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Volume 00, Number 00, 2017
ª Mary Ann Liebert, Inc.
DOI: 10.1089/mdr.2017.0097
The Activity of Fosfomycin Against Extended-Spectrum
Beta-Lactamase-Producing Isolates of Enterobacteriaceae
Recovered from Urinary Tract Infections:
A Single-Center Study Over a Period of 12 Years
Parisa Aris,1 Mohammad Ali Boroumand,2 Mohammad Rahbar,3 and Masoumeh Douraghi1,4
Despite global efforts to tackle resistance in extended-spectrum beta-lactamase (ESBL)-producing isolates via
old antibiotics, there are limited data on the efficacy of fosfomycin—an old oral antibiotic—against Enterobacteriaceae in the Middle East. The purpose of this study was to evaluate the in vitro activity of fosfomycin against urinary ESBL-producing isolates of Enterobacteriaceae. Between 2004 and 2015, 363 isolates of
ESBL-producing Enterobacteriaceae were recovered from high-risk patients suffering from cardiac disorders
and were subjected to polymerase chain reaction using specific primers for the blaTEM, blaSHV, and blaCTX-M
genes. Antibiotic susceptibility testing was performed for fosfomycin and other antibiotic comparators. For the
isolates considered nonsusceptible to fosfomycin by disk diffusion, the minimum inhibitory concentration
(MIC) was determined. The susceptibility rate to fosfomycin remained almost steady (90–100%) over a 12-year
period, although it fluctuated vis-à-vis ciprofloxacin (0–54%), trimethoprim/sulfamethoxazole (9.1–31.7%), and
nitrofurantoin (41.7–100%). Of all the antibiotics tested, fosfomycin was the most active antimicrobial agent
(97%) against the ESBL-positive isolates. Fosfomycin maintained higher activity against ESBL-Escherichia
coli than against ESBL-Klebsiella pneumoniae. Only 11 (3%) isolates were not susceptible to fosfomycin
according to disk diffusion and they had MICs greater than 1,024 mg/ml. All of the fosfomycin-nonsusceptible
isolates were positive for the blaCTX-M gene (100%), while 5 (45.4%) and 3 (27.3%) of the isolates harbored the
blaTEM and blaSHV genes, respectively. We showed that fosfomycin had a numerically higher susceptibility rate
than the other antibiotics against the ESBL-producing isolates of the most common Enterobacteriaceae. Given
its low resistance rate and oral administration, fosfomycin may be deemed a promising antibiotic for the
treatment of urinary tract infections caused by ESBL-producing Enterobacteriaceae.
Keywords: extended-spectrum beta-lactamase, fosfomycin, Enterobacteriaceae
research into multidrug-resistant microorganisms. Detected as
the most frequent ESBL genes, blaTEM, blaSHV, and blaCTX-M
are commonly located on plasmids and are horizontally
transferring between different bacterial species.3–5 In addition, ESBL-carrying organisms are resistant to such a variety of antibiotics as penicillin, third- and fourth-generation
cephalosporins, and monobactams.6 Altogether, therapeutic
options for UTIs are limited owing to the alarming level of
resistance among ESBL-harboring Enterobacteriaceae and
the imprudent use of antibiotics.3,7
Antibiotic-resistant UTIs are potentially serious problems.
In addition, severe consequences of UTIs such as recurrent
mong Enterobacteriaceae, Escherichia coli and
Klebsiella pneumoniae are considered the predominant
causes of healthcare- and community-associated urinary tract
infections (UTIs) around the world. On the strength of their
capacity to produce extended-spectrum beta-lactamases
(ESBLs), Enterobacteriaceae are classified as ‘‘hazard level:
serious’’ by the Centers for Disease Control and Prevention
(CDC).1–3 Over the past decades, ESBLs have been identified
as the main mechanism of antibiotic resistance in E. coli and
K. pneumoniae and have currently become the main focus of
Division of Microbiology, Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
Department of Pathology, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran.
Department of Microbiology, Reference Health Laboratories, Ministry of Health, Tehran, Iran.
Food Microbiology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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UTIs, kidney damage, and eventually sepsis may prove life
threatening. The treatment of these infections is, therefore, a
major therapeutic challenge magnified by the lack of development of new antibiotics.8–11
Reviving old and neglected antibiotics is regarded as a
new strategy to overcome antibiotic resistance and to expand the treatment options. Of old antibiotics, fosfomycin
has been recommended for the treatment of UTIs, despite
the fact that its development dates back to more than four
decades. For all the efforts the world over to tackle this
problem, there is a dearth of data on the efficacy of fosfomycin against the most common Enterobacteriaceae in
Iran—one of the largest countries in the Middle East. We,
consequently, aimed to evaluate the in vitro activity of
fosfomycin against ESBL-producing E. coli, K. pneumoniae, Klebsiella oxytoca, and Enterobacter cloacae isolates
recovered from UTIs in high-risk patients suffering from
cardiac disorders.
trimethoprim/sulfamethoxazole (1.25 mg/23.75 mg), and cefepime (30 mg) using disk diffusion according to the CLSI
guidelines.14 In addition, MIC Test Strips (Liofilchem, Italy)
were used to determine the minimum inhibitory concentrations (MICs) of fosfomycin against the isolates considered
nonsusceptible (intermediate/resistant) by the disk diffusion
method. The results were evaluated using the CLSI breakpoints and interpretive categories for the zone diameter
and the MIC.13 Because no fosfomycin breakpoints for K.
pneumoniae were recommended by the CLSI, the disk diffusion breakpoints for E. coli were considered for interpretation. E. coli strain ATCC 25922 was used as the
susceptibility test quality control.
Materials and Methods
This study was conducted at Tehran Heart Center (THC),
a tertiary care center. A 460-bed hospital, THC is affiliated
with Tehran University of Medical Sciences and provides a
variety of diagnostic, surgical, nonsurgical, therapeutic, and
rehabilitation services for substantial numbers of patients
with cardiovascular diseases from various districts of Tehran, Iran, and all other cities around the country.
The study population comprised patients who were referred to THC because of cardiovascular diseases such as
myocardial infarction, cardiomyopathy, heart failure, congenital heart disease, mitral regurgitation, and arrhythmia
between 2004 and 2015. The patients were admitted to units
dedicated to high-risk cardiac patients such as the intensive
care unit, coronary care unit, heart surgery department, and
emergency department. Demographic characteristics and
medical histories were collected from medical files.
Cases and isolates
The isolates were identified using standard phenotypic microbiologic tests and commercial strips, API 20 E (bioMérieux,
France).12 The ESBLs were detected using the combination
disk test in accordance with the guidelines of the Clinical and
Laboratory Standards Institute (CLSI). In this test, a ceftazidime (30 mg) and cefotaxime (30 mg) disk was applied alone
and in combination with clavulanic acid (30/10 mg). An increase equal to or greater than 5 mm in the inhibition zone of
the agent in combination with clavulanic acid was considered
positive for the production of ESBLs.13 E. coli ATCC 25922
and K. pneumoniae ATCC 700603 strains were used as negative control and positive control, correspondingly. In addition, following the extraction of total DNA, the ESBL genes,
namely blaTEM, blaSHV, and blaCTX-M, were identified via
polymerase chain reaction using gene-specific primers.14
Antimicrobial susceptibility testing
The susceptibility of the isolates of E. coli and K. pneumoniae as well as that of the other isolates was determined to fosfomycin (200 mg), imipenem (10 mg), amikacin
(30 mg), nitrofurantoin (300 mg), meropenem (10 mg), gentamicin (10 mg), ciprofloxacin (5 mg), ceftazidime (30 mg),
Statistical analysis
Data analysis was performed using SPSS version 18.0
(SPSS, Inc.). The descriptive results were shown as frequencies and means.
Over a 12-year period, a collection of 363 nonduplicated
ESBL-producing E. coli (ESBL-EC), K. pneumoniae (ESBLKP), K. oxytoca, and E. cloacae were recovered from cardiac patients suffering from UTIs. The number of isolates
between 2004 and 2015 ranged from 1 to 103 and from 1 to
11 for E. coli and K. pneumoniae, respectively. The patients’ age ranged from 3 to 93 with mean – SD of 64.6 –
14.8 years and median of 66 years. Most of the isolates
were obtained from individuals admitted as inpatients
(either nosocomial or community acquired) (286 out of 356,
80.3%), and the remaining 19.7% of the isolates were obtained from outpatients. Fewer than 50% (47.7%) of the
infected cases were hospitalized in the critical care unit; the
remaining patients were hospitalized in the heart surgery
department (23.0%), the intensive care unit (8.7%), and the
emergency department (0.9%). More than half of the ESBLproducing Enterobacteriaceae isolates were obtained from
females (n = 251, 69.1%). The demographic characteristics
and medical histories of the patients are presented in Table 1.
Between 2004 and 2015, the majority of the collected
ESBL-producing Enterobacteriaceae were E. coli (n = 313,
86.2%), with the other isolates comprising K. pneumoniae
(n = 47, 12.9%), K. oxytoca (n = 2, 0.5%), and E. cloacae
(n = 1, 0.3%).
Susceptibility of the isolates
The susceptibility trend of the ESBL-producing isolates to
fosfomycin, compared to the other antibiotics of choice for UTI
treatment, including ciprofloxacin, nitrofurantoin, and trimethoprim/sulfamethoxazole, during the study period is depicted in
Fig. 1. As is illustrated, the susceptibility to fosfomycin ranged
from 90% to 100%, which was substantially higher than ciprofloxacin (0–54%) and trimethoprim/sulfamethoxazole
(9.1–31.7%). Moreover, the susceptibility rate to nitrofurantoin (41.7–100%) was higher than that to ciprofloxacin,
but the in vitro activity of nitrofurantoin was not comparable to that of fosfomycin. While the susceptibility rate to
ciprofloxacin and nitrofurantoin fluctuated over the 12-year
period, it remained almost steady for fosfomycin.
Table 1. Characteristics and Demographics of Patients Who Endured
Extended-Spectrum Beta-Lactamase-Associated Urinary Infection
No. of tested
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Number of samples
Age, range (median)
Mean age – SD
Male, n (%)
Female, n (%)
Unit of admission
Outpatients, n (%)
Inpatients (either nosocomial or community acquired), n (%)
No. (%)
313 (86.2)
3–93 (66)
65 – 14.9
47 (12.9)
10–82 (63)
63 – 14.0
3–93 (66)
64.6 – 14.8
91 (29.1)
222 (70.9)
20 (42.5)
27 (57.4)
112 (30.9)
251 (69.1)
63 (20.4)
246 (79.6)
6 (13.6)
38 (86.4)
70 (19.7)
286 (80.3)
ESBL, extended-spectrum beta-lactamase; EC, Escherichia coli; KP, Klebsiella pneumonia.
The susceptibility rates of the isolates to fosfomycin and
the other antibiotics are demonstrated in Table 2. Among
the antibiotics tested, fosfomycin was the most active
antimicrobial agent (97%) against the ESBL-positive isolates and imipenem had a notable in vitro activity (94.7%).
However, among the ESBL isolates, there were differences in the susceptibility rates to imipenem and meropenem: the susceptibility rate to imipenem was higher
than that to meropenem. For 306 (97.8%) of the ESBL-EC
isolates, the inhibition zone ranged from 18 to 42 mm,
whereas for 42 (91.3%) of the ESBL-KP isolates, the inhibition zone varied from 16 to 30 mm; all were considered susceptible to fosfomycin. Fosfomycin, in particular,
maintained higher activity to ESBL-EC than ESBL-KP.
Furthermore, the ESBL-EC isolates had a numerically higher
susceptibility rate than the ESBL-KP isolates to nitrofurantoin, ceftazidime, and cefepime.
According to the disk diffusion test, in total, only 11/
363 (3%) of the isolates were not susceptible to fosfomycin: 7/313 (2.2%) of the ESBL-EC and 4/46 (8.7%) of the
ESBL-KP isolates. The isolates classified as ‘‘intermediate
FIG. 1. Percentages of susceptibility of ESBL-producing
Enterobacteriaceae isolates against fosfomycin (C),
nitrofurantoin (;), ciprofloxacin (-), and trimethoprim/
sulfamethoxazole (>) in relation to year of isolation, 2004–
2015. ESBL, extended-spectrum beta-lactamases.
susceptible’’ to fosfomycin by the disk diffusion method
were found resistant using the MIC Test Strips ( MIC
>1,024 mg/ml).
Apropos the detection of the ESBL genes, the most frequent gene was blaCTX-M (74.2%), followed by blaTEM
(54.6%) and blaSHV (14.4%). Although the distributions of
the blaCTX-M and blaTEM genes were almost similar between
the ESBL-EC and ESBL-KP isolates (Table 3), the blaSHV
gene was more frequently found in the ESBL-KP (91.1%)
than in the ESBL-EC (2.6%) isolates. The 11 fosfomycinnonsusceptible isolates (with intermediate susceptibility or
resistance to fosfomycin) were positive for the blaCTX-M
(100%) gene, while 5 (45.4%) and 3 (27.3%) of the isolates harbored the blaTEM and blaSHV genes, correspondingly (Table 4).
Notwithstanding the high distribution of ESBL-producing
Enterobacteriaceae in various regions around the world,15,16
the studies pointing to the activity of fosfomycin against
such isolates in the Middle East are few. Fosfomycin has
been utilized for the treatment of infections, particularly
against veterinary infections, over the past decades.17,18 In
addition, the usefulness of fosfomycin has been highlighted
in recent CLSI reports, proposing the effectiveness of fosfomycin for the treatment of ESBL-associated UTIs.13 Due
to the increasing rate of antibiotic resistance and resultant
limited antibiotics of choice, there is a significant demand
for reviving old antibiotics, mainly those prescribed orally
such as fosfomycin. Accordingly, we conducted the present
study to analyze the activity of fosfomycin against a collection of large series of ESBL-EC and ESBL-KP.
We observed a steady trend of susceptibility of the ESBL
isolates to fosfomycin over a 12-year period. Nevertheless,
the susceptibility rates of the other antibiotics, including
ciprofloxacin, nitrofurantoin, and trimethoprim/sulfamethoxazole,
were lower than that of fosfomycin. Another finding of the
current study is that the majority of the ESBL isolates exhibited susceptibility to fosfomycin, despite their considerable resistance to several beta-lactams.
Although the overall activity of fosfomycin against ESBLEnterobacteriaceae was good, it should be taken into
Table 2. Number and Percentage of Susceptibility to the Antibiotics in Extended-Spectrum
Beta-Lactamase-Producing Enterobacteriaceae Isolates
No. of tested
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Antimicrobial agents
Total susceptibility
No. of tested (no of total), %
account that the ESBL-KP isolates were more likely to be
resistant than the ESBL-EC isolates. The higher activity of
fosfomycin against ESBL-EC was previously supported by
other studies.1,19,20 We found an overall resistance rate of
3% to fosfomycin in the current study, with the resistance
rates being 2.23% in the ESBL-EC and 8.7% in the ESBLKP isolates. A systematic review by Falagas et al. showed
an approximately similar resistance rate (3.2%) for ESBLEC to fosfomycin.1 A study conducted in Spain via the disk
diffusion method reported susceptibility results for ESBLKP to fosfomycin (7.2%) similar to those in our study.21
Using the disk diffusion method, other studies have reported
resistance rates of 0–13.1% for ESBL-EC1,19,21–28 and 7.2–
42.4% for ESBL-KP.1,19,20,22,24–26,28,29 Similar studies using disk diffusion in our neighboring countries such as
Turkey and Pakistan have reported 5.9% and 7% resistance
rates in E. coli and 33.9% and 36% resistance rates in K.
pneumoniae, which are higher than those in our study.24,26
In a study recently conducted in the northwest of Iran with
the disk diffusion method, 2.7% of the ESBL isolates were
found resistant to fosfomycin.30 In the present study, we
detected 11 isolates as fosfomycin nonsusceptible with intermediate susceptibility or resistance. All the fosfomycinnonsusceptible isolates harbored at least 1 ESBL gene. A
notable issue is that the MICs for these isolates were equal
to or greater than 1,024 mg/ml. Despite the low resistance
rate to fosfomycin for the tested isolates, the fosfomycinnonsusceptible isolates exhibited high levels of resistance
via the E-test.
First and foremost among the limitations of the present
study is that it was performed at only a single tertiary hos-
pital. This single center is a specialty cardiac hospital, which
may reduce the generalizability of our results. Another
drawback of note is that we used MIC Test Strips (Liofilchem), containing glucose-6-phosphate, while the approved MIC method for MIC determination is agar dilution
using agar media supplemented with 25 mg/ml of glucose-6phosphate.31
On the contrary, it is of prime importance to assess the
susceptibility of ESBL pathogens in a large number of patients at high risk for the acquisition of drug-resistant bacteria
and admitted at such long-term care facilities. Fosfomycin
was approved by the Food and Drug Administration (FDA)
in 1996 and is currently used in some European countries
and the United States as an intravenous and/or oral antibiotic; nonetheless, resistance to fosfomycin is rare. The story
is somehow different in our country as fosfomycin was not
included in Iran’s pharmacopoeia for clinical setting until
2015. The low rate of resistance in isolates from clinical
setting over the years may imply that fosfomycin has its own
mechanisms of resistance and also it has no cross-resistance
to other antibiotics. In addition, the very high concentrations
of fosfomycin in urine may kill microorganisms and prevent
the selection of mutants.32,33
In conclusion, we showed that fosfomycin had a numerically higher in vitro susceptibility rate than other antibiotics
against ESBL-producing isolates of the most common Enterobacteriaceae such as E. coli and K. pneumoniae. Given
its low resistance rate and oral administration, fosfomycin
could be a promising antibiotic for the treatment of high-risk
cases. Further research is required to investigate the in vivo
efficacy of this antibiotic against UTIs.
Table 3. Frequency of Extended-Spectrum
Beta-Lactamase Genes in ESBL-Producing
Enterobacteriaceae Isolates
Table 4. The Distribution of Extended-Spectrum
Beta-Lactamase Genes
in Fosfomycin-Nonsusceptible Isolates
(n = 313)
(n = 45)
(n = 3)
(n = 361)
No (%)
226 (72.2)
8 (2.6)
173 (55.3)
39 (86.7)
41 (91.1)
23 (51.1)
3 (100)
3 (100)
1 (33.3)
268 (74.2)
52 (14.4)
197 (54.6)
(n = 11)
(n = 4)
No (%)
7 (100)
3 (42.8)
0 (0)
4 (100)
2 (50)
3 (75)
11 (100)
5 (45.4)
3 (27.3)
The authors acknowledge the valuable contribution of the
staff of Tehran Heart Center, Tehran University of Medical
Sciences, Tehran, Iran.
Disclosure Statement
The authors declare that they have no conflict of interest.
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Address correspondence to:
Masoumeh Douraghi, PhD
Division of Microbiology
Department of Pathobiology
School of Public Health
Tehran University of Medical Sciences
Iran 14155-6446
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2017, mdr, 0097
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