b r a z j i n f e c t d i s .

2 0 1 5;1 9(3):319–323

The Brazilian Journal of

INFECTIOUS DISEASES
www.elsevier.com/locate/bjid

Brief communication

Bacterial sensitivity to fosfomycin in pregnant

women with urinary infection

Rodrigo Batista Souza a , Daisson José Trevisol a,b , Fabiana Schuelter-Trevisol a,b,∗
aPostgraduate Program in Health Sciences at Universidade do Sul de Santa Catarina (UNISUL), Tubarão, SC, Brazil
bAffiliate member of the National Network of Clinical Research (RNPC), Clinical Research Center at Hospital Nossa Senhora da
Conceição, Tubarão, SC, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: The aim this study was to determine the in vitro susceptibility to fosfomycin of bacteria iso-
Received 24 November 2014 lated from urine samples of pregnant women with urinary tract infection. Samples of urine
Accepted 30 December 2014 culture with bacterial growth of pregnant women were collected from clinical laboratories in
Available online 24 January 2015 Tubarão, state of Santa Catarina, Brazil, between September 2012 and May 2013. In the exper-
imental stage, the colonies were tested for sensitivity to fosfomycin by using the Kirby–Bauer
Keywords: method. The following information relating to the samples was also collected: patients’ age,
Fosfomycin colony count, type(s) of identified bacterial(s) and result of the antimicrobial sensitivity test.
Pregnancy Student’s t-test was used for mean comparison. A total of 134 samples were selected for
Urinary tract the study. The age of the subjects ranged from 15 to 40 years (mean 26.7). Escherichia coli
Microbial sensitivity tests (Gram-negative) and Staphylococcus aureus (Gram-positive) were the most commonly identi-
fied species. In 89% of cases, the microorganisms were sensitive to fosfomycin. E. coli and S.
aureus were the main species of bacteria responsible for urinary tract infections in women in
the study area. The most prevalent microorganisms in pregnant women with urinary tract
infection were susceptible to fosfomycin.
© 2015 Published by Elsevier Editora Ltda.

Urinary tract infections (UTI) are common during pregnancy The choice of antimicrobial agents should preferably
due to hormonal and anatomo-physiological changes that consider the urinalysis results, which allow for pathogen iden-
facilitate the growth and dissemination of bacteria in the tification, in addition to antimicrobial susceptibility testing
maternal urinary tract.1 It is estimated that 5–10% of women that indicates the susceptibility of microorganisms to spe-
develop some kind of UTI during pregnancy.2 Asymptomatic cific groups of antimicrobials.4 However, the correct choice
bacteriuria is the most common situation, followed by acute of an antimicrobial agent to treat UTI during pregnancy is
cystitis and pyelonephritis.3 These infections have potentially complex because it requires full attention to maternal and
serious consequences for maternal and fetal health if they are fetal safety, in addition to ease of use, access, and cost of
not properly treated.1 treatment.5

∗
Corresponding author at: Avenida José Acácio Moreira, n◦ 787 Bairro Dehon, Tubarão, Santa Catarina 88704-900, Brazil.
E-mail address: [email protected] (F. Schuelter-Trevisol).
http://dx.doi.org/10.1016/j.bjid.2014.12.009
1413-8670/© 2015 Published by Elsevier Editora Ltda.
320 b r a z j i n f e c t d i s . 2 0 1 5;1 9(3):319–323

Knowing the sensitivity of the etiological agents against The selected samples were tested for sensitivity to
antimicrobial drugs available, linked to relevant epidemiolog- fosfomycin by the disk diffusion method known as the
ical data, helps to make appropriate therapeutic decisions Kirby–Bauer method, as recommended by the Clinical and
based on updated scientific information for adequate treat- Laboratory Standards Institute, described in document M100-
ment, which shortens the symptomatic period and prevents S23, as of January 2013, and based on studies of Minimum
the possibility of recurrences and complications. However, Inhibitory Concentration. The disc used was SENSIBIODISC
in recent years, the problem of antimicrobial resistance has CECON Fosfomicina® for antibiogram in standard concentra-
become very common, mainly because the antimicrobials tion of 200 mcg of the drug, approved by the Brazilian Ministry
once so successful, are no longer effective against several of Health (Registration No. 10000600103) for testing Gram-
bacterial species responsible for infections in the urinary positive and Gram-negative bacteria isolated from human
tract.3–6 urinary tract.
Although the introduction rate of new classes of antibiotics All data obtained in both stages of the study were organized
on the market is limited, some old drugs such as fosfomycin and stored in Excel spreadsheet (Microsoft Office 2010) and
can still provide a temporary solution to the emerging problem analyzed with the use of descriptive statistics, and presented
of resistance, since they have proven to be effective against the in a narrative, tabular, or graphical form. Statistical analysis
prevailing pathogens. was performed using the Statistical Product for Service Solu-
The aim of this study was to demonstrate the in vitro tions v.20.0. Student’s t test was used for mean comparison.
antibacterial susceptibility to fosfomycin of bacteria taken The confidence level was set at 95%.
from urine samples of pregnant women with UTI. A total of 139 samples were selected for the study, of which
This study was approved by the Research Ethics Committee five (3.6%) were excluded; three because of contamination and
of the University of Southern Santa Catarina in November 29, two due to lack of laboratory antimicrobial susceptibility test-
2012 (code number 12.289.4.01.III). ing results.
The study was conducted in two stages: first, an epidemi- The age of participants ranged from 15 to 40 years (mean
ological cross-sectional study to collect data related to urine 26.7; SD 6.2). The most commonly identified microorganism
cultures of pregnant women performed in laboratories of the was Escherichia coli (66.2%), followed by Staphylococcus aureus
city of Tubarão, Santa Catarina, Brazil, between September (14.3%), Klebsiella pneumoniae (3.8%), Enterobacter (3.0%), and
2012 and May 2013; in the second stage, in vitro antibacterial others (12.7%).
susceptibility to fosfomycin of isolated bacterial colonies from The antimicrobial agents tested for antimicrobial sen-
the urinary tract of pregnant women was evaluated. sitivity included nalidixic acid, ampicillin, sulphazotrim,
Thus, the samples consisted of positive urine cultures ciprofloxacin, norfloxacin, and nitrofurantoin (Table 1).
obtained from the participating laboratories, as well as the Eighty-nine percent of the microorganisms were sensitive
following information contained in the reports or patients’ to fosfomycin. Intermediate or resistant isolates included the
records: colony count, identification of isolated species, strains of E. coli (5.9%; n = 8), S. aureus (2.2%; n = 3), Staphylococcus
antimicrobial susceptibility of the tested agents, and age of sp. (1.5%; n = 2), Enterococcus sp. (0.7%; n = 1), and Staphylococcus
pregnant women. saprophyticus (0.7%, n = 1).
The sample size was calculated according to the average The mean age of pregnant women with UTI caused by
annual number of live births in that city, which was 2470, and microorganisms sensitive to fosfomycin was 26.6 years (SD
represented the estimated total number of annual pregnan- 6.2), whereas the mean age of those with UTI caused by resis-
cies in the last decade (2001–2010), according to data from the tant microorganisms was 27.2 years (SD 6.3), [p = 0.731].
Information System on Live Births. Relative sensitivity of the two most commonly isolated
The study sample was collected during nine months, and bacteria in this study to the orally administered antimicrobials
the final sample size of 186 pregnant women took into account safe for use during pregnancy is shown in Table 2.
the average annual number of pregnancies adjusted for the 9- E. coli was the most commonly identified microorganism,
month period (1853 pregnancies), and the percentage of UTI which supports the findings of other studies that indicate
in pregnancy of 10%, as reported in the literature.2 For a con- the predominance of this species in community-acquired
fidence level of 95%, a minimum of 126 urine samples would UTIs among pregnant and non-pregnant women of different
have to be obtained. age-groups.2,4–7 E. coli, in addition to be part of the normal
The inclusion criteria included positive urine culture of intestinal microbial flora, is able to invade and remain in the
pregnant women living in the city of Tubarão, Santa Cata- urinary tract due to structural factors that facilitate adher-
rina, according to Kass’ classification, regardless of symptoms. ence, which justify its predominance when compared to other
There was no access to clinical information regarding the species of the same family (Enterobacteriaceae), also causing
patients’ signs and symptoms. Samples characterized by UTI.8
dehydrated cultures were excluded from the study because Among the Gram-positive microorganisms, about 15% of
of possible contamination by non-pathogenic environmental the samples revealed the presence of S. aureus as the etio-
fungi or other contaminant external agents. Cultures in which logic agent of UTIs. A study performed in a health center in
the necessary information was unavailable or inaccessible for Curitiba, Paraná that evaluated 120 urine samples of men and
any reason were excluded as well. women with suspected UTI found a prevalence rate similar
Information about the age of participating pregnant to that of this study, and S. aureus was isolated in 18.2% of
women, date of urine culture, and date of birth were retrieved cases.9 However, these findings differ from those of other stud-
from records and reports of the participating laboratories. ies in Portugal that found 0.9% of S. aureus in urine samples of
 b r a z j i n f e c t d i s . 2 0 1 5;1 9(3):319–323 321

uncomplicated cystitis in women, and 2.1% in urine samples of

Table 1 – Results of antimicrobial susceptibility testing
based on the sensitivity percentage and number of patients from a pathology service, which can be explained by
tested samples (n = 134). the fact that S. aureus has been considered rare in community-
acquired ITUs. In general, they are responsible for less than 4%
Antimicrobial agents Sensitivity Number of samples
(%) tested (n) of cases.10
Contradictory findings require clarification through new
Aztreonan 100.0 2 epidemiological studies in the geographic areas under
Cefazolin 100.0 1
scrutiny. This study did not aim to examine the criteria
Cefepime 100.0 22
Ceftriaxone 100.0 6
and methods for bacterial identification in the laboratories
Ertapenem 100.0 1 involved, which characterizes one of its limitations.
Linezolid 100.0 1 In this study, fosfomycin was effective in vitro useful
Merapenem 100.0 3 against most strains and identified bacteria, which supports
Oxacillin 100.0 2 the findings of several other authors in similar studies11–13
Penicillin G 100.0 2
and suggests a possible effectiveness in vivo. Andrade and
Piperazobactan 100.0 4
collaborators have obtained 88% of UTI clinical cure among
Vancomycin 100.0 2
Cefoxitin 97.4 39 pregnant women through a single-dose oral administration of
Cephalexin 95.6 23 three grams of fosfomycin trometamol. They also found that
Norfloxacin 94.4 72 the dose did not affect the development of fetuses and that
Ciprofloxacin 93.9 131 adverse effects occurred in less than 10% of cases, limited to
Imipinen 91.9 37 nausea or vomiting.14 In other clinical study, the treatment of
Cefadroxil 90.0 50
cystitis in pregnant women with a single dose of fosfomycin
Chloramphenicol 90.0 10
trometamol was as effective as multiple doses. This medica-
Fosfomycina 89.0 134
Levofloxacin 88.0 50 tion is the preferred treatment of choice due to its ease of
Tetracycline 87.5 24 use.15
Amoxicillin/clavulanic acid 80.0 5 Fosfomycin has a bactericidal effect by inhibiting pep-
Nitrofurantoin 72.2 126 tidoglycan synthesis and blocking the formation of N-
Sulphazotrin 71.8 117 acetylmuramic acid. Its wide spectrum of action reaches the
Ampicillin 62.9 62
target site in Gram-positive and Gram-negative bacteria.16 A
Cephalothin 53.6 28
Nalidixic acid 50.0 60
single dose of fosfomycin is usually effective for the treatment
Pipemidic acid 28.8 59 of uncomplicated UTIs.17 Moreover, it is classified as a preg-
Gentamicin 24.4 45 nancy category B drug by the Food and Drug Administration,3
Amikacin 20.0 35 which means that it is quite safe during pregnancy.
Amoxicillin 10.5 38 With regard to the performance of other antimicrobials,
Erythromycin 0.0 1
the analysis was focused on the most widely prescribed oral
a
Result obtained in the experimental stage of the study. drugs for pregnant women, according to the literature. The
most reliable medications include penicillin, cephalosporin

Table 2 – Relative sensitivity profile of Escherichia coli and Staphylococcus aureus compared to the orally administered
group of antimicrobial drugs safe for use during pregnancy.
Antimicrobial agents S R/I n Duration of treatment

n (%)

Escherichia coli
Cephalexin 93.3 6.7 15 10 days
Fosfomycin 90.9 9.1 88 Single dose
Cefadroxil 88.9 11.1 27 3 days
Amoxicillin/clavulanic acid 80.0 20.0 5 7–10 days
Ampicillin 64.9 35.1 37 7–14 days
Amoxicillin 13.6 86.4 22 7–10 days

Staphylococcus aureus
Cefadroxil 100.0 0 6 3 days
Cephalexin 100.0 0 2 10 days
Fosfomycin 84.2 15.8 19 Single dose
Ampicillin 83.3 16.7 6 7–14 days
Amoxicillin 7.1 92.9 14 7–10 days
Amoxicillin/clavulanic acid NA NA – 7–10 days

S, sensitive; R/I, resistant or intermediate.

322 b r a z j i n f e c t d i s . 2 0 1 5;1 9(3):319–323

and related compounds, which have low toxicity, even though The results of this study maintain fosfomycin as an option
they may cause unpredictable allergic reactions.18 Nitrofu- of choice for empiric use in cystitis among pregnant women,
rantoin has been shown to be effective, but it is associated as recommended by the guidelines of the Brazilian Society of
with hemolytic anemia of the newborn when used in the last Infectious Diseases and the Brazilian Society of Urology. In
trimester of gestation, although it is the most appropriate most cases, empirical therapy is necessary to accelerate symp-
choice in the case of recurring infections.19 Quinolones are toms remission and prevent infection progression, at least
a pharmacological alternative, because they are classified as while the urine culture and antimicrobial sensistivity test-
a pregnancy category B drug by the Food and Drug Admin- ing are processed by the clinical laboratory. In Brazil, there
istration, although its use is controversial because of the is a paucity of research in antimicrobial resistance of urinary
risk of damage to fetal cartilage and joint development.20,21 pathogens among adults in the community. Based on these
In this study, ciprofloxacin had a similar effect to that of results, new studies are warranted to define the prevalence of
fosfomycin. Contrastingly, the percentage of bacterial resis- UTIs and clinical effectiveness of prescribed antibiotics.
tance to nitrofurantoin was almost one-third of the samples In conclusion, out of the 136 analyzed isolates, E. coli and
tested. S. aureus were the main species responsible for UTIs among
The present study found that amoxicillin associated pregnant women in the study area. The most commonly
with a clavulanic acid (beta-lactamase inhibitor) showed used antimicrobial agents in the sensitivity tests performed
low performance for S. aureus, because the percentage of by clinical laboratories included nalidixic acid, pipemidic
antibiotic-resistance was relatively high. Laboratories do not acid, cefadroxil, nitrofurantoin, amoxicillin, ampicillin, sulp-
commonly test amoxicillin associated with beta-lactamase hazotrim, ciprofloxacin, norfloxacin, and levofloxacin, many
inhibitor, and this is a limiting factor for the conclusions of of which are contraindicated for pregnant women. Sensitivity
this study. of isolated bacteria to fosfomycin was 89%, which indicates
E. coli was resistant to amoxicillin, as well as to ampi- that it might be an effective, safe and convenient therapeutic
cillin, showing a high rate of resistance (above 20%). On option for the treatment of uncomplicated UTIs during preg-
the other hand, the sensitivity rate to cephalosporins and nancy.
amoxicillin associated with clavulanic acid was equal to
or above 80%. However, the number of samples tested for
the latter was small, making the comparative analysis with Conflicts of interest
fosfomycin less valid. It is noteworthy that the appear-
ance of strains that produce beta-lactamases of an extended The authors declare no conflicts of interest.
spectrum has increased among community- and nosocomial-
acquired enterobacteria.22
It should be emphasized that none of the participating Acknowledgements
laboratories included fosfomycin on the list of antimicrobial
agents for performing antimicrobial susceptibility testing of We are thankful to the following clinical analysis laborato-
isolated bacteria. The results presented here were obtained in ries of Tubarão, Santa Catarina: LAC/UNISUL, Santa Catarina,
the evaluation phase of this study. Santa Clara, Santé, Dr. Roberto and Cabral, and their respective
In the context of a rational use of antimicrobial agents, administrative and technical staff, who voluntarily collabo-
the drug choice has to take into account its efficacy, safety, rated with this study, and made it possible.
convenience, and access. This means that the rational use of
medications occurs when patients receive medications appro-
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