receptor 4 signaling in rats. An in vitro study also showed that Chinese herbal solutions had a significant effect on bacterial growth rates and markedly reduced bacterial adherence.¹⁹ Another study also indicated that Chinese herbs may have an anti-inflammatory effect via the NF-kB and apoptosis pathways in UTI.²⁰ As an alternative treatment, Chinese herbs may regulate immunity through different pathways; In addition, Chinese herbs may also regulate the endocrinology to reduce recurrence rates of UTI. Some phytoestrogens, such as icariin(ingredient of Epimedium), have been shown to increase estradiol levels and increase uterine weight in female rats.²¹ Estrogen deficiency may lead to vaginal and urethral mucosal atrophy, capillary damage, direct reduction of immunoglobulin secretion.²² Vaginal oestrogen replacement has shown a trend towards preventing rUTI in post-menopausal women. It may also explain the effect of Chinese herb on reducing the rUTI recurrence rates. However, rigorous studies are still needed to further illustrate the mechanisms in vivo and in vitro.

This study had some limitations. First, we did not include a standardized TCM group to better identify individualized TCM that could improve patients’ symptoms and reduce the recurrence rate of rUTIs. Second, we were not able to collect SIgA data from all patients, which may have affected the results.

In conclusion, this multicenter randomized trial was conducted to identify whether an individualized Chinese medicine decoction guided by syndrome differentiation effectively reduced UTI recurrence. In this study, we show that syndrome differentiation-based Chinese medicine decoction treatment improved patients' quality of life and reduced the recurrence rate of rUTIs, which provides reliable clinical data to confirm that Chinese medicine has an effective role in rUTI treatment.