Evaluation of the efficacy and tolerance of a short 7 day third-generation
cephalosporin treatment in the management of acute pyelonephritis
in young women in the emergency department
F. Moustafa
1*, G. Nguyen
1, T. Mathevon
1, O. Baud
2, J. Saint-Denis
1,3, N. Dublanchet
1, B. Pereira
4, C. Shinjo
1,
J. P. Romaszko
5, L. Dopeux
1, F. Dutheil
1,6,7and J. Schmidt
1,31
Service des urgences, Poˆle SAMU-SMUR-Urgences, CHU Gabriel Montpied, Clermont-Ferrand, France;2Service de maladies infectieuses, Poˆle SAMU-SMUR-Urgences, CHU Gabriel Montpied, Clermont-Ferrand, France;3Universite´ d’Auvergne, Clermont-I, UFR de Me´decine, Clermont-Ferrand, France;4Service de Biostatistiques, CHU Gabriel Montpied, Clermont-Ferrand, France;5Laboratoire de bacte´riologie, mycologie et parasitologie, CHU Gabriel Montpied, Clermont-Ferrand, France;6School of Exercise Science, Australian Catholic University, Melbourne, VIC, Australia;7Laboratory of Metabolic Adaptations to Exercise in Physiological and Pathological Conditions (AME2P, EA 3533),
Blaise Pascal University, Clermont-Ferrand, France
*Corresponding author. Tel:+33-(0)4-73-75-19-99; Fax: +33-(0)4-73-75-15-53; E-mail: fmoustafa@chu-clermontferrand.fr Received 15 October 2015; returned 2 December 2015; revised 18 January 2016; accepted 18 January 2016 Objectives: Urinary tract infections, among the leading causes of antibiotic prescriptions in adult women, are complicated by increasing antibiotic resistance. Current recommendations propose a 7 day treatment with fluoroquinolones or a 10 – 14 day course of third-generation cephalosporins (3GC). Our aim was to study the efficiency and tolerance of a short 7 day treatment with 3GC in uncomplicated acute pyelonephritis in women aged between 18 and 65 years.
Patients and methods: This study was an open, prospective, non-comparative, monocentric pilot study with consecutive patients. We included women between 18 and 65 years old who had been admitted to the emergency department with a diagnosis of acute pyelonephritis. The treatment consisted of 1 g of ceftriaxone injection followed by 6 days of 400 mg of cefixime per day. The primary endpoint was negative urine cultures on day 9. We opted for Fleming’s multistage design for this trial. ClinicalTrials.gov number: NCT01390623. Results: Thirty-seven patients were analysed. The bacteriological response consisted of negative urine cultures for all 37 patients on day 9. On day 9, 30 patients were completely asymptomatic, while 7 exhibited clinical improvement though persistence of bladder irritation or flank pain. On day 37, there were no remaining symptoms and no recurrences of urinary tract infection, as noted during the last follow-up visits.
Conclusions: These results suggest that acute pyelonephritis in women could be successfully treated with a short-term course of 1 g of ceftriaxone on the first day followed by 400 mg of cefixime per day for 6 days. These positive results must be confirmed by a non-inferiority study.
Introduction
Background
Urinary infections remain one of the leading causes of antibiotic prescriptions in women.1,2Currently, international clinical practice
guidelines for the treatment of acute pyelonephritis recommend 7 days of fluoroquinolones, 10 –14 days of b-lactams and 14 days of trimethoprim/sulfamethoxazole.2Quinolones are among the most frequently prescribed class of antibiotics. Their intensive use in hospitals, long-term care institutions and the community has been accompanied by an emergence of bacterial resistance mechanisms.3–5These resistances are likely to be greater in urin-ary tract infections, since, according to the French National
Observatory for Epidemiology of Bacterial Resistance to Antibiotics, Escherichia coli resistance to ciprofloxacin in commu-nity urinary tract infections is now reported to be 15%.6
Importance
The rise in incidence of resistant strains underlines the urgency with which we must prevent the emergence of new strains produ-cing ESBL, particularly the need for a new therapeutic regimen that excludes fluoroquinolones and, by that reasoning, the need for new guidelines on the duration of antibiotic prescription.7 Like fluoroquinolones, third-generation cephalosporins (3GC) are a key risk factor for ESBL emergence and spread.8,9Elsewhere in
#The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com
J Antimicrob Chemother 2016; 71: 1660 – 1664
doi:10.1093/jac/dkw021 Advance Access publication 21 February 2016
the literature, there is consensus that limiting the duration of anti-biotic treatment, and in particular the use of 3GC, is crucial in urin-ary infection cases in women, though no study has yet defined the optimal duration of treatment.2,10
Goals of this investigation
In this study, we evaluated the efficacy and tolerance of a 7 day treatment with 3GC, consisting of an injection of ceftriaxone on day 1 followed by cefixime for 6 days, in the management of acute uncomplicated pyelonephritis in young women aged 18–65 years.
Methods
Study design
This pilot study was open, prospective and monocentric, with consecutive patients, and was conducted between 22 July 2011 and 5 June 2013 (date of last follow-up: 11 July 2013) at the emergency department of Clermont-Ferrand University Hospital, France. The French Research Ethics Committee (CPP Sud-Est I, 2010-023697-39) granted approval for the study design. Written informed consent was obtained from each patient participating in the study, following a clear explanation of the trial. This trial was registered at ClinicalTrials.gov under number NCT01390623.
Inclusion criteria
During this period, 24 h a day and 7 days a week, the medical doctor of the emergency department identified women who met the eligibility criteria and obtained their informed consent when they agreed to participate in the study.
Patients were eligible for study inclusion if they fulfilled the following criteria: (i) female sex; (ii) age 18 – 65 years old; and (iii) diagnosis of acute pyelonephritis established based on the presence of fever, lumbar pain, physical findings of cystitis and positive urinary stick (Siemens Healthcare Diagnostics, Tarrytown, NY, USA) with the presence of leucocy-turia or nitrileucocy-turia. Renal and bladder ultrasound were systematically per-formed before inclusion by a senior radiologist in order to exclude any complicated acute pyelonephritis. The significant thresholds chosen for cytobacteriological examination of the urine (CBEU) were≥105cfu/mL for bacteriuria and≥104cfu/mL for leucocyturia.
Exclusion criteria
Patients were excluded from study participation if they met any of the fol-lowing criteria: uro-nephrology history of vesicoureteral reflux, uropathy, nephropathy (any kidney disease), fistula, vesical or ureteric catheter or renal transplantation; immunosuppression history; chronic pyelonephritis; known allergies to b-lactams and cephalosporins; palliative care patients; patients presenting cognitive impairment; patients exhibiting a depriv-ation of judicial/administrative liberty; and patients taking part in any other interventional trial.
Outcome measures
The primary outcome measure was bacteriological efficacy, demon-strated by negative CBEU on day 9 defined as leucocyturia ,104/mL or
bacteriuria ,105cfu/mL. The secondary outcome measures were the
rate of acute pyelonephritis recurrence (defined as new diagnosis of acute pyelonephritis) and the rate of clinical efficacy (defined as no phys-ical findings of cystitis, no fever and no lumbar pain) up to 1 month after stopping treatment (between days 9 and 37) and evaluation of antibiotic tolerance based on the number of adverse events.
The assessments of symptom evolution, healing and treatment toler-ance were conducted during follow-up visits on days 3 and 9 and during a phone consultation on day 37. The day 3 visit confirmed the diagnosis of pyelonephritis (≥105cfu/mL for bacteriuria and≥104cfu/mL for
leucocy-turia) with the result of CBEU and allowed exclusion of patients with 3GC resistance or multidrug resistance. The absence of complicated pyelo-nephritis was confirmed by renal and bladder ultrasound on day 1.
We collected symptomatology data via anamnesis of kidney dysfunc-tion signs and fever. Inflammatory syndrome was assessed initially on day 1 by evaluating C-reactive protein (CRP) levels and leucocyte count follow-ing blood samplfollow-ing and complete blood count. CBEU was performed on days 1, 3 and 9 during follow-up visits, with the results sent to the bacteri-ology laboratory of Clermont-Ferrand University Hospital, France.
Each patient initially received 1 g of intravenous ceftriaxone on day 1, before starting a course of 400 mg of oral cefixime per day at home for 6 days.
Statistical analysis
Since this protocol was a pilot study evaluating the efficacy of the bacterial response to a 3GC treatment, the estimated number of subjects required was obtained using a multistep Fleming design.11,12This pattern
com-prised a single group and sequential analyses (multisteps: between one and five steps), enabling us to assess the efficacy, defined according to a dichotomous success/fail choice, along with its CI. Such a strategy is often implemented in initial Phase II studies in the oncology setting, but is rarely used in other domains.13Taking into account recruitment
capaci-ties, study feasibility and literature data, we decided to consider a two-step process with a lower limit for maximum ineffectiveness set at 85% and an upper limit for minimum efficacy at 95%. Based on these assump-tions, with risks of ‘alpha and beta’ error fixed, respectively, at 0.05 and 0.20, the decision-making rules were at the end of the first step (37 included patients) as follows:
† if ≤33 responses were observed, the treatment was not effect-ive (b¼0.112);
† if ≥36 responses were observed, the treatment was effective (a¼0.018); and
† if 34 or 35 responses were observed, 23 additional patients were to be included.
Statistical analysis was performed using Stata software, version 13 (StataCorp, College Station, TX, USA).
Results
One hundred and thirty acute uncomplicated pyelonephritis cases were diagnosed, of which 124 met the inclusion criteria and only 39 were included in the study (Figure1).
Population characteristics (Table
1
)
Of the 39 patients, 2 were excluded at a later time, the first owing to her first CBEU revealing MDR bacteria and the second due to loss of urine sample.
The average patient age was 32.8+15.1 years. Biological examination revealed evidence of inflammation via increases in leucocyte and CRP levels. Urinary stick assays were positive in 100% of cases, with 32 (86.5%) cases positive for leucocyturia and 14 (37.8%) cases positive for nitrituria.
Clinical outcome
On day 3, 35 patients (94.6%) were afebrile, 5 (13.5%) exhibited no urinary syndrome or lumbar pain, 15 (40.5%) exhibited no
JAC
urinary signs but had persistent lumbar pain, 6 (16.2%) showed improved urinary syndrome and pain and 10 (27.0%) still exhib-ited urinary signs associated with an improvement in lumbar pain. Fever persisted in 2 patients (5.4%), though both showed improvement in urinary syndrome and lumbar pain, while 16 patients (43.2%) presented digestive disorders
On day 9, all patients were afebrile and 30 (81.1%) exhibited no abnormal urinary signs or digestive disorders and had no pain. Among the other seven, all demonstrated clinical improvement, two exhibited persistent urinary irritation, three had lumbar pain and two had both urinary syndrome and lumbar pain. Three patients still presented digestive symptoms.
On day 30, no recurrence of urinary tract infection was observed in any of the patients. Bladder irritation persisted in the majority of cases until day 9, as well as slight lumbar pain. According to the interviews, however, the pain had systematically reduced in the following few days, with these signs no longer reported during the day 37 telephone interviews. In addition, while 43.2% (n ¼ 16) of patients exhibited digestive disorders (nausea and diarrhoea), these disorders had, for the most part, manifested during the course of the protocol but had disappeared by the end of treatment (day 8).
Bacteriological response (Table
2
)
On day 3, 13 urinary sticks (35.1%) were positive, 3 (8.1%) of which were still positive on day 9. Nevertheless, CBEU results on days 3 and 9 were all negative. Among the 37 CBEUs, we found 35 E. coli strains and 2 staphylococci (1 Staphylococcus aureus and 1 Staphylococcus saprophyticus).
Regarding the bacteriological efficacy, we sought to assess, over this period, the bacterial ecology by identifying all the antibiogram results of acute uncomplicated pyelonephritis. In total, 130 acute uncomplicated pyelonephritis cases were diagnosed in our depart-ment. Among these uncomplicated forms, 107 CBEUs were posi-tive, with 95 E. coli strains, 8 S. aureus strains, 7 S. saprophyticus strains, 1 Klebsiella pneumoniae strain, 1 Streptococcus strain and 1 Enterococcus faecium strain.
On resuming the E. coli strain antibiogram (89% of strains) and comparing the resistance rate to the population’s resistance rate we obtained the following results: ampicillin 37% versus 49%; amoxicil-lin/clavulanic acid 12% versus 17%; 3GC 2% versus 0%; nalidixic acid 12% versus 20%; norfloxacin 7% versus 14%; ofloxacin 7% ver-sus 11%; and ciprofloxacin 5% verver-sus 9%. We thus noted that the resistance rate in our population was comparable to that of the excluded patients with acute uncomplicated pyelonephritis, sug-gesting the efficacy of our treatment in this patient population.
It must be underlined that, for two patients, one with a positive S. aureus CBEU and the other with a positive S. saprophyticus CBEU, we achieved treatment efficacy using 3GC, confirming the latter’s Table 1. Characteristics of the 37 patients analysed in the emergency department (N¼37)
Age (years), mean (SD) 32.8 (15.1)
Medical history
uro-nephrology, n (%) 13 (35.1)
diabetes, n (%) 0 (0.0)
allergies, n (%) 4 (10.8)
other, n (%) 13 (35.1)
recent travel abroad, n (%) 4 (10.8)
Clinical examination fever, n (%) 26 (70.3) temperature (8C), mean (SD) 38.4 (0.6) antipyretics, n (%) 19 (51.4) painful urination, n (%) 28 (75.7) pollakiuria, n (%) 24 (64.9)
imperious mictional urge, n (%) 17 (45.9)
lumbar pain, n (%) 36 (97.3)
visual analogue pain scale, mean (SD) 6.8 (1.4)
digestive disorders, n (%) 15 (40.5) other, n (%) 6 (16.2) Haematology leucocytes (×109/L), mean (SD) 12.0 (2.7) neutrophils (×109 /L), mean (SD) 11.4 (12.0) Biochemistry
urea (mmol/L), mean (SD) 3.7 (1.2)
creatinine (mmol/L), mean (SD) 64.7 (9.1)
CRP (mg), mean (SD) 70.6 (62.4)
Bacteriology
positive urinary stick, n (%) 37 (100.0)
positive nitrituria, n (%) 14 (37.8) positive leucocyturia, n (%) 32 (86.5) CBEU, n (%) 37 (100.0) 130 Acute uncomplicated pyelonephritis
6 patients not meeting inclusion criteria (pregnancy, allergies)
- 10 refusal of the informed consent
- 6 demand omissions - 5 impossible follow-up - 49 not feasable kidney ultrasound
- 15 antibiotics self-medication
- 1 patient with loss of urine sample
- 1 patient with MDR bacteria 124
Patients meeting inclusion criteria
39 Included patients
37 Evaluable patients Figure 1. Flow chart.
Moustafa et al.
potential activity against staphylococci susceptible to methicillin, even if 3GC are not reference molecules for staphylococcal infection.
Efficacy
The efficacy pertaining to the management of acute uncompli-cated pyelonephritis was based on a negative CBEU on day 9. All CBEUs were sterile, including for the two patients whose CBEUs had identified a Staphylococcus strain. The study cure rate was thus 100% (93.2% – 100%). The 37 study patients were assessed to be above the maximum level of ineffectiveness (fixed at 90%), leading to the conclusion that this treatment was effect-ive without the need for an additional recruitment process, since ≥36 patients (minimum number for concluding on therapeutic success) were cured.
Discussion
Our study has demonstrated that a short 7 day antibiotic treat-ment with 3GC can be considered to be an effective and well-tolerated treatment in the management of acute uncomplicated pyelonephritis in women aged 18 –65 years.
Several studies have reported the value of short treatment, which enables, in particular, the improvement of therapeutic com-pliance, preservation of the bacterial ecology and prevention of new bacterial resistance, along with the reduction of costs and adverse events.14–16To corroborate these findings, a meta-analysis
conducted by Kyriakidou et al.,14based on PubMed, Cochrane and
Scopus records, compared the efficacy and tolerance of short- ver-sus long-term antibiotic treatment in the management of acute uncomplicated pyelonephritis in adults and teenagers. This meta-analysis, however, did not demonstrate the superiority of the short-term treatment (7 –14 versus 14 –42 days) in terms of clinical efficacy and tolerance. We also wish to underline that, while using the same efficacy and tolerance criteria, Sandberg et al.15recently demonstrated, in their 2012 randomized, double-blind study, the ‘non-inferiority’ of a short-term treatment of 7 days with ciprofloxacin versus a longer-term treatment of 14 days with ciprofloxacin. In this same study, Sandberg et al.15claimed that this
efficacy cannot be extrapolated to other antibiotic classes. This last point appears significant, as the great majority of previous studies were interested in different antibiotics and treatment durations, yet were only focused on the quinolone class.16In contrast, our prospective study is the first to evaluate short-term treatment with 3GC in the management of acute uncomplicated pyelonephritis in women, proving both the treat-ment’s efficacy and good tolerance.
Our study population was similar, in terms of demographics, to those included in studies evaluating short-term fluoroquinolone treatment.16
Nevertheless, our study did introduce some bias as it was monocentric in design, although all patients received ambulatory care, thus rendering this monocentric bias less significant to the therapeutic care. Moreover, given the study’s ‘pilot’ character, no randomization was performed as the efficacy and tolerance of this 3GC treatment had first to be demonstrated. Despite the study’s small sample size, the calculation of the number of patients required allowed us to obtain statistically significant effi-cacy by using the multistep Fleming process, thus validating our hypothesis. A study with a greater number of subjects should Table 2. Antibiotic susceptibility pattern of the bacterial isolates
Susceptible Intermediate Resistant E. coli: 35 isolates b-lactam antibiotics ampicillin 17 1 17 amoxicillin/clavulanic acid 21 8 6 ticarcillin 18 0 17 piperacillin/tazobactam 35 0 0 cefalotin 23 11 1 cefoxitin 35 0 0 cefotaxime 35 0 0 ceftazidime 35 0 0 imipenem 35 0 0 ertapenem 35 0 0 aminoglycosides tobramycin 35 0 0 amikacin 35 0 0 gentamicin 35 0 0 netilmicin 35 0 0 quinolones/fluoroquinolones nalidixic acid 28 0 7 norfloxacin 30 0 5 ofloxacin 30 1 4 ciprofloxacin 31 1 3 other antibiotics trimethoprim/ sulfamethoxazole 28 0 7 nitrofurantoin 35 0 0
Staphylococcus sp.: 2 isolates (1 S. saprophyticus and 1 S. aureus) b-lactam antibiotics oxacillin 2 0 0 aminoglycosides kanamycin 2 0 0 tobramycin 2 0 0 amikacin 2 0 0 gentamicin 2 0 0 macrolides/lincosamides/streptogramins erythromycin 0 0 2 lincomycin 2 0 0 clindamycin 2 0 0 pristinamycin 2 0 0 fluoroquinolones ofloxacin 1 1 0 glycopeptides vancomycin 2 0 0 teicoplanin 2 0 0 other antibiotics tetracycline 2 0 0 minocycline 2 0 0 linezolid 2 0 0 trimethoprim/ sulfamethoxazole 2 0 0 nitrofurantoin 2 0 0 fusidic acid 2 0 0 fosfomycin 1 0 1 rifampicin 2 0 0
JAC
now be conducted in order to compare our therapeutic approach with the one currently recommended in a prospective and non-inferiority randomized study allowing confirmation of our thera-peutic approach.
The proposed therapeutic regimen, to be applied in ambulatory care, showed significant efficacy and good tolerance in our study, further proven by the regular patient follow-up results, on days 3 and 9, which facilitated completion of the study in the community.
Conclusions
Our results suggest the efficacy of short-term ambulatory treat-ment in the managetreat-ment of acute uncomplicated pyelonephritis in young women. The therapeutic regimen included 7 days of 3GC, consisting of one injection of 1 g of ceftriaxone on day 1, followed by cefixime at 200 mg twice daily for 6 days.
Funding
This study was carried out as part of our routine work and no funding has been received for this study.
Transparency declarations
F. M. reports receiving personal fees from Bayer and Sanofi-Aventis and non-financial support from Sanofi-Aventis. N. D. has received personal fees from Bayer and non-financial support from Novartis. J. S. has received fees for board membership from Bayer, Daichi, Lilly and Pfizer, and per-sonal fees from bioMe´rieux, Boehringer Ingelheim, Sanofi and Novartis. All other authors: none to declare.
Author contributions
All authors have had full access to all the study data (including statistical reports and tables) and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors participated in critical revi-sion of the manuscript with regard to its main intellectual content and all approved the final version submitted for publication.
References
1 Salvatore S, Salvatore S, Cattoni E et al. Urinary tract infections in women. Eur J Obstet Gynecol Reprod Biol 2011; 156: 131– 6.
2 Gupta K, Hooton TM, Naber KG et al. International clinical practice guide-lines 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 2011; 52: e103–20.
3 Cohen AE, Lautenbach E, Morales KH et al. Fluoroquinolone-resistant Escherichia coli in the long-term care setting. Am J Med 2006; 119: 958–63.
4 Johnson L, Sabel A, Burman WJ et al. Emergence of fluoroquinolone resistance in outpatient urinary Escherichia coli isolates. Am J Med 2008; 121: 876–84.
5 Gagliotti C, Buttazzi R, Sforza S et al. Resistance to fluoroquinolones and treatment failure/short-term relapse of community-acquired urinary tract infections caused by Escherichia coli. J Infect 2008; 57: 179–84. 6 Robert J, Pe´an Y, Varon E et al. Point prevalence survey of antibiotic use in French hospitals in 2009. J Antimicrob Chemother 2012; 67: 1020–6. 7 Rabaud C. SPILF comments on procedures to be proposed in order to preserve antibiotics as priceless goods, and fight bacterial resistance spreading. Med Mal Infect 2013; 43: 97 –9.
8 Rodrı´guez-Ban˜o J, Picon E, Gijon P et al. Community-onset bacteremia due to extended-spectrum b-lactamase-producing Escherichia coli: risk factors and prognosis. Clin Infect Dis 2010; 50: 40– 8.
9 Courpon-Claudinon A, Lefort A, Panhard X et al. Bacteraemia caused by third-generation cephalosporin-resistant Escherichia coli in France: preva-lence, molecular epidemiology and clinical features. Clin Microbiol Infect 2011; 17: 557–65.
10 Eliakim-Raz N, Yahav D, Paul M et al. Duration of antibiotic treatment for acute pyelonephritis and septic urinary tract infection—7 days or less versus longer treatment: systematic review and meta-analysis of rando-mized controlled trials. J Antimicrob Chemother 2013; 68: 2183–91. 11 Fleming T. One-sample multiple testing procedure for phase II clinical trials. Biometrics 1982; 38: 143–51.
12 Medioni J, de Rycke Y, Tournoux Facon C et al. Phase II multi-step plan-ning methods in oncology: comparison, recommendations and potential applications. Contemp Clin Trials 2007; 28: 249–57.
13 Ratain MJ, Sargent DJ. Optimising the design of phase II oncology trials: the importance of randomisation. Eur J Cancer 2009; 45: 275–80. 14 Kyriakidou KG, Rafailidis P, Matthaiou DK et al. Short- versus long-course antibiotic therapy for acute pyelonephritis in adolescents and adults: a meta-analysis of randomized controlled trials. Clin Ther 2008; 30: 1859– 68.
15 Sandberg T, Skoog G, Hermansson AB et al. Ciprofloxacin for 7 days ver-sus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial. Lancet 2012; 380: 484–90.
16 Klausner HA, Brown P, Peterson J et al. A trial of levofloxacin 750 mg once daily for 5 days versus ciprofloxacin 400 mg and/or 500 mg twice daily for 10 days in the treatment of acute pyelonephritis. Curr Med Res Opin 2007; 23: 2637– 45.
