Acute uncomplicated cystitis: is antibiotic unavoidable?

Abstract

Background:

Acute uncomplicated cystitis in women is one of the most frequently diagnosed bacterial infections.

Methods:

In a pilot, open, noncomparative prospective study, 29 nonpregnant, sexually active women with acute uncomplicated cystitis were enrolled. The mean age was 28.9 ± 4.3, range 22–36 years. All patients received unique therapy: the nonsteroidal anti-inflammatory drug (NSAID) ketoprofen, 100 mg once a day for 5 days, and Canephron, 2 dragees three times a day for 1 month.

Results:

In 2 days, four patients (13.8%) had no tendency to improvement; they were considered as nonresponders and antibiotics were prescribed for them. The remaining 25 patients (86.2%) showed significant improvement and were considered as responders; they continued the therapy with ketoprofen and Canephron. In 7 days, 21 patients (72.4%) had no dysuria and leucocyturia; they were considered as fast responders to phytotherapy. In four patients (13.8%), after 7 days of therapy insignificant dysuria and leucocyturia were found; they were considered as slow responders to phytotherapy. All 25 patients continued the intake of Canephron for 1 month to prevent a relapse. When treatment finished, all patients were well. In 6 months, no relapses were diagnosed.

Conclusion:

The majority (86.2%) of young, nonpregnant women with acute uncomplicated cystitis were cured by 30 days of phytotherapy combined initially (5 days) with the NSAID ketoprofen; an antibiotic was indicated in only 13.8% of patients. Patients with acute uncomplicated cystitis may be divided into three subgroup: nonresponders to phytotherapy; slow responders to phytotherapy; fast responders to phytotherapy. Antibiotic therapy is indicated in nonresponders, but slow and fast responders may be treated without an antibiotic, by phytotherapy with an initial short course of an NSAID only.

Introduction

Acute uncomplicated cystitis (AUC) is a common disease. It is considered as a benign disease, but standard antimicrobial treatment may fail. Since cystitis is prone to recurrence, women receive several courses of antibiotics annually. Overuse of antibiotics leads to the selection of resistant strains and contributes to frequent development of side effects of antibiotic therapy.^1,2 The results of a recent study suggested that first-line antimicrobials might show poor efficacy in cases of unresolved AUC and alternative therapy should be considered in these cases.³ Uropathogens, causing AUC, have a good sensitivity rate for fosfomycin and nitrofurantoin in vitro, but have variable resistance to ciprofloxacin, trimethoprim/sulfamethoxazole and to amoxicillin/clavulanic acid.⁴ Nitrofurantoin remains a key oral antibiotic stewardship program option in the treatment of AUC. But nitrofurantoin is not recommended if creatinine clearance is less than 60 ml/min.⁵ Significantly greater susceptibility of Escherichia coli to cefazolin (87.0%), trimethoprim/sulfamethoxazole (89.4%) and levofloxacin (84.6%) was found in outpatients with AUC in Japan.⁶ Multivariate analysis has shown that two or more episodes of cystitis within the past year were associated with levofloxacin resistance of E. coli in female patients with AUC (p = 0.004).⁷ Longer treatment of cystitis was not associated with lower recurrence rates. On the contrary, there was a higher risk of early recurrence in female patients with AUC when antibacterial treatment duration was more than 5 days.⁸ Fluoroquinolone-resistant E. coli isolated from patients with AUC is a matter of increasing concern.⁹ The main solution to the global antibiotic resistance crisis is reducing the volume of antibiotic use in medicine.¹⁰ To evaluate changes in fluoroquinolone and nitrofurantoin resistance among E. coli isolates in outpatients with AUC, two periods were compared. First, when fluoroquinolones were recommended as first-line therapy, and second, when nitrofurantoin was recommended for AUC empirical therapy. There was a significant decrease in fluoroquinolone-resistant E. coli of −0.4% per quarter [95% confidence interval (CI) −0.6% to −0.1%; p = 0.004] between these periods.¹¹ Trimethoprim should be indicated in the third-line empirical treatment of AUC (sparing fluoroquinolones and nitrofurantoin), in the prevention of recurrent acute cystitis when an antibiotic prophylaxis is required, and in the treatment of documented acute cystitis with the risk of complications.¹² The increasing prevalence of resistant uropathogens, including extended-spectrum β lactamases, carbapenemase-producing Enterobacteriaceae, and other multidrug-resistant Gram-negative organisms, further compromise treatment of urinary tract infections.¹³ Antibiotic therapy is standard for AUC and common for asymptomatic bacteriuria, but definite benefits are few. ‘Urinary tract infection’ too often can lead to marked, harmful antibiotic overtreatment.¹⁴ If bacteriuria and specific for AUC, symptoms may disappear spontaneously.¹⁴ In addition, antibiotics for acute cystitis therapy have adverse effects at a rate of up to 21.6%,¹⁵ therefore we have to look for alternative treatment, for example with phytotherapy. A recent randomized, prospective, double-dummy, double-blind trial compared the efficacy and safety of a herbal combination containing Tropaeoli majoris herba and Armoraciae rusticanae radix with co-trimoxazole in patients with AUC in 26 centers in Germany. The trial demonstrated comparable efficacy of the herbal combination (horseradish root and nasturtium herb) and the antibiotic (co-trimoxazole), although noninferiority was not proved.¹⁶

The purpose of our study was to estimate the results of nonantibiotic therapy for patients with AUC. The design was a pilot, open, noncomparative, prospective study.

Material and methods

Twenty-nine women with AUC were enrolled in the study. The mean age was 28.9 ± 4.3, range 22–36 years. The inclusion criteria were as follows:

1. Diagnosis of AUC.

2. Nonpregnant, sexually active women of reproductive age;

3. Use of optimal contraception; the fact there is a correlation between sexual activity as well as method of contraception and frequency of cystitis is well known. Condoms and spermicides provoke relapse of cystitis,^17–19 while patients who prefer oral contraceptives have significantly rarer recurrence of the disease.²⁰

4. Duration of the disease should not be longer than 12 h. The patient must consult a doctor within 1–12 h after the appearance of the first symptoms of cystitis. We consider a duration of cystitis of more than 12 h as a complicating factor.

5. Signed an informed consent form.

The exclusion criteria were as follows:

1. Use of condoms or spermicides.

2. Pregnancy or lactation.

3. Menopause.

4. Consumption of even one dose of any antibiotic for any reason within 10 days of study inclusion.

5. Symptoms suspicious for pyelonephritis (flank pain, febrile body temperature, intoxication).

6. Presence of complicating factors (comorbidity with diabetes mellitus, urinary tract anomalies, trauma or surgical intervention of pelvic organs, pelvic prolapse).

7. Duration of disease of more than 12 h.

Unique treatment was prescribed to all patients. Therapy consisted of the following: the nonsteroid anti-inflammatory drug (NSAID) ketoprofen, 100 mg daily for 5 days; and the phytotherapeutic drug, Canephron N (Bionorica, Germany), containing the medicinal plants Centaurium erythraea, Levisticum of cinale, and Rosmarinus of cinalis, two dragees three times a day for 1 month. Efficiency criteria were as follows: disappearance of dysuria, normal urinalysis and abacteriuria.

Diagnosis was first performed using symptoms, physical examination and anamnesis, and this was confirmed in 1–2 days by laboratory investigation results: urinalysis and microbiological test. We analyzed the spectrum of uropathogens and their susceptibility. Matrix assisted laser desorption/ionization time of flight mass spectrometry was used for microbial typing and identification at the subspecies level. Rapid identification was made on Phoenix (Becton Dickinson, USA), which was located in Microbiological Laboratory of Novosibirsk Research TB Institute. For antimicrobial susceptibility testing, the Phoenix 100 (Becton Dickinson USA) was used too.

There were five visits. For the first visit, screening was performed and inclusion and exclusion criteria were evaluated. If the patient was included, she was enrolled in the study, laboratory tests were performed and unique therapy started. The second visit was after 2 days of therapy when patients visited the doctor again to estimate the tolerance and primary efficiency of the treatment. The third visit was in 7 days. This visit aimed to estimate the immediate results of the therapy. The fourth visit was in 1 month to evaluate the final results of the therapy. The fifth visit was in 6 months for follow up to reveal a possible relapse.

Results

We estimated the results step by step, on each visit.

First visit (baseline, before therapy)

All women presented with dysuria; eight of them also had terminal hematuria. All patients had abnormal urinalysis: the number of leucocytes in the urine was at least 15 cells. All samples of middle-stream urine were sent for bacteriological investigations.

Second visit (2 days of Canephron plus ketoprofen)

Bacteriuria (growth of uropathogen, 10⁴ colony-forming units/ml or more) was found in all patients: E. coli in 19 (65.5%) patients, Klebsiella spp. in 5 (17.2%), Enterobacter spp. in 3 (10.3%), and Acynetobacter spp. in 2 (6.9%).

E. coli was resistant to amoxicillin/clavulonat in 54.5%, to cefotaxim in 54.5%, to gentamycin in 45.5%, to ciprofloxacin in 63.6%, to levofloxacin in 54.5%, and to nitrofurantoin in 18.2%. Other uropathogens also had resistance to the main antibiotics at a high level (28.2–47.4%).

Four patients (13.8%) had the same symptoms after 2 days of phytotherapy. They were considered as nonresponders and an antibiotic (fosfomycin) was prescribed for them; they were excluded from the study. But another 25 (86.2%) patients demonstrated a significant decrease in the intensity of dysuria and they continued to receive ketoprofen and Canephron N. After 3 days, the course of ketoprofen was finished and monotherapy with Canephron N only continued. Tolerance of the therapy was good; no adverse effects were noted.

Third visit (7 days of therapy)

In 7 days, 21/29 (72.4%) patients were well, had no complaints, and their urinalyses were also normal. These patients were considered as fast responders. Nevertheless, all patients continued to take Canephron N for 1 month with the aim of preventing a relapse. Four patients (13.8% of cohort) demonstrated insignificant leucocyturia and mild dysuria on this visit; they also showed a low level of bacteriuria (Enterobacter spp. 10² CFU/ml). These patients were considered as slow responders. They also continued consumption of Canephron N as monotherapy.

Fourth visit (1 month course of treatment completed)

In 1 month, 25 patients were responders. They were well, had no complaints, their urinalyses were normal and there was no bacteriuria. Among all responders, 84.0% with AUC showed a fast response and 16.0% showed a slow response. In both groups, 1 month of phytotherapy with Canephron N in combination with ketoprofen for the first 5 days resulted in recovery. Tolerance of the therapy was good.

Fifth visit (follow up 6 months after end of treatment)

A visit was made 6 months after the end of therapy for follow up. All 25 patients remained well, had no complaints, their urinalyses were normal and there was no bacteriuria.

Thus, none of the young women with AUC who responded to phytotherapy with Canephron had a relapse of the disease, while after antibiotic therapy, relapse developed in about half of patients.²¹

Discussion

Urinary tract infections are an economic burden for public health.²² The extensive and sometimes irrational use of antibiotics for the treatment of AUC has led to an increase in multiresistant uropathogens in recent years.²¹ Actually there is a crisis of antibiotic therapy for AUC, and nonantibiotic approaches to urinary tract infections are of great interest.²¹

There are several nonantimicrobial options for management of such patients, including behavioral factors.²³ A multicenter clinical study revealed good efficacy and tolerability of a new dietary supplement containing Vaccinium macrocarpon and propolis extract in the treatment and prevention of urinary disorders in peri- and postmenopausal women.²⁴ A recent study demonstrated good results for phytotherapy (berberine, arbutin, birch and forskolin) in patients with recurrent cystitis; this therapy resulted in a lower incidence of relapses.²⁵

With new therapeutic concepts, the treatment of the inflammatory (over)reaction of the host rather than the elimination of bacteria is highlighted.²⁶ This was the reason for a randomized, controlled, double-blind trial investigating whether treatment of cystitis with a NSAID is as effective as an antibiotic in achieving symptomatic resolution. Female patients with AUC received 600 mg of ibuprofen three times a day or 200 mg mecillinam three times a day for three days. The authors stated that treatment of AUC with ibuprofen is as effective as mecillinam for symptom relief, but they did not report objective symptoms, such as leucocyturia and growth of uropathogens, as well as frequency of relapses.²⁷

In another study, efficiency of ibuprofen and ciprofloxacin was compared, again by subjective symptoms. On day 4, 58.3% of patients in the ibuprofen group were symptom free versus 51.5% in the ciprofloxacin group. Every third patient in the ibuprofen group had to start antibiotic treatment due to ongoing or worsening symptoms.²⁸

Thus, NSAIDs may relieve symptoms via an anti-inflammatory effect, but monotherapy with NSAID does not have an impact on the cause of the disease, the uropathogen. However, a combination of an NSAID and phytotherapy provides very fast pain and dysuria relief, as well as having an antibacterial effect.

A meta-analysis of five randomized controlled trials of antibiotics versus placebo in the treatment of women with uncomplicated cystitis has shown that antibiotics are superior to placebo in achieving clinical and microbiological success in adult nonpregnant women with microbiologically confirmed AUC. However, they are associated with more adverse events.²⁹

Kurt Naber estimated the efficacy and safety of the phytotherapeutic drug Canephron N in the prevention and treatment of urogenital and gestational disease by review of clinical experience in Eastern Europe and Central Asia. All studies concluded that a combination of Canephron with an antibiotic was more efficient than monotherapy with an antibiotic.³⁰ Using Canephron in a complex therapy of diabetic nephropathy also showed good results. After 6 months of therapy, the level of microalbuminuria decreased significantly. Canephron had a positive effect on the antioxidant defense status and lipid peroxidation levels. The authors reported excellent tolerability of this phytotherapy.³¹ The high efficiency of Canephron was confirmed in other studies.^32,33

An open-label, noncontrolled, multicenter, interventional trial to investigate the safety and efficacy of Canephron in the management of uncomplicated urinary tract infections demonstrated the responder rate to be 71.2 % on day 7 and 85.6 % on day 37, with a significant improvement in all symptoms (all p < 0.001). Only 2.4 % of patients required antibiotics during the treatment period and none of the patients met the definition of recurrence until day 37.³⁴

Thus, many authors have made attempts to avoid antibiotics for patients with AUC, but the optimal approach still is unclear. Our study is small but its results are promising, and further investigations in this field are needed.

Conclusion

The majority (86.2%) of young nonpregnant women with acute uncomplicated cystitis were cured by 30 days of phytotherapy combined initially (5 days) with the NSAID ketoprofen; antibiotic use was indicated in only 13.8% of patients.

Patients with acute uncomplicated cystitis may be divided into three subgroups: nonresponders to phytotherapy; slow responders to phytotherapy; and fast responders to phytotherapy. Antibiotic therapy is indicated in nonresponders, but both slow and fast responders may be treated by phytotherapy with an initial short course of an NSAID, without an antibiotic.