Effect of a Herbal Therapy on Clinical Symptoms of Acute Lower Uncomplicated Urinary Tract Infections in Women: Secondary Analysis from a Randomized Controlled Trial

Winfried Vahlensieck, Horst Lorenz, Anne Schumacher-Stimpfl, Roland Fischer, Kurt G Naber, Winfried Vahlensieck, Horst Lorenz, Anne Schumacher-Stimpfl, Roland Fischer, Kurt G Naber

Abstract

Background: Antibiotics are commonly used as first-line treatment for acute lower uncomplicated urinary tract infections (uUTIs). However, antimicrobial resistance is a growing global problem and efficacious nonantibiotic treatment options are urgently needed.

Methods: A secondary analysis was conducted with data from a randomized, controlled, double-blind trial comparing a fixed combination of extracts of restharrow root, Java tea, and goldenrod herb (Aqualibra®) to placebo in 200 women with acute lower uUTI. Symptom scores reported in the original trial were reanalyzed and adjusted to the definitions of the Acute Cystitis Symptom Score (ACSS).

Results: Based on a subgroup of patients with evaluable microbiologic data (n = 122), the decrease of the mean sum-score of three typical ACSS-adjusted symptoms showed significant superiority of the herbal preparation over placebo already after one day of treatment (p = 0.0086); on Day 7, the average difference was -1.9 score points (p < 0.0001). The superior efficacy of the herbal preparation on Day 1 was mainly driven by a difference in response rates of the symptom 'dysuria' (group difference: -29.4%, p = 0.0042). Furthermore, significantly fewer patients in the verum group required antibiotic therapy (15.3% vs. 49.2%, p = 0.0001). These results were confirmed in the intention-to-treat (ITT) population (n = 200).

Conclusions: A fixed combination of extracts of restharrow root, Java tea, and goldenrod herb was superior to placebo regarding symptom relief and prevention of antibiotic use in women with lower uUTI.

Trial registration: ClinicalTrials.gov: NCT04032574.

Keywords: ACSS; Acute Cystitis Symptom Score; herbal treatment; patient-reported outcomes; symptomatic treatment; urinary tract infection.

Conflict of interest statement

The clinical trial and the present paper were sponsored by Medice Arzneimittel Pütter GmbH & Co. KG, Germany. Medice Arzneimittel Pütter GmbH & Co. KG provided writing and editorial support for this publication. Although the sponsor was involved in the planning and design of the present study and has contributed to the development of the present manuscript, the final decision to submit the paper for publication was made by the authors independently.K.G.N. reports personal consulting fees from Medice Arzneimittel Pütter GmbH & Co. KG during the analysis of the study, and personal fees outside the submitted work from Adamed, Allecra, Apogepha, Aristo, Bionorica SE, Biomerieux, Enteris, GSK, Gruenenthal Mexico, Helperby, Hermes, MerLion, MSD Sharp & Dohme, OM Pharma/Vifor, Paratek, Roche, Saxonia, and Zambon.W.V. reports personal consulting fees from Medice Arzneimittel Pütter GmbH & Co. KG during the analysis of the study, and personal fees outside the submitted work from Bene, Bionorica, Congress Communication Consulting, CGC Cramer, Fischerappelt, Fresenius, Gilead, Infectopharm, MDS, MedConcept, Mediconomics, MIM-Verlag, Omega/Abtei, Pfleger, Repha, Springer-Verlag, Strathmann, and Uromed. A.S.S. and R.F. report employment at Medice Arzneimittel Pütter GmbH & Co. KG.

Figures

Figure 1
Figure 1
Comparison of mean sum-scores of the Acute Cystitis Symptom Score (ACSS)-adjusted ‘typical domain’ symptoms from Day 0 to Day 7 in the (A) population of patients with evaluable microbiologic data (microPP) and (B) intention-to-treat (ITT) population (Wilcoxon’s 2-sample test).
Figure 2
Figure 2
Proportion of patients achieving improvement by at least one point for an individual ACSS-adjusted symptom in the (A) microPP and (B) ITT population (chi-squared test).
Figure 3
Figure 3
Proportion of “clinically cured” patients (defined as patients who had a total ACSS-adjusted score below 3 and no individual ACSS-adjusted symptom score above 1) on Day 7 in the microPP and ITT population (chi-squared test).
Figure 4
Figure 4
Proportion of patients who were prescribed additional antibiotic therapy on Day 1 or Day 7 in the microPP and ITT population (chi-squared test).

References

    1. Foxman B. The epidemiology of urinary tract infection. Nat. Rev. Urol. 2010;7:653–660. doi: 10.1038/nrurol.2010.190.
    1. The European Association of Urology (EAU) Guidelines. Edn. Presented at the EAU Annual Congress Copenhagen. 978-94-92671-01-1 [(accessed on 10 October 2019)];2018 Available online:
    1. Goossens H., Ferech M., Vander Stichele R., Elseviers M., ESAC Project Group Outpatient antibiotic use in Europe and association with resistance: A cross-national database study. Lancet. 2005;365:579–587. doi: 10.1016/S0140-6736(05)70799-6.
    1. Tandogdu Z., Cek M., Wagenlehner F., Naber K., Tenke P., van Ostrum E., Johansen T.B. Resistance patterns of nosocomial urinary tract infections in urology departments: 8-year results of the global prevalence of infections in urology study. World J. Urol. 2014;32:791–801. doi: 10.1007/s00345-013-1154-8.
    1. Schito G.C., Naber K.G., Botto H., Palou J., Mazzei T., Gualco L., Marchese A. The ARESC study: An international survey on the antimicrobial resistance of pathogens involved in uncomplicated urinary tract infections. Int. J. Antimicrob. Agents. 2009;34:407–413. doi: 10.1016/j.ijantimicag.2009.04.012.
    1. Kahlmeter G., ECO.SENS An international survey of the antimicrobial susceptibility of pathogens from uncomplicated urinary tract infections: The ECO.SENS Project. J. Antimicrob. Chemother. 2003;51:69–76. doi: 10.1093/jac/dkg028.
    1. Leitlinienprogramm, DGU AWMF: Interdisziplinäre S3 Leitlinie: Epidemiologie, Diagnostik, Therapie, Prävention und Management Unkomplizierter, Bakterieller, Ambulant Erworbener Harnwegsinfektionen bei Erwachsenen Patienten. Kurzversion 1.1.-2. 2017 AWMF Registernummer: 043/044. [(accessed on 4 December 2019)]; Available online: .
    1. Kronenberg A., Butikofer L., Odutayo A., Muhlemann K., da Costa B.R., Battaglia M., Meli D.N., Frey P., Limacher A., Reichenbach S., et al. Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: Randomised, double blind trial. BMJ. 2017;359:j4784. doi: 10.1136/bmj.j4784.
    1. Gagyor I., Bleidorn J., Kochen M.M., Schmiemann G., Wegscheider K., Hummers-Pradier E. Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: Randomised controlled trial. BMJ. 2015;351:h6544. doi: 10.1136/bmj.h6544.
    1. Vik I., Bollestad M., Grude N., Baerheim A., Damsgaard E., Neumark T., Bjerrum L., Cordoba G., Olsen I.C., Lindbæk M. Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women—A double-blind, randomized non-inferiority trial. PLoS Med. 2018;15:e1002569. doi: 10.1371/journal.pmed.1002569.
    1. Afshar K., Fleischmann N., Schmiemann G., Bleidorn J., Hummers-Pradier E., Friede T., Wegscheider K., Moore M., Gágyor I. Reducing antibiotic use for uncomplicated urinary tract infection in general practice by treatment with uva-ursi (REGATTA)—A double-blind, randomized, controlled comparative effectiveness trial. BMC Complement. Altern. Med. 2018;18:203. doi: 10.1186/s12906-018-2266-x.
    1. Wagenlehner F.M., Abramov-Sommariva D., Holler M., Steindl H., Naber K.G. Non-Antibiotic Herbal Therapy (BNO 1045) versus Antibiotic Therapy (Fosfomycin Trometamol) for the Treatment of Acute Lower Uncomplicated Urinary Tract Infections in Women: A Double-Blind, Parallel-Group, Randomized, Multicentre, Non-Inferiority Phase III Trial. Urol. Int. 2018;101:327–336.
    1. European Medicines Agency Assessment Report on Orthosiphon stamineus Benth., folium. [(accessed on 4 December 2019)];2011 Available online: .
    1. European Medicines Agency Assessment Report on Ononis spinosa L., radix. [(accessed on 4 December 2019)];2014 Available online: .
    1. European Medicines Agency Assessment Report on Solidago virgaurea L., herba. [(accessed on 4 December 2019)];2008 Available online: .
    1. Sarshar S., Asadi Karam M.R., Habibi M., Bouzari S., Qin X., Goycoolea F.M., Brandt S., Hensel A. Cytoprotective and antiadhesive effects of aqueous leaf extract from Orthosiphon aristatus against uropathogenic E. coli. Planta Med. 2016;81:S1–S381. doi: 10.1055/s-0036-1596551.
    1. Sarshar S., Brandt S., Asadi Karam M.R., Habibi M., Bouzari S., Lechtenberg M., Dobrindt U., Qin X., Goycoolea F.M., Hensel A. Aqueous extract from Orthosiphon stamineus leaves prevents bladder and kidney infection in mice. Phytomedicine. 2017;28:1–9. doi: 10.1016/j.phymed.2017.02.009.
    1. Fischer R., Kotzolt B. Therapie unkomplizierter Harnwegsinfektionen mit einem pflanzlichen Aquaretikum: Ergebnisse einer offenen Verlaufsstudie. Der Kassenarzt. 1998;38:39–43.
    1. Fischer R., Kühnau S., Widey K.D., Braun R. Wirksamkeit einer Phytotherapeutikakombination bei Harnwegsinfekten. Der Allgemeinarzt. 1994;11:863–869.
    1. EMA Guideline on the Evaluation of Medicinal Products Indicated for Treatment of Bacterial Infections, Rev 3 Draft. [(accessed on 4 December 2019)];2018 Available online: .
    1. FDA Uncomplicated Urinary Tract Infections—Developing Drugs for Treatment. Guidance for Industry. [(accessed on 4 December 2019)];2019 Available online: .
    1. Alidjanov J.F., Naber K.G., Abdufattaev U.A., Pilatz A., Wagenlehner F.M.E. Reevaluation of the Acute Cystitis Symptom Score, a Self-Reporting Questionnaire. Part I. Development, Diagnosis and Differential Diagnosis. Antibiotics. 2018;7:6. doi: 10.3390/antibiotics7010006.
    1. Alidjanov J.F., Naber K.G., Abdufattaev U.A., Pilatz A., Wagenlehner F.M. Reevaluation of the Acute Cystitis Symptom Score, a Self-Reporting Questionnaire. Part II. Patient-Reported Outcome Assessment. Antibiotics. 2018;7:43. doi: 10.3390/antibiotics7020043.
    1. Alidjanov J.F., Naber K.G., Pilatz A., Radzhabov A., Zamuddinov M., Magyar A., Tenke P., Wagenlehner F.M. Evaluation of the draft guidelines proposed by EMA and FDA for the clinical diagnosis of acute uncomplicated cystitis in women. World J. Urol. 2019 doi: 10.1007/s00345-019-02761-3.
    1. Alidjanov J.F., Naber K.G., Pilatz A., Radzhabov A., Zamuddinov M., Magyar A., Tenke P., Wagenlehner F.M. Additional assessment of Acute Cystitis Symptom Score questionnaire for patient-reported outcome measure in female patients with acute uncomplicated cystitis: Part II. World J. Urol. 2019 doi: 10.1007/s00345-019-02948-8.
    1. Alidjanov J.F., Lima H.A., Pilatz A., Pickard R., Naber K.G., Safaev Y.U., Wagenlehner F.M. Preliminary Clinical Validation of the English Language Version of the Acute Cystitis Symptom Score. [(accessed on 4 December 2019)];JOJ Urol. Nephron. 2017 1:55561. Available online: .
    1. Diggle P.J., Heagerty P., Liang K., Zeger S.L. Analysis of Longitudinal Data. 2nd ed. Oxford University Press; Oxford, UK: 2005.
    1. Pocock S.J. Clinical Trials, A Practical Approach. Wiley; Hoboken, NJ, USA: 1991. pp. 50–63, 187–242.
    1. The R Project for Statistical Computing. Version 3.3.2. [(accessed on 4 December 2019)]; Available online:

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する