Filip Jansaker1*, Frederik Boetius Hertz1, Niels Frimodt-Moller2 and Jenny Dahl Knudsen1
1Department of Clinical Microbiology. Copenhagen University hospital, Hvidovre Hospital.
2Department of Clinical Microbiology. Copenhagen University Rigs Hospitalet, Copenhagen Denmark
Received: 18 September, 2015; Accepted: 19 October, 2015; Published: 21 October, 2015
Filip Jansaker, Department of Clinical Microbiology. Copenhagen University Hospital, Hvidovre Hospital, Kettegaard Allé 30, DK-2650, Hvidovre, Denmark, Tel: +45-4270-0602; Fax: +45-3862-3357; E-Mail:
Jansaker F, Hertz FB, Frimodt-Moller N, Knudsen JD (2015) Pivmecillinam Treatment of Community-Acquired Uncomplicated Pyelonephritis Based on Sparse Data. Glob J Infect Dis Clin Res 1(1): 014-017.DOI: 10.17352/2455-5363.000004
© 2015 Jansaker F, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Pivmecillinam; Antimicrobial therapy; Pyelonephritis; Community-acquired infections; Old antibiotics
Background: Pivmecillinam has good pharmacokinetic properties for treatment of infections in the urinary tract, and the mecillinam resistance rate in Enterobacteriaceae is very low. In a European guideline pivmecillinam is recommended as a first-line drug for treatment of lower urinary tract infections. In Danish and Norwegian guidelines pivmecillinam is also recommended for acute uncomplicated pyelonephritis, although with very sparse documentation of effect.
Objectives:We intended to investigate the therapeutic outcome of pivmecillinam treatment of uncomplicated pyelonephritis caused by Enterobacteriaceae treated by general practitioners (GP's) in primary care.
Material and methods: We included patients clinically diagnosed with pyelonephritis at the GP, urine samples positive for Enterobacteriaceae and empirical treatment with pivmecillinam. We intended to include patients prospectively, but due to slow inclusion we also included patients retrospectively. The prospectively included patients were asked to fill out a questionnaire and submit control urine samples. The retrospectively included patients were followed by available urine samples and the text on the requisition only. The patients were followed by their urine samples for three months.
Results: We identified 22 patients (i.e. six patients prospectively and found another 16 patients retrospectively). Bacterial and clinical cure rate was 77% (95%c.i.: 60-95%), respectively. In seven (32%) of the patients, we observed a recurrent or new infection within three months.
Conclusion:There is indication for safe oral treatment with pivmecillinam in uncomplicated pyelonephritis caused by a mecillinam susceptible E. coli. More studies and especially prospective and randomized clinical studies are needed before pivmecillinam can be recommended as first line option for treatment of pyelonephritis.
Pivmecillinam is one of the first-line options in a European guideline for treatment of lower urinary tract infections (LUTI) . In Denmark and Norway it is also recommended for 7-14 days as an oral treatment for acute pyelonephritis without signs of urosepsis [2-4]. Escherichia coli (E. coli) is the major pathogen in both LUTIs and pyelonephritis . Pivmecillinam has especially good in-vitro activity against uropathogenic E. coli with or without production of extended-spectrum beta-lactamase (ESBL) [6-8]. Recent studies have shown that pivmecillinam in 400 mg three times daily for five days have clinical and bacteriological effect in LUTIs caused by ESBL producing E. coli [9,10]. The long-term use of pivmecillinam in the Nordic countries has shown it to be safe and effective in the treatment of LUTI, with continuously low rates of mecillinam resistance [11-13]. Danish physicians have for several years adapted the regular use of pivmecillinam in treatment of acute pyelonephritis, as 400 mg three times daily for 14 days [2,4].
To our knowledge there are only few small clinical studies published on the effect of mono- or concomitant therapy with pivmecillinam for pyelonephritis [14,15]. Randomized clinical controlled studies are much needed before pivmecillinam can be widely recommended in everyday clinical practice. Prior to any larger comparison studies, we performed an observational study in order to investigate the prevalence of acute uncomplicated pyelonephritis (AUP) treated in Danish primary care and the clinical and microbiological outcome of such infections treated with pivmecillinam.
Material and Methods
The Department of Clinical Microbiology (DCM), Hvidovre Hospital, serves five hospitals and more than 700 General Practitioners (GPs) based on a population of app. 900,000 inhabitants. The DCM receives urine samples both from hospital departments and GP´s. All urine samples are processed according to laboratory routine and susceptibility tested according to EUCAST guidelines . Significant bacteriuria is defined as growth of > 103 bacteria/ml urine for E. coli, and as > 104 bacteria/ml urine for other Enterobacteriaceae.
A prospective observational study was planned for 30 patients. During a nine months' time period (September 2014 to May 2015) we asked the GP's in the catchments area of the DCM to report, by an electronic prompt on the electronic requisition for analyses, when an urine sample was collected from an adult patient with AUP, and to state the antibiotic therapy initiated after the urine sample was collected. These patients received two self-urine sample kits for control samples and questionnaires for the clinical effect.
As patient-inclusion was slow, we decided to supplement with a retrospective study. In the retrospective analysis we used the laboratory database to identify the patients, and to analyze the bacteriological effect, i.e. further urine samples were scrutinized for growth of relevant bacteria. However, we could not, in all cases, see if the new or a second urine sample were collected as a control of treatment or because of new symptoms. If no urine samples were sent for analyses after the initial AUP sample from a surviving patient, it was considered as satisfactorily clinical outcome.
Bacteriological cure in the prospectively included patients was defined as urine samples with no, non-significant growth (5), or significant reduction of growth by a factor 100 of Enterobacteriaceae. Bacteriological failure or recurrent infection was defined as significant growth of uropathogenic bacteria in the control urine samples within 28 days, or between 28 days and 3 months, respectively. Probable bacteriological cure was defined as no urine samples or negative urine sample less than seven days after the antibiotic therapy was initiated.
Clinical cure was defined as resolution of AUP symptoms reported by patients or by the GP (retrospectively, by requisition form on new urine sample). Clinical failure was defined as a non-reduction of symptoms reported by patient or GP (retrospective, by requisition form on new urine sample). Clinical relapse was defined as symptoms of AUP reported by the patient, or new urine sample with symptoms of AUP (retrospectively, reported on by GP on requisition form). Probable clinical cure or relapse was defined as non-availability or negative control urine sample, or significant growth in new urine sample, respectively.
The patient with an E. coli resistant to mecillinam, with relapse, was considered probable clinical and bacteriological failure.
The study was approved by the local Ethical Committee (H-4-2014-071), and the Danish Data Protection Agency (2012-58-0004).
Results and Discussion
Over a period of nine months, we could identify 22 patients empirically treated with pivmecillinam for AUP, with urine samples positive for Enterobacteriaceae (Table 1). Six patients were followed prospectively and 16 patients were analysed retrospectively. Three patients were male, 19 were females. The median age was 46 years (range 21-83).
In the prospective observational study, six patients with diagnosed pyelonephritis caused in five cases by E. coli, and in one by Klebsiella pneumoniae. All six bacterial isolates were susceptible to mecillinam. All six patients experienced bacteriological and clinical cure, and no relapses were seen in these cases.
In the retrospective analysis, 16 patients were included with AUP all caused by E. coli. In two cases the E. coli isolate was mecillinam resistant and one of these experienced bacteriological re-infection and feasible clinical relapse. In the other case we found bacteriological failure, but the GP reported clinical cure.
Five patients were either men (N=3) or older than 70 years (N=3). Arguably, by definition  these patients should probably not have been considered to be uncomplicated pyelonephritis, but were nonetheless treated with oral pivmecillinam by their GP. Two of these cases (one man) experienced treatment failure and both had several positive urine samples both before and after the investigated episode.
Two patients were admitted to hospital after the urine sample was collected, however, with no indication of treatment failure. In two cases the E.coli were resistant to mecillinam, with unsuccessful bacteriological outcome in both, but one with reported clinical cure. One patient had an ESBL producing E. coli (susceptible to mecillinam), and had a negative control urine sample. This is also in accordance with a report from Nicolle et al. who reported a patient, successfully treated with mecillinam for relapsing pyelonephritis caused by ESBL producing E. coli .
Cumulatively, the indicated bacteriological and clinical cure was 77 % (95%c.i.: 60-95%), respectively, Table 2. In seven of the patients, we observed a relapse or new infection, 32% (95%c.i.: 12-51%).
We are unable from the present study to calculate an actual prevalence-rate of AUP in primary care, since we have little information on how many of such patients were seen by GP´s and not reported to us. And some patients with AUP may not be recognized as such by the GP. Anyway, with 22 cases only found over a 9-month period in our catchment area, the prevalence of AUP treated in primary care seems to be low.
Although pivmecillinam in Europe only is recommended as a first line choice against LUTI, Danish physicians have for several years used pivmecillinam in treatment of acute pyelonephritis [2,4]. There are only few publications on the outcome of treatment of pyelonephritis with pivmecillinam; In one study, 600 mg mecillinam intravenously followed by 400 mg pivmecillinam orally twice daily, concomitant with ampicillin treatment, demonstrated a 63% cure rate for pyelonephritis, which was similar to the comparative cephalosporin .
Of other oral antibiotics tried for treatment of AUP, cephalosporines, trimethoprim/sulphamethoxazole and fluoroquinolones have shown more or less the same clinical and bacteriological effect as pivmecillinam in this study [17-20]. For all these antibiotics bacterial resistance is becoming a problem in many parts of the world  and since no new antibiotics are appearing especially with activity against Enterobacteriaceae, it is crucial to re-vitalize old effective antibiotics such as pivmecillinam.
There are many limitations in our study (only six patients were included in the initial prospective study and further 16 patients in the retrospective study). However, since there (to our knowledge) are no clinical studies on the effect of pivmecillinam as mono-therapy for AUP, we believe that our results can be of interest as a possible supplementary oral treatment option for outpatients with AUP in times with increasing resistance against common urinary antibiotics. Still, we believe a randomized comparative clinical study is needed before a general recommendation can be made.
We thank the personnel at the department of clinical microbiology, Hvidovre Hospital, for their outstanding technical work.
FJ came up with the idea of the study, developed the study design, conducted the acquisition of data and drafted the article. FBH helped with the above mentioned processes. JDK is the primary mentor in the study, helped with the above mentioned processes, revised the analysis and interpretation of the data and manuscript. NFM helped develop the idea, revised the analysis and interpretation of the data and manuscript.
- Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, et al. (2011) International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis 52: e103-120.
- http://www.sundhed.dk/sundhedsfaglig/laegehaandbogen/nyrer-og-urinveje/tilstande-og-sygdomme/infektioner/nyrebaekkenbetaendelse/-15 (2015.06.26.
- http://www.helsebiblioteket.no/retningslinjer/antibiotika/antibiotika-kortversjon (2015.06.26.
- http://pro.medicin.dk/Specielleemner/Emner/318561 - a000 (2015.06.26.
- Nicolle LE (2008) Uncomplicated urinary tract infection in adults including uncomplicated pyelonephritis. The Urologic clinics of North America 35: 1-12 .
- Bjerager L, Skov R, Frimodt-Moller N (2000) In vitro study of the susceptibility of Escherichia coli to mecillinam. J Antimicrob Chemother 45: 920-921 .
- Kahlmeter G, Poulsen HO (2012) Antimicrobial susceptibility of Escherichia coli from community-acquired urinary tract infections in Europe: the ECO.SENS study revisited. Int J Antimicrob Agents 39: 45-51 .
- Lampri N, Galani I, Poulakou G, Katsarolis I, Petrikkos G, et al. (2012) Mecillinam/clavulanate combination: a possible option for the treatment of community-acquired uncomplicated urinary tract infections caused by extended-spectrum beta-lactamase-producing Escherichia coli. J Antimicrob Chemother 67: 2424-2428 .
- Jansåker F, Frimodt-Møller N, Sjögren I, Dahl Knudsen J (2014) Clinical and bacteriological effects of pivmecillinam for ESBL-producing Escherichia coli or Klebsiella pneumoniae in urinary tract infections. J Antimicrob Chemother 69: 769-772.
- Frimodt-Møller N. LCV, Henriksen AS (2008) Mecillinam is active against ESBL-CTX-M producing E. coli in vivo in experimental UTI. In: Abstract P1917, S562, European Society for Microbiology 19-22.
- Ferry SA, Holm SE, Stenlund H, Lundholm R, Monsen TJ (2007) Clinical and bacteriological outcome of different doses and duration of pivmecillinam compared with placebo therapy of uncomplicated lower urinary tract infection in women: the LUTIW project. Scand J Prim Health Care 25: 49-57 .
- Graninger W (2003) Pivmecillinam--therapy of choice for lower urinary tract infection. International journal of antimicrobial agents 22: 73-78 .
- Nicolle LE (2000) Pivmecillinam in the treatment of urinary tract infections. J Antimicrob Chemother 46: 35-39.
- Cronberg S, Banke S, Bruno AM, Carlsson M, Elmrud H, et al. (1995) Ampicillin plus mecillinam vs. cefotaxime/cefadroxil treatment of patients with severe pneumonia or pyelonephritis: a double-blind multicentre study evaluated by intention-to-treat analysis. Scand J Infect Dis 27: 463-468 .
- Nicolle LE, Mulvey MR (2007) Successful treatment of ctx-m ESBL producing Escherichia coli relapsing pyelonephritis with long term pivmecillinam. Scand J Infect Dis 39: 748-749 .
- (2013)The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters - Version 3.1. EUCAST V, Sweden.
- Monmaturapoj T, Montakantikul P, Mootsikapun P, Tragulpiankit P (2012) A prospective, randomized, double dummy, placebo-controlled trial of oral cefditoren pivoxil 400mg once daily as switch therapy after intravenous ceftriaxone in the treatment of acute pyelonephritis Int J Infect Dis 16: e843-e849 .
- Peterson J, Kaul S, Khashab M, Fisher AC, Kahn JB (2008) A double-blind, randomized comparison of levofloxacin 750 mg once-daily for five days with ciprofloxacin 400/500 mg twice-daily for 10 days for the treatment of complicated urinary tract infections and acute pyelonephritis. Urology 71: 17-22 .
- Sandberg T, Skoog G, Hermansson AB, Kahlmeter G, Kuylenstierna N, et al. (2012) Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial. Lancet 380: 484-90 .
- Talan DA1, Stamm WE, Hooton TM, Moran GJ, Burke T, et al. (2000) Comparison of ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) for acute uncomplicated pyelonephritis pyelonephritis in women: a randomized trial. JAMA 283: 1583-1590 .