This article is protected by copyright. To share or copy this article, please visit copyright.com. Use ISSN#1543953X. To subscribe, visit imjournal.com The Long-term Health Implications of Depo-Provera Edra Spevack, ND The reproductive health of adolescents and young indicate a correlation between DMPA use and an adults is a major determinant of their future well-being. increased risk of fracture and HIV infection. These
Symptomatic treatment (ibuprofen) or antibiotics (ciprofloxacin) for uncomplicated urinary tract infection? - results of a randomized controlled pilot trialBleidorn et al. BMC Medicine 2010, 8:30
Symptomatic treatment (ibuprofen) or antibiotics (ciprofloxacin) for uncomplicated urinary tract infection? - Results of a randomized controlled pilot trial Jutta Bleidorn†1, Ildikó Gágyor*†2, Michael M Kochen2, Karl Wegscheider3 and Eva Hummers-Pradier1 Background: Uncomplicated lower urinary tract infections (UTI) are usually treated with antibiotics. However, there is
little evidence for alternative therapeutic options.
This pilot study was set out 1) to make a rough estimate of the equivalence of ibuprofen and ciprofloxacin for uncomplicated urinary tract infection with regard to symptom resolution, and 2) to demonstrate the feasibility of a double-blind, randomized controlled drug trial in German general practices.
Methods: We performed a double-blind, randomized controlled pilot trial in 29 German general practices. Eighty
otherwise healthy women aged 18 to 85 years, presenting with at least one of the main UTI symptoms dysuria and
frequency and without any complicating factors, were randomly assigned to receive either ibuprofen 3 × 400 mg oral
or ciprofloxacin 2 × 250 mg (+1 placebo) oral, both for three days.
Intensity of main symptoms - dysuria, frequency, low abdominal pain - was recorded at inclusion and after 4, 7 and 28 days, scoring each symptom from 0 (none) to 4 (very strong). The primary endpoint was symptom resolution on Day 4. Secondary outcomes were the burden of symptoms on Days 4 and 7 (based on the sum score of all symptoms), symptom resolution on Day 7 and frequency of relapses. Equivalence margins for symptom burden on Day 4 were pre-specified as +/- 0.5 sum score points. Data analysis was done by intention to treat and per protocol. Randomization was carried out on patient level by computer programme in blocks of six.
Results: Seventy-nine patients were analyzed (ibuprofen n = 40, ciprofloxacin n = 39). On Day 4, 21/36 (58.3%) of
patients in the ibuprofen-group were symptom-free versus 17/33 (51.5%) in the ciprofloxacin-group. On Day 4,
ibuprofen patients reported fewer symptoms in terms of total sum score (1; SD 1,42) than ciprofloxacin patients (1,3; SD
1,9), difference -0,33 (95% CI (-1,13 to +0,47)), PP (per protocol) analysis. During Days 0 and 9, 12/36 (33%) of patients in
the ibuprofen-group received secondary antibiotic treatment due to ongoing or worsening symptoms, compared to
6/33 (18%) in the ciprofloxacin-group (non significant). A total of 58 non-serious adverse events were reported, 32 in
the ibuprofen group versus 26 in the ciprofloxacin group (non significant).
Conclusions: Our results support the assumption of non-inferiority of ibuprofen compared to ciprofloxacin for
treatment of symptomatic uncomplicated UTI, but need confirmation by further trials.
Trial registration: Trial registration number: ISRCTN00470468
* Correspondence: [email protected] Department of General Practice/Family Medicine, University of Göttingen, Humboldtallee 38, 37073 Göttingen, Germany† Contributed equallyFull list of author information is available at the end of the article 2010 Bleidorn et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.
Bleidorn et al. BMC Medicine 2010, 8:30
(GPs) in Lower Saxony, Germany, agreed to screen and Uncomplicated lower UTI are common in general prac- enrol eligible patients for a six-month-period. All adult tice . Antibiotic treatment is recommended by primary women (>18 ys) suspected to have uncomplicated UTI care guidelines [,], as it is effective for fast symptom due to typical symptoms (dysuria and/or frequency) and resolution. However, facing increasing resistance rates, not having any exclusion criteria were to be asked for efforts to optimize appropriate antimicrobial use gain in informed consent to be enrolled successively. Exclusion importance]. The effect of reducing antibiotic pre- criteria were, comparable with other UTI tria, any scriptions on resistance has been shown . There is little signs evoking complicated UTI (that is, fever, back pain), evidence neither for the natural course of untreated any conditions that may lead to complicated infections uncomplicated UTI nor for alternative therapeutic (that is, pregnancy, diabetes, renal diseases, urinary tract options. It is known that many women do not seek medi- abnormalities or past urinary surgery, urine catheteriza- cal help immediately but try to wait or treat themselves tion, immunosuppressive therapy, other serious diseases, with home remedies ]. Only a few trials compared cancer), UTI within the last two weeks, current use of antibiotic therapy to placebo for uncomplicated UTI antibiotics or non-steroidal anti-inflammatory drugs; his- . The results showed significantly delayed symp- tory of gastrointestinal ulcers; epilepsy, allergies or other tomatic improvement and bacteriological cure in the pla- contraindications for trial drugs; current participation in cebo groups. However, placebo groups fared surprisingly other clinical trials, disability to understand the trial well with a symptomatic improvement/cure rate of about information or to give informed consent. Dipstick results 50% after three days erious complications need were not required for inclusion.
not to be feared as long as prompt reconsultation in caseof persisting or worsening symptoms is conceded To our knowledge, no study yet analyzed whether At inclusion, patients completed a symptom score similar symptomatic treatment might be an effective treatment to those used in other UTI trials [,]. Severity of dysu- strategy for pain relief in UTI. Therefore, we performed a ria, frequency and low abdominal pain (which was not an pilot study to make a rough estimate of the equivalence of inclusion criterion) was scored from 0 (not at all) to 4 ibuprofen and ciprofloxacin in women with symptoms of (very strong). In addition, patients recorded how much uncomplicated UTI. Ibuprofen was chosen as an alterna- they felt bothered by their symptoms (impairment score, tive treatment option to antibiotics, considering analgesia range 0 to 4) and for how long they had been suffering and inflammatory activity as the basis for symptomatic from them. After four and seven days, symptoms and improvement as the most important factor for patients to impairment were assessed by a trained study nurse via cope with UTI,]. Bacteriological cure was ranged telephone interviews. The nurse also inquired about any second since there is no need to treat asymptomatic bac- additional symptoms or conditions. At Day 28, patients teriuriaiprofloxacin is not recom- were called again to find out about relapses or adverse mended as a first line therapy for uncomplicated UTI, it events. GPs were asked to record contacts or consulta- was chosen as a reference due to its low resistance rates tions for any complaint or symptom during the entire ficacygh prescribing rates in trial (28 days).
Germany. The trial was funded by the German Ministry All participants provided a urine specimen for culture of Research and Technology, which, however, required it at inclusion. If GPs chose to do a dipstick test (not to be conducted as a feasibility and proof-of-concept required for inclusion), they were to document the study with a limited sample size. As double-blind, ran- results. In all participants, a follow-up urine culture was domized controlled trials (RCTs) are not usually per- done on Day 7. All urine cultures were performed by the formed in German general practice, this approach was same laboratory (Medical Partnership Wagner, Stibbe, considered as a prerequisite to a fully powered trial.
Kast, Bispink and Partners). In accordance with current The aim of this pilot study was to investigate first recommenda2 colony-forming units trends in clinical equivalence of a three-day treatment per ml were used as a cut-off. GPs were informed about course of 3 × 400 mg ibuprofen compared to 2 × 250 mg culture results, but asked not to contact patients who had ciprofloxacin for women with uncomplicated UTI, with a positive culture on Day 7 but did not consult for com- regard to symptomatic outcome.
All patients provided written informed consent. The trial was conducted according to the Good Clinical Prac- Study design and population
tice guidelines and the declaration of Helsinki and was This was a double-blind, randomized controlled equiva- approved by the local ethics committee (University of lence trial, conducted between July 2007 and April 2008.
Twenty-nine of 169 (18%) invited general practitioners Bleidorn et al. BMC Medicine 2010, 8:30
the course of the study, based on blind interim data, it Randomization was carried out on a patient level by com- was decided to perform a formal equivalence analysis puter program in blocks of six. Code numbers were based on the Day 4 total symptom scores with equiva- assigned from the random list to drug units by an inde- lence margins of +/- 0.5 score points that were judged to pendent supply company specialized in clinical trials.
be the limit of clinical relevance. A two-sided confidence Active ingredients were encapsulated for identical interval approach was used. It was decided to perform appearance, and drug units were identically prepared and this analysis in the ITT (intention-to-treat) as well as in packed. Each drug unit was marked individually with a the PP (per protocol) population, the latter being the pri- code number. Participating practices received a pack of mary analysis since it is better suited to detect differences six blinded drug sets to hand out to participating between treatments than the former. In case of missing patients, and ultimately another pack of six drug units if symptom documentation, patients were excluded from recruiting enough patients. At inclusion, each patient was the PP population, but not from the ITT analysis.
assigned the code number from their drug set by their GP, Baseline characteristics were analyzed descriptively.
who then used pre-printed labels to mark the patient's Group differences were examined by using t-tests (con- study documents, urine specimen and questionnaires.
tinuous scales), u-tests (rank scales) or chi-square tests The randomization list was kept in a sealed envelope.
(binary scales). All analyses were carried out for both the However, for each code number, GPs had received sealed, ITT and the PP population. P-values of less than 0.05 opaque envelopes to be opened only in case of a true were considered statistically significant.
medical emergency requiring de-blinding of the study Software: SPSS 13.0, SPSS Inc., Chicago, IL 60606- drug. The study team as well as enrolling GPs had no 6307. APL 5.0, APL 2000 Rockville, Maryland 20850.
access to the code list; study nurses were blinded to allo-cation as well.
Participants received either ibuprofen 3 × 400 mg or Participating GPs screened a total of 195 patients. Eighty ciprofloxacin 2 × 250 mg (+1 placebo), both for three patients were finally enrolled and randomized (Figur.
days. The efficacy of this antibiotic treatment strategy has The mean number of included patients was 2.8 per prac- been shown in other trials befohe GPs tice (range 0 to 12). One screening failure (patient was handed out the blinded drug sets to participating patients randomized and then excluded before starting trial drug and told them to start taking the drug with the next meal.
due to exclusion criteria) was excluded from the study.
Patients were instructed to consult their GP in case of Patients with incomplete symptom data on Day 0/4/7 (n persistent or recurrent symptoms. In case patients = 9) or exclusion criteria detected after inclusion (n = 3) returned with ongoing complaints during the three days were excluded from the PP-analysis, resulting in a PP of trial treatment, further treatment depended on GPs' population of 36 in the ibuprofen and 33 in the ciproflox- estimation. In patients returning with worsened com- acin group. Since there was good agreement between ITT plaints, trial drug should be stopped and antibiotic treat- and PP analyses, with exception of the primary compari- ment should be started. According to the study protocol son only PP analysis results are shown.
patients with secondary antibiosis were analysed in their At baseline there were no significant differences between both groups (Table). The rate of positive nitritetests in both groups (29/30%) is low, however, compara- ble results have been described else.
Symptom resolution on Day 4 (defined as the number of As for symptom resolution, 21/36 (58.3%) of patients in patients with a symptom sum score of 0) was the primary the ibuprofen group and 17/33 (51.5%) in the ciprofloxa- outcome of this trial. Secondary outcomes were the bur- cin group were completely free of symptoms on Day 4 den of symptoms on Days 4 and 7 (based on the total sum (difference non significant). On Day 7, the proportion of score of all dysuria, frequency, low abdominal pain, rang- symptom free patients had increased further in both ing from 0 to 12) as well as symptom resolution on Day 7, groups, without a significant group difference (Tab.
frequency of relapses until day 28, and incidence of The course of symptoms in terms of mean symptom adverse events. The numbers of secondary antibiotic sum scores is presented in Table/Figure. With respect treatments and urine cultures on Day 7 were also com- to Day 4, the difference of total sum scores was -0.33 pared between groups.
score points (95% CI (-1.13; +0.47)) in the PP analysis(primary analysis). The corresponding ITT analysis resulted in a difference of 0.50 (95% CI: (-1.31; + 0.31).
The trial was designed as an equivalence study. However, With regard to general impairment, there were no signifi- as the study was understood as a pilot, no formal equiva- cant differences between ibuprofen and ciprofloxacin lence margins were defined in the study protocol. During
Bleidorn et al. BMC Medicine 2010, 8:30
Figure 1 Participant flow.
groups. In particular, for the course of dysuria no differ- In regards to re-consultation with persistent or worsen- ence between groups could be shown (Table).
ing symptoms up to Day 4, four patients in the ciprofloxa- Considering urine cultures on Day 7, negative urine cin group and five patients in the ibuprofen group cultures (less than 102 cfu/ml) occurred more often in the returned during the treatment period. Most often GPs ciprofloxacin group (23/33, 71.9%) than in the ibuprofen then prescribed one of the following antibiotics: group (16/36, 48.5%). However, this was not significant (P trimethoprim, ciprofloxacin or cotrimoxazole. Most = 0.093, data not shown).
patients did not re-consult again, with one exception Bleidorn et al. BMC Medicine 2010, 8:30
Table 1: Baseline characteristics
Ibuprofen n = 36
Ciprofloxacin n = 33
Previous UTI (in last two years)
Mean symptom duration, days (SD)
leukocytes positive Positive urine culture
Enterococcus faecalis Streptococcus agalactiae Klebsiella spp.
resistance to ciprofloxacin Symptoms at inclusion
low abdominal pain Mean score at inclusion (range 0 to 4)
low abdominal pain sum score (range 0 to 12) where the antibiotic therapy was changed again. In line On follow up on Day 28, one ciprofloxacin patient and with the study protocol, these patients remained in their two ibuprofen patients (P = 1.0) reported a relapse. A groups for the analysis. In total, 12/36 (33.3%) patients in total of 58 adverse events were retrieved by telephone the ibuprofen group and 6/33 (18.2%) in the ciprofloxacin interviews, 32 in the ibuprofen group vs. 26 in the cipro- group required secondary antibiotic treatment. This dif- floxacin group, thus including also conditions or symp- ference was notable, but not significant within this sam- toms with no obvious association with the drug ple size (Tab.
medication. Non-serious adverse events were reported inboth groups (11 in the ibuprofen group, 9 in the cipro-floxacin group). Mostly common gastrointestinal disor-ders were involved, followed by upper respiratory tract Table 2: Symptom resolution Day 4/Day7
infections, which are likely to be coincident rather than Ibuprofen n = 36
Ciprofloxacin n = 33
related to the study treatment, and headache.
The results of this pilot study suggest a tendency towardsequivalence of ibuprofen as compared to ciprofloxacin for treatment of uncomplicated UTI with regard to symp- Complete symptom resolution (sum score = 0), per protocol tom resolution and symptom course. The difference in
Bleidorn et al. BMC Medicine 2010, 8:30
Figure 2 Symptom course Days 0 to 7. Symptom course, mean sum score (range 0 to 12) Days 0 to 7.
symptom scores at any follow-up time was insignificant tively common in healthy women and is not an and small in absolute numbers. Approximately two thirds indication for treatment in patients without particular of patients presenting with UTI symptoms seem to risk factTherefore, symptom control may be recover without antibiotics. In total, one third (33%) of sufficient in a majority of cases. The surprisingly high the patients in the ibuprofen group returned for ongoing number of patients re-consulting with persistent/recur- or recurring symptoms within the first week. The main rent symptoms while taking ciprofloxacin (18%) could reasons for re-consultation might have been the lack of indicate that antibiotic treatment takes a few days to therapeutic effect or the blinded trial situation that is resolve symptoms, a fact which may have worried trial rather unusual for patients and GPs alike.
patients who did not know which drug they were taking.
Thus, our results suggest the assumption that UTI is a To our knowledge, this is the first study which analyses self-limiting disorder in many patients. Even without whether symptomatic treatment might be a therapeutic antibiotic treatment, symptomatic infection seems to alternative in women with symptoms of uncomplicated heal or convert to asymptomatic bacteriuria in a substan- UTI. Christiaens et al. (2002) compared nitrofurantoin to tial number of women. Asymptomatic bacteriuria is rela- placebo in 78 UTI patients and reported symptomimprovement/resolution rates of about 50% after three Table 3: Total symptom course
Table 4: Dysuria course
Ibuprofen n = 36
Ciprofloxacin n = 33
Ibuprofen n = 36
Ciprofloxacin n = 33
d4 difference I-C:-0.3395% CI (-1.13; +0.47) d7 difference I-C:-0.0695% CI (-0.47; +0.59) Total symptom course Day 0/4/7, mean sum score (SD), range 0 to Dysuria course Days 0/4/7, symptom score (SD), range 0 to 4, per 12, per protocol analysis protocol analysis Bleidorn et al. BMC Medicine 2010, 8:30
Table 5: Secondary antibiotic treatment
The authors declare that they have no competing interests.
Ibuprofen n = 36
Ciprofloxacin n = 33
EHP and MMK had the original idea for the study. All authors developed study
the design and protocol, assisted by the Hannover Clinical Trial Center. IG and
JB recruited and supervised the practices and managed the trial on a day-to- day basis. Data analysis was performed by KW. All authors read and approvedthe final manuscript.
Secondary antibiotic treatment due to persistent or recurrent symptoms, per protocol analysis Acknowledgements
We thank all participating practices (Auer, Baumgarten, Beermann, Borchers,
and seven daysontrast, Ferry et al. (2007) com- Bortfeld, Brockstedt, Buck/Leugner, Fleige, Rehmann, Jänicke, Klinger-Bülte-mann, Köhler, Knoche, Lang, Pallinger/Olowson, Ottlewski/Sutor, Pullwitt, pared different antibiotic strategies and a placebo in a Scheibe, Sommer, and others) and their patients for their confidence, time and large UTI trial with slightly poorer results for the placebo group (25% symptom resolution after seven da We gratefully acknowledge Prof. Heiko von der Leyen and Hannover Clinical Prolonged symptom duration following delayed antibi- Trial Center staff for their supervision, expertise in monitoring and assistance in data management.
otic prescription was reported by Little et al We thank Dr. Matthias Koch for microbiological support, and the Medical Part- However, none of these studies involved a symptomatic nership Wagner, Stibbe, Kast, Bispink & Partners, medical laboratory, for per- treatment arm. A strength of our study is that it is based forming the urine cultures.
on symptomatic patients and symptomatic outcomes.
This fits in the needs and current recommendations of 1Institute of General Practice/Family Medicine, Hanover Medical School, Carl- GPs for symptom-oriented, therapeutic management Neuberg-Str.1, 30625 Hannover, Germany, 2Department of General Practice/ without expensive laboratory diagnostics.
Family Medicine, University of Göttingen, Humboldtallee 38, 37073 Göttingen, Germany and 3Department of Medical Biometry and Epidemiology, University The main limitation of our study is that due to its pilot Medical Centre Hamburg, Martinistr. 53, 20246 Hamburg, Germany character it was not sufficiently powered to give definite Received: 9 April 2010 Accepted: 26 May 2010 answers to all the questions of clinical interest. Further- Published: 26 May 2010 more, in the first three days the symptom course was not mmons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Cite this article as: Bleidorn et al., Symptomatic treatment (ibuprofen) or
antibiotics (ciprofloxacin) for uncomplicated urinary tract infection? - Results
of a randomized controlled pilot trial BMC Medicine 2010, 8:30
January - March 2010 / # 1 2 hours ago our wandering female harrier from the west In this issue: coast flew straight into the heart of Lesotho! She is now close to a smal stream in a high altitude val ey, about 1 More travels by Lockie . . . . . . Rob Simmons 32 km from the Katse Dam. She has flown a straight line distance of 1173 km from her coastal "home" near