Infection/Inflammation

Fosfomycin Trometamol versus Comparator Antibiotics for the

Treatment of Acute Uncomplicated Urinary Tract Infections in
Women: A Systematic Review and Meta-Analysis
Tommaso Cai,* Irene Tamanini, Carlo Tascini, Bela Ko € ves, Gernot Bonkat, Mauro Gacci,
Andrea Novelli, Juan Pablo Horcajada,† Truls E. Bjerklund Johansen and George Zanel
From the Departments of Urology (TC, IT), Santa Chiara Hospital, Trento, Infectious Diseases (CT), Cotugno Hospital, Naples and Urology (MG) and Health Sciences
(AN), University of Florence, Florence, Italy, Departments of Urology, South-Pest Teaching Hospital (BK), Budapest, Hungary, and alta uro AG (GB), Basel, Switzerland,
 diques, Universitat
Infectious Diseases Service, Hospital del Mar, Infectious Pathology and Antimicrobials Research Group, Institut Hospital del Mar d’Investigacions Me
Auto noma de Barcelona, CEXS-Universitat Pompeu Fabra Barcelona, Barcelona (JPH), Spain, Department of Urology, Oslo University Hospital and Institute of
Clinical Medicine, University of Oslo, Oslo (TEBJ), Norway, and Department of Medical Microbiology and Infectious Diseases, University of Manitoba (GZ), Winnipeg,
Manitoba, Canada

Purpose: We performed a systematic review and meta-analysis to compare the

Abbreviations
effectiveness and safety profile of fosfomycin vs comparator antibiotics in women
and Acronyms
with acute uncomplicated cystitis.
EAU [ European Association of
Urology
Materials and Methods: Relevant databases were searched using methods rec-
ommended by the PRISMA (Preferred Reporting Items for Systematic Reviews
FT [ fosfomycin trometamol
and Meta-Analysis) guidelines. We assessed the risk of bias and confounders.
MDR [ multidrug resistant The study primary end point was clinical or microbiological success, defined as
RCT [ randomized controlled complete (cure) and/or incomplete resolution of symptoms at the end of treatment
trial (improvement) and/or microbiological eradication.
UTI [ urinary tract infection Results: After screening 539 articles 15 were included which recruited a total of
2,295 adult female patients. Of the studies 14 were used for microbiological
Accepted for publication October 15, 2019.
eradication analysis. We used 11 of the 15 articles in a total of 1,976 patients for
No direct or indirect commercial, personal,
academic, political, religious or ethical incentive clinical resolution and 11 in a total of 1,816 patients for safety outcome analysis.
is associated with publishing this article. No difference was found for clinical resolution in all comparators combined in 11
The corresponding author certifies that, when
randomized controlled trials in a total of 1,976 patients (OR 1.16, 95% CI 0.91-
applicable, a statement(s) has been included in
the manuscript documenting institutional review 1.49, p[0.13). No difference was found for microbiological eradication in 14
board, ethics committee or ethical review board randomized controlled trials in a total of 2,052 patients (OR 1.03, 95% CI 0.83-
study approval; principles of Helsinki Declaration
1.30, p[0.09) or for safety outcome in 11 randomized controlled trials in a total
were followed in lieu of formal ethics committee
approval; institutional animal care and use of 1,816 patients (OR 1.17, 95% CI 0.86-1.58, p[0.33). Most adverse effects re-
committee approval; all human subjects provided ported for fosfomycin were transient and single dose therapy seems to have
written informed consent with guarantees of
resulted in better patient compliance.
confidentiality; IRB approved protocol number;
animal approved project number. Conclusions: Single dose oral fosfomycin trometamol is equal to comparator
* Correspondence: Department of Urology, regimens in terms of clinical and microbiological effectiveness and safety in
Santa Chiara Hospital, Largo Medaglie d'Oro
9, Trento, Italy (telephone: þ39 0461 903306 women with microbiologically confirmed and/or clinically suspected, acute un-
or þ39 3339864943; FAX: þ39 0461 903101; complicated cystitis. It is associated with high patient compliance.
e-mail: [email protected]).
† Financial interest and/or other relationship
with Zambon, MSD, Pfizer and Astellas. Key Words: urinary bladder; cystitis; fosfomycin; drug resistance, bacterial;
women’s health

IN the last several years the treat- of antimicrobial stewardship.1 Inter-

ment of acute uncomplicated UTI has national guidelines recommend a
changed due to the worldwide in- prudent antibiotic approach to the
crease in antimicrobial resistance management of uncomplicated UTI
and implementation of the principles by reducing the prescription of

0022-5347/20/2033-0570/0 https://doi.org/10.1097/JU.0000000000000620
THE JOURNAL OF UROLOGY® Vol. 203, 570-578, March 2020
Ó 2020 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. Printed in U.S.A.

570 j www.auajournals.org/jurology
Copyright © 2020 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 FOSFOMYCIN TROMETAMOL FOR URINARY TRACT INFECTIONS 571

fluoroquinolones and recommending FT and nitro- functional abnormalities in the urinary tract or comor-
furantoin as first line agents.2,3 bidities.2 For this meta-analysis we only included studies
These recommendations are based on 2 types of written in the English language. Abstracts presented at
evidence, including 1) surveillance reports demon- scientific conferences were not considered. Data extrac-
tion, risk of bias assessment using the Cochrane RoB
strating an alarming increase in uropathogens
(Risk of Bias) Tool and quality assessment using the
resistant to fluoroquinolones and other antibiotics
GRADE (Grading of Recommendations, Assessment,
commonly used to treat UTI4 and 2) the favorable Development and Education)11 approach were performed
pharmacokinetic and pharmacodynamic profiles of by 2 of us (TC and IT) working independently, as
fosfomycin and nitrofurantoin along with their high described in our previous study.12
clinical and microbiological efficacy and low risk of
resistance.5 Main Outcome Measures
Oral fosfomycin has also been studied in the The study primary end point was clinical or microbiolog-
ical success, defined as the complete (cure) and/or non-
treatment of complicated UTI with encouraging re-
complete resolution of symptoms (improvement) at the
sults.6 However, recently a comparison between FT end of treatment or microbiological eradication in line
and nitrofurantoin in the empirical treatment of with researcher definitions and the criteria used by
uncomplicated UTI revealed that nitrofurantoin Falagas et al.8 In that study microbiological success was
was superior to FT in terms of clinical cure.7 In a defined as eradication of the infecting strain with no
recent meta-analysis Falagas et al concluded that in recurrent bacteriuria (defined as less than 103 cfu/ml) at
the era of high antimicrobial resistance rates to the end of treatment. Secondary end points included the
alternative antimicrobials fosfomycin represents an presence of adverse events, defined as any adverse event
interesting alternative treatment of acute cystitis in reported at any time during the study period.
nonpregnant and pregnant women as well as in Statistical Considerations
elderly and pediatric patients.8 After extraction we pooled the data to perform a meta-
With this background and bearing in mind the analysis. Outcomes of continuous variables are
worldwide increase in multidrug resistance we expressed as the mean difference and the 95% CI. To
compared the clinical and microbiological effective- analyze dichotomous data we calculated crude (unad-
ness and safety profile of fosfomycin vs comparator justed) ORs and log ORs. The inverse variance method
antibiotics in women with acute uncomplicated was used for the combination of results. Meta-analysis
cystitis in a meta-analysis of relevant RCT and forest plot diagrams were designed using a random
outcomes. effect model since sample sizes differed in the selected
studies. The trim and fill missing study imputation
approach was applied to funnel plots and adjusted overall
MATERIALS AND METHODS effect sizes were calculated according to Duval and
Research Strategy and Literature Search Tweedie.13 We used RevMan, version 5.3.5 software
Two of us (TC and IT) independently searched the (https://community.cochrane.org/help/tools-and-software/
PubMedÒ, Cochrane CENTRAL (Central Register of revman-5).
Controlled Trials) and ScopusÒ databases from July to Variations among studies were calculated using the
October 2018. Any disagreement between the 2 reviewers chi-square test. In addition, I2 was evaluated to indicate
was resolved by a supervisor (MG). All references cited in the proportion of inconsistency among selected studies
relevant articles were also reviewed and analyzed. The which could not be attributed to chance. Separate ana-
search strategy was (fosfomycin) AND (urinary tract lyses were done of all clinical and microbiological out-
infection OR cystitis).8 The filters used included clinical comes to compare fosfomycin with each different type of
trial, humans, female, English language and adults. This antibiotic agent. The risk of publication bias and small
search was performed in 2019 in line with the PRISMA study effects was evaluated by funnel plot analysis.
(Preferred Reporting Items for Systematic Reviews and Finally, the Jadad criteria were used to assess the meth-
Meta-Analyses) statement9 and the recommendations of odological quality of each included trial.14
the EAU guidelines office for performing systematic re-
views and meta-analyses.10 RESULTS
Selection Criteria for Study Inclusion in Meta- Evidence Synthesis and Study Characteristics
Analysis and Data Extraction Our search identified 539 potentially relevant arti-
In this meta-analysis we included all RCTs performed in cles. After screening 15 RCTs in a total of 2,295
female patients older than 18 years old with microbio-
patients were considered eligible for inclusion in the
logically confirmed and/or clinically suspected acute un-
meta-analysis. Figure 1 shows the detailed selection
complicated cystitis who were randomized to receive
treatment with FT or a comparator antibiotic agent used process of included trials. All RCTs were published
to treat UTIs, in line with Falagas et al.8 According to from 1990 to 2018, including 13 before 2000 and 1
EAU guidelines we defined uncomplicated cystitis as each in 2006, 2010 and 2018. A total of 14 studies
acute, sporadic or recurrent cystitis limited to nonpreg- were used for microbiological eradication analysis
nant women with no known relevant anatomical or while 11 of 15 were used for clinical resolution and

Copyright © 2020 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
572 FOSFOMYCIN TROMETAMOL FOR URINARY TRACT INFECTIONS

Figure 1. Search strategy according to PRISMA recommendations

adverse effects analyses. In terms of clinical or a 3 gm single dose treatment with FT. Fosfomycin
microbiological outcomes we selected studies based was compared to fluoroquinolones in 5 of these tri-
on the data available in each study at the followup als, that is to norfloxacin or ciprofloxacin. Moreover,
evaluation. Median followup was 30 days. The fosfomycin was compared with trimethoprim or co-
supplementary table (https://www.jurology.com) trimoxazole in 3 trials, to nitrofurantoin in 3 and
lists characteristics of all included RCTs. to b-lactams (cefalexin and amoxicillin) in 2 (sup-
plementary table, https://www.jurology.com).
Quality Assessment Results Finally, in 2 trials fosfomycin was compared to more
The median Jadad score of all included studies was than 1 antibiotic (ciprofloxacin, nitrofurantoin or co-
2. Two studies had a Jadad score of 1 while only 1 trimoxazole).
had a Jadad score of 5. Six of the 15 studies were double blind and 5 were
multicenter. In 5 of the 15 trials single dose fosfo-
Antibiotic Agent Types and Duration vs mycin treatment was compared to a single dose
Fosfomycin treatment of amoxicillin, norfloxacin, ofloxacin/co-
In all trials included in this analysis the patients trimoxazole or trimethoprim. In the other 10 trials
allocated to the fosfomycin treatment arm received single dose fosfomycin was compared with a longer

Copyright © 2020 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 FOSFOMYCIN TROMETAMOL FOR URINARY TRACT INFECTIONS 573

treatment schedule as the comparators. The sup- (eradication) in women with cystitis who were
plementary table (https://www.jurology.com) lists treated with fosfomycin compared with other
the various types and durations of antibiotic agent antibiotic agents. No study was excluded by funnel
treatment compared with fosfomycin. plot analysis (fig. 3).

Cure Safety Outcomes

Clinical. We considered 11 of 15 RCTs for the eval-
For the safety outcome evaluation we considered 11
uation of clinical cure. In terms of clinical resolu- RCTs providing safety data. No difference was
tion in 11 RCTs in a total of 1,976 patients no found in adverse effects in 11 RCTs in a total of
significant difference was found when all compar- 1,816 patients (OR 1.17, 95% CI 0.86-1.58, p[0.33).
ators were combined (OR 1.16, 95% CI 0.91-1.49, Most adverse effects reported for fosfomycin were
p[0.13). Figure 2 shows clinical success (cure or transient and short-lived. The most commonly re-
improvement) in women with cystitis who were ported adverse effects were of the gastrointestinal
treated with fosfomycin compared with other anti- type. There were no study withdrawals due to
biotic agents. Funnel plots were generated to adverse events in any compared treatment groups
analyze publication bias and small study effects. in the 3 trials providing relevant data. Figure 4
Funnel plot analysis did not suggest the exclusion of shows adverse events analysis in women with
any study (fig. 2). cystitis treated with fosfomycin vs other antibiotic
agents.
Microbiological. We considered 14 of the 15 RCTs for
the evaluation of microbiological eradication. No
DISCUSSION
significant difference was found in terms of
microbiological eradication in 14 RCTs in a total of Main Findings
2,052 patients (OR 1.03, 95% CI 0.83-1.30, We found that single dose oral fosfomycin was not
p[0.09). Figure 3 shows microbiological success inferior to comparator regimens in terms of

Figure 2. Forest plot of clinical resolution and funnel plot of publication bias. ABTs, antibiotics. Event, recurrent UTI.

Copyright © 2020 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
574 FOSFOMYCIN TROMETAMOL FOR URINARY TRACT INFECTIONS

Figure 3. Forest plot of microbiological resolution and funnel plot of publication bias. ABTs, antibiotics. Event, recurrent UTI.

clinical effectiveness in women with microbio- avoid study population heterogeneity and provide
logically confirmed and/or clinically suspected a more valid recommendation for everyday clin-
acute uncomplicated cystitis. Moreover, we ical practice.
observed that fosfomycin treatment was associ- A single dose of fosfomycin is associated with a
ated with only limited and transient adverse low risk of bacterial resistance development, as
events, underlining high clinical efficacy with a noted by Falagas et al8 and Silver.15 In fact, after a
tolerable safety profile. It is worth highlighting single oral dose of 3 gm FT the peak urine con-
that single dose fosfomycin achieved the same centration (above the minimum inhibitory concen-
clinical efficacy as comparator antibiotics with tration of the most common uropathogens) is
longer treatment schedules (single dose vs achieved within 4 hours and persists after 48
several days). hours, when the concentration is still greater than
100 mg/l.8,15,16 The rapid, concentration depen-
Fosfomycin Trometamol Role in Antibiotic dent killing limits resistance selection and when
Stewardship Programs resistant mutants are identified, they show
The latest systematic review and meta-analysis reduced fitness due to the high biological cost of the
of the clinical and microbiological efficacy of fos- genetic modification.16 In addition, the limited use
fomycin was the 2010 study by Falagas et al. 8 of fosfomycin in veterinary medicine also limits
Those researchers concluded that single dose oral resistance development.16 However, administering
fosfomycin treatment was equal to other regi- fosfomycin to manage UTI requires ongoing sur-
mens in terms of clinical effectiveness in mixed veillance to assess the potential spread of plasmid
populations (nonpregnant females, older females borne resistance. In this sense FT represents a
and male patients). The meta-analysis included prudent approach to uncomplicated UTIs and a
many patient subgroups. In contrast, we consid- valuable means of optimizing antimicrobial
ered only women with uncomplicated UTI to stewardship.

Copyright © 2020 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 FOSFOMYCIN TROMETAMOL FOR URINARY TRACT INFECTIONS 575

Figure 4. Forest plot of adverse events in women with cystitis treated with fosfomycin vs other antibiotic agents

Adverse Effects were susceptible to fosfomycin21,22 and a synergis-

Our meta-analysis showed no significant difference tic effect was obtained against Pseudomonas aeru-
in reported adverse effects between fosfomycin and ginosa when fosfomycin was combined with
comparator antibiotics but several aspects should b-lactams.23 This is of particular interest since fos-
be addressed. All reported adverse effects were fomycin is generally considered to have only mod-
mild and transient, and did not cause treatment erate antimicrobial activity against this pathogen.23
withdrawal. However, Van Pienbroek et al re- Moreover, in a systematic review of MDR
ported an overall incidence of side effects twice as Enterobacteriaceae involving 5,057 isolates Fala-
high in the FT group as in the norfloxacin group.17 gas et al observed high fosfomycin activity against
They stated that a possible explanation might be MDR Enterobacteriaceae with extended spectrum
the high dose of FT received by patients on day 1 b-lactamase E. coli as the most susceptible
and a possible placebo effect since by day 9 there isolate.24 Furthermore, in 2010 Falagas et al found
were still patients in the FT group who reported no uropathogen with resistance to fosfomycin8 in
side effects, although receipt of medication ended studies in which a sufficient number of microbial
on day 1. strains were analyzed.18,25,26 This finding has high
In addition, Boerema and Willems reported a clinical relevance. Moreover, the activity of fosfo-
13% incidence of “probably drug related” side effects mycin is also good for carbapenemase-producing
in the fosfomycin group compared with a 3% rate in Enterobacteriae.27 In the era of multidrug resis-
the norfloxacin group.18 They discussed how several tance fosfomycin could be considered an option in
factors might influence this incidence, such as the patients with risk factors for multidrug resistant
placebo effect, concomitant medications and symp- UTI.
toms of underlying disease. Considering the conve-
nience of a single dose of fosfomycin vs multiple
daily and multiday treatment regimens of other Study Strengths and Limitations
antibiotics, we think that FT is a reasonable treat- To our knowledge this is the first meta-analysis
ment alternative in women with uncomplicated comparing fosfomycin treatment with other anti-
UTI. biotic regimens in women with uncomplicated UTI,
excluding pregnant women and including post-
menopausal women. Several limitations should be
Antibiotic Resistance considered, such as considerable heterogeneity in
Fosfomycin has received increasing attention as comparator antibiotics, treatment duration and in-
treatment of UTI due to a low risk of bacterial clusion criteria among the included trials. Also, as
resistance and excellent in vitro activity against highlighted by Falagas et al,8 most included trials
extended spectrum b-lactamase producing MDR were old and had low Jadad scores. Even if we had
Escherichia coli.19,20 In vitro studies demonstrated included only trials on uncomplicated UTI in women
that 99% of E. coli and 46% of Klebsiella species to avoid bias due to subpopulation heterogeneity, we

Copyright © 2020 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
576 FOSFOMYCIN TROMETAMOL FOR URINARY TRACT INFECTIONS

found certain limitations in all included studies. Clinical Implications

1) A considerable number of included trials did not Fosfomycin appears suitable for UTI management
use a blinded design, which could have influenced due to a low incidence of resistance and a good
the clinical resolution. 2) Clinical and microbiolog- safety record. In line with international guidelines
ical efficacy could have been influenced by selection the results of this systematic review support a sin-
and performance bias due to inadequate informa- gle dose of oral FT as treatment of acute uncompli-
tion on allocation concealment. cated cystitis. Fosfomycin offers proven clinical
In particular there has been heavy criti- efficacy, infrequent side effects and low risk of
cism28,29 of the methodology in the study by resistance. All these characteristics are of the
Huttner et al, including the UTI diagnosis (at utmost importance in contemporary management of
least 1 symptom of acute lower UTI and a urine UTI.
dipstick test result positive for nitrites or leuko-
cyte esterase), the study schedule, the timing and CONCLUSIONS
dose of antibiotics and the fact that microbiolog- We found that a single dose of oral fosfomycin was
ical responses were not integrated into the pri- not inferior to comparator antibiotic regimens in
mary outcome but were evaluated as secondary terms of clinical effectiveness and safety in women
outcomes.7 That methodology was contrary to the with microbiologically confirmed and/or clinically
methodology used in other included studies.8,30 suspected acute uncomplicated cystitis. It was also
Moreover, the study by Huttner et al also included associated with high patient compliance. As sup-
hospitalized patients, who represented 7% of the ported by favorable pharmacological characteristics,
nitrofurantoin group and 8% of the fosfomycin we consider oral fosfomycin to be a first choice agent
group.7 in the treatment of uncomplicated UTI.

REFERENCES
1. Lopez Romo A and Quiros R: Appropriate use of randomized clinical trial. JAMA 2018; 319: trials: is blinding necessary? Control Clin Trials
antibiotics: an unmet need. Ther Adv Urol 2019; 1781. 1996; 17: 1.
11: 1756287219832174.
8. Falagas ME, Vouloumanou EK, Togias AG et al: 15. Silver LL: Fosfomycin: mechanism and resistance.
2. Bonkat G, Bartoletti R, Cai T et al: EAU Guidelines Fosfomycin versus other antibiotics for the Cold Spring Harb Perspect Med 2017; 7:
on Urological Infections. Available at https:// treatment of cystitis: a meta-analysis of ran- a025262.
uroweb.org/guideline/urological-infections/. domized controlled trials. J Antimicrob Chemo-
16. Zhanel GG, Walkty AJ and Karlowsky JA: Fos-
Accessed April 21, 2019. ther 2010; 65: 1862.
fomycin: a first-line oral therapy for acute un-
3. Gupta K, Hooton TM, Naber KG et al: Inter- 9. Moher D, Liberati A, Tetzlaff J et al: Preferred complicated cystitis. Can J Infect Dis Med
national clinical practice guidelines for the reporting items for systematic reviews and Microbiol 2016; 2016: 2082693.
treatment of acute uncomplicated cystitis and meta-analyses: the PRISMA statement. Ann
Intern Med 2009; 151: 264. 17. Van Pienbroek E, Hermans J, Kaptein AA et al:
pyelonephritis in women: a 2010 update by
Fosfomycin trometamol in a single dose versus
the Infectious Diseases Society of America 10. K€oves B, Cai T, Veeratterapillay R et al: Benefits seven days nitrofurantoin in the treatment of
and the European society for Microbiology and harms of treatment of asymptomatic acute uncomplicated urinary tract infections in
and Infectious Diseases. Clin Infect Dis 2011;
bacteriuria: a systematic review and meta- women. Pharm World Sci 1993; 15: 257.
52: e103. analysis by the European Association of Urol-
ogy Urological Infection Guidelines Panel. Eur 18. Boerema JB and Willems FT: Fosfomycin tro-
4. Goff DA, Kullar R, Goldstein EJ et al: A global metamol in a single dose versus norfloxacin for
call from five countries to collaborate in anti- Urol 2017; 72: 865.
seven days in the treatment of uncomplicated
biotic stewardship: united we succeed, divided 11. Cochrane Training: Cochrane Handbook for urinary infections in general practice. Infection,
we might fail. Lancet Infect Dis 2017; 17: e56. Systematic Reviews of Interventions. Available suppl., 1990; 18: S80.
5. Novelli A and Rosi E: Pharmacological properties at http://handbook.cochrane.org/. Accessed
September 22, 2019. 19. Zhanel GG, Zhanel MA and Karlowsky JA: Oral
of oral antibiotics for the treatment of uncom- fosfomycin for the treatment of acute and
plicated urinary tract infections. J Chemother, 12. Cai T, Verze P, La Rocca R et al: The role of chronic bacterial prostatitis caused by multidrug-
suppl., 2017; 29: 10. flower pollen extract in managing patients resistant Escherichia coli. Can J Infect Dis Med
affected by chronic prostatitis/chronic pelvic pain Microbiol 2018; 2018: 1404813.
6. Cai T, Cocci A, Verze P et al: The use of oral
syndrome: a comprehensive analysis of all pub-
fosfomycin-trometamol in patients with catheter- 20. Maraki S, Samonis G, Rafailidis PI et al: Sus-
lished clinical trials. BMC Urol 2017; 17: 32.
associated urinary tract infections (CAUTI): new ceptibility of urinary tract bacteria to fosfomycin.
indications for an old antibiotic? J Chemother 13. Duval S and Tweedie R: Trim and fill: a simple Antimicrob Agents Chemother 2009; 53: 4508.
2018; 30: 290. funnel-plot-based method of testing and adjust-
ing for publication bias in meta-analysis. Bio- 21. Marchese A, Gualco L, Debbia EA et al: In vitro
7. Huttner A, Kowalczyk A, Turjeman A et al: Ef- activity of fosfomycin against gram-negative
metrics 2000; 56: 455.
fect of 5-day nitrofurantoin vs single-dose urinary pathogens and the biological cost of
fosfomycin on clinical resolution of uncompli- 14. Jadad AR, Moore RA, Carroll D et al: Assessing fosfomycin resistance. Int J Antimicrob Agents,
cated lower urinary tract infection in women: a the quality of reports of randomized clinical suppl., 2003; 22: 53.

Copyright © 2020 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
 FOSFOMYCIN TROMETAMOL FOR URINARY TRACT INFECTIONS 577

22. Kahlmeter G: An international survey of the 25. Gupta K, Hooton TM and Stamm WE: Isolation of 28. Vallee M and Bruyere F: Re: Angela Huttner,
antimicrobial susceptibility of pathogens from fluoroquinolone resistant rectal Escherichia coli Arina Kowalczyk, Adi Turjeman, et al. Effect of 5-
uncomplicated urinary tract infections: the after treatment of acute uncomplicated cystitis. day nitrofurantoin vs single-dose fosfomycin on
ECO.SENS project. J Antimicrob Chemother J Antimicrob Chemother 2005; 56: 243. clinical resolution of uncomplicated lower urinary
2003; 51: 69. tract infection in women: a randomized clinical
26. Minassian MA, Lewis DA, Chattopadhyay D trial. JAMA 2018; 319: 1781-9. Eur Urol 2018;
23. Takahashi K and Kanno H: Synergistic activities of et al: A comparison between single-dose fosfo-
74: e124.
combinations of beta-lactams, fosfomycin, and mycin trometamol (Monuril) and a 5-day course
tobramycin against Pseudomonas aeruginosa. of trimethoprim in the treatment of uncompli-
29. Barros BS: Antibiotic treatment for uncompli-
Antimicrob Agents Chemother 1984; 26: 789. cated lower urinary tract infection in women. Int
cated urinary tract infections. JAMA 2018; 320:
J Antimicrob Agents 1998; 10: 39.
24. Falagas ME, Kastoris AC, Kapaskelis AM et al: 1284.
Fosfomycin for the treatment of multidrug- 27. Endimiani A, Patel G, Hujer KM et al: In vitro
resistant, including extended-spectrum beta- activity of fosfomycin against blaKPC-containing 30. Stein GE: Comparison of single-dose fosfomycin
lactamase producing, Enterobacteriaceae in- Klebsiella pneumoniae isolates, including those and a 7-day course of nitrofurantoin in female
fections: a systematic review. Lancet Infect Dis nonsusceptible to tigecycline and/or colistin. patients with uncomplicated urinary tract infec-
2010; 10: 43. Antimicrob Agents Chemother 2010; 54: 526. tion. Clin Ther 1999; 21: 1864.

EDITORIAL COMMENTS

As MDR organisms become a more frequent cause of included studies. Most studies were published
uncomplicated UTIs, determining appropriate and before 2000 and had relatively small sample sizes
responsible antibiotic treatment is essential. The and heterogeneous subjects as well as outcomes.
choice of a first line agent should weigh clinical ef- While the authors suggest that fosfomycin should be
ficacy and minimize the “collateral damage” of a first choice agent for uncomplicated UTI, attention
creating resistance (reference 3 in article). These to local microbiograms is prudent. It is important to
authors performed a meta-analysis of the available consider that the availability and cost of fosfomycin
literature to investigate fosfomycin as a treatment may impede access for some patients.
option in these patients. They used the most recent Despite these issues the meta-analysis was
EAU guidelines for uncomplicated cystitis and appropriately designed and lends credence to the
included premenopausal and post-menopausal use of fosfomycin as a first line option as UTI
women, making the study outcomes more clinically treatment in this population. As all physicans in-
relevant. The appeal of fosfomycin in terms of con- crease the focus on antimicrobial stewardship and
venience (single dose administration) as well as the patient compliance, fosfomycin should remain a
lack of resistance is undeniable. Given prior con- solid choice in the armamentarium of tools.
flicting data on the efficacy of fosfomycin, this study
reassures those planning to incorporate fosfomycin Natasha Ginzburg
in practice (reference 7 in article). Department of Urology
SUNY Upstate
Unfortunately, the study is limited in some ways.
Syracuse, New York
As in any meta-analysis, the results depend on the

Although FT is an old antibiotic, in many guide- nitrofurantoin 100 mg 3 times daily for 5 days in
lines it is still recommended as one of the first 255 showed significantly better clinical resolution
antibiotic choices as therapy of acute, uncompli- (75% to 66% vs 70% to 58%) resolution (the primary
cated UTI in women. Therefore, a systematic re- outcome) and microbiological resolution (82% to
view and meta-analysis is highly appreciated. 73% vs 74% to 63%) 14 to 28 days after therapy
The authors included 15 RCTs in a total of 2,295 completion in patients with a positive baseline cul-
patients in the meta-analysis. Of the studies 13 ture who received nitrofurantoin vs FT (reference 7
were published before 2000 and 1 each was pub- in article). The authors included women with at
lished in 2006, 2010 and 2018. No significant least 1 symptom of acute lower UTI and urine
difference was found when all comparators were dipstick findings positive for nitrites and/or leuko-
combined regarding clinical resolution, microbio- cyte esterase. A positive urine culture (103 cfu/ml or
logical eradication (less than 103 cfu/ml) and greater) was found in 194 patients (76%) treated
adverse effects. with nitrofurantoin and in 183 (71%) treated with
Only 1 most recent, open label, analyst blinded, FT.
multicenter, randomized clinical trial comparing a This study differed from earlier studies in that
single 3 gm dose of FT in 258 patients with clinical resolution was the primary outcome

Copyright © 2020 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.
578 FOSFOMYCIN TROMETAMOL FOR URINARY TRACT INFECTIONS

instead of a composite outcome incorporating

Kurt G. Naber
clinical and microbiological responses and Department of Urology
excluding all patients without a positive culture at Technical University of Munich
baseline (representing 27% of patients). This Munich
approach is most meaningful for patients and and
better reflects the clinical reality. However, in
such a study design the implementation of vali-
Florian M. E. Wagenlehner
dated questionnaires would be most helpful for Clinic for Urology, Pediatric Urology and Andrology
clinical diagnostics and patient reported outcome Justus-Liebig University of Giessen
measures.1,2 Giessen, Germany

REFERENCES
1. Alidjanov JF, Naber KG, Pilatz A et al: 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.
2. Alidjanov JF, Naber KG, Pilatz A et al: Additional assessment of Acute Cystitis Symptom Score questionnaire for patient-reported outcome measure in female patients
with acute uncomplicated cystitis. World J Urol 2019; doi: 10.1007/s00345-019-02948-8.

REPLY BY AUTHORS
The comments highlight 2 important aspects, strains all physicians are also requested to
including that as in any meta-analysis the results administer fosfomycin appropriately while
depend on the included studies and the need to considering the role of the local microbiogram
improve physician adherence to the principle of pattern of resistance. Finally, from the methodo-
antimicrobial stewardship. In this sense our meta- logical point of view, we totally agree with the
analysis shows from a practical point of view (as second comment about the need for standardized
highlighted in the first comment) that FT is a valid tools to manage UTIs. In this sense all authors are
option for managing uncomplicated UTIs in the motivated to use validated questionnaires for
era of antimicrobial resistance. In this sense and to clinical diagnostics and patient reported outcome
maintain a low prevalence of fosfomycin resistant measures.

Copyright © 2020 American Urological Association Education and Research, Inc. Unauthorized reproduction of this article is prohibited.