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Year : 2022  |  Volume : 9  |  Issue : 2  |  Page : 125-129

Fosfomycin susceptibility among multidrug resistant and extended spectrum β-Lactamase producing uropathogenic Escherichia coli isolates at a tertiary care hospital of Western India

Department of Microbiology, SMS Medical College, Jaipur, Rajasthan, India

Date of Submission07-Feb-2021
Date of Acceptance17-Apr-2021
Date of Web Publication20-Dec-2022

Correspondence Address:
Nita Pal
Department of Microbiology, SMS Medical College, Jaipur, Rajasthan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cjhr.cjhr_21_21

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Introduction: Urinary tract infections are mostly treated empirically with broad-spectrum antibiotics which have resulted in development of multi-drug resistant strains. Limited options of newer antibiotics have necessitated the reintroduction of some old antimicrobial agents such as fosfomycin. Aim: To evaluate the in-vitro activity of fosfomycin against uropathogenic E.coli. Method: A total of 145 E.coli isolates were identified by conventional microbiological procedures and antimicrobial susceptibility performed by Kirby-Bauer disk diffusion method. They were screened for extended spectrum β-lactamase (ESBL) production and screen positives were confirmed by phenotypic confirmatory test (CLSI). Results: Out of 145 isolates, 91 (62.76 %) were found in males and 54 (37.24%) from females. Majority of the isolates were detected in the age group of 21-30 years 48.96%. A very high susceptibility of 94.48% was observed with fosfomycin. Suceptibility to tigecycline and nitrofurantoin was 87.58 % and 77.24 % respectively. Multi-drug resistance was observed in 85.51% isolates and 45.51% were ESBL producers. Conclusion: Fosfomycin showed an excellent in vitro activity against MDR and ESBL producing E.coli, therefore it should be considered as a potential therapeutic alternative in the treatment of UTI.

Keywords: Escherichia coli, fosfomycin, multi-drug resistance, urinary tract infection

How to cite this article:
Jain R, Pal N, Hooja S. Fosfomycin susceptibility among multidrug resistant and extended spectrum β-Lactamase producing uropathogenic Escherichia coli isolates at a tertiary care hospital of Western India. CHRISMED J Health Res 2022;9:125-9

How to cite this URL:
Jain R, Pal N, Hooja S. Fosfomycin susceptibility among multidrug resistant and extended spectrum β-Lactamase producing uropathogenic Escherichia coli isolates at a tertiary care hospital of Western India. CHRISMED J Health Res [serial online] 2022 [cited 2023 Jan 30];9:125-9. Available from: https://www.cjhr.org/text.asp?2022/9/2/125/364532

  Introduction Top

Urinary tract infections (UTIs) are one of the most common clinical entities encountered by medical practitioners. It is commonly caused by Gram-negative bacteria, Escherichia coli being the predominant pathogen and is responsible for both community- and hospital-acquired infections.[1]

Most of the UTIs are treated empirically with broad-spectrum antibiotics. Extensive and inappropriate use of antimicrobial agents has resulted in the development of multidrug resistance (MDR) which has become a major health problem worldwide.[2] Increasing report of extended spectrum β-lactamase (ESBL), Amp C β-lactamase, and carbapenemases producing uropathogens, especially E. coli poses a considerable difficulty in the clinical treatment because of the limited options left for treatment.[3]

Fosfomycin is a phosphonic acid derivative and has a broad-spectrum bactericidal activity against Gram-positive and Gram-negative bacteria. The mechanism of action is by inhibition of cell wall synthesis. It enters the cytosol either by the glucose 6 phosphate inducible hexose monophosphate shunt (UhpT) system which is the primary portal or less efficiently through the glycerol-3-phosphate uptake system (GlpT).[3] Within 4 h of oral dose, the mean peak urinary concentration reaches 2000 μg/ml and is maintained for 1–2 days in sufficient concentrations to inhibit the majority of urinary pathogens. Resistance is commonly chromosomally encoded. However, co-transmission of resistance to fosfomycin and resistance to other antimicrobials through plasmids has been reported but are very rare.[4] Fosfomycin has also shown a good inhibitory effect on multi-drug resistant (MDR) microorganisms producing biofilms.[5]

To ensure proper empiric treatment of UTI and to avoid the emergence of drug resistance, antibiotic resistance pattern of uropathogens should be updated periodically. There is a paucity of data in this part of the country, hence this study was undertaken to assess the susceptibility of fosfomycin among uropathogenic E. coli.

  Materials and Methods Top

This prospective study was conducted in the department of microbiology from June to December 2019. Urine samples were collected from symptomatic patients from both inpatient department (IPD) and outpatient department (OPD) settings. Samples were collected and transported according to recommended guidelines to prevent contamination.[6]

The urine samples were inoculated on MacConkey's agar and blood agar plates using calibrated loop and incubated aerobically at 37°C for 24 h. Single type of colonies >105/ml of urine was considered significant. Significant isolates were biochemically characterized using indole production, citrate utilization, urease production, triple sugar iron agar, and motility.[6] Samples with significant growth of E. coli were included in the study.

Antibiotic susceptibility test was done by Kirby–Bauer disc diffusion method using bacterial suspension matched to 0.5 McFarland standards as inoculum on Mueller Hinton agar (MHA) (HiMedia Laboratories Pvt. Limited, India). Isolates were tested for susceptibility to amikacin (30 μg), gentamicin (10 μg), cefoperazone-sulbactam (75 + 30 μg), imipenem (10 μg), meropenem (10 μg), cefazolin (30 μg), cefotaxime (30 μg), cefepime (30 μg), ciprofloxacin (5 μg), levofloxacin (10 μg), co-trimoxazole (trimethoprim + sulfamethoxazole − 1.25 + 23.7 μg), piperacillin + tazobactam (100 μg + 10 μg), tigecycline (15 μg), ampicillin (10 μg), amoxicillin + clavulanic acid (20 μg + 10 μg), fosfomycin (200 μg + 50 μg glucose-6-phosphate), nitrofurantoin (300 μg), and tetracycline (30 μg) (HiMedia Laboratories Pvt. Limited, India). The zones of inhibition were interpreted according to CLSI guidelines 2019.[7] E. coli ATCC 25922 was used as a control strain. Isolates nonsusceptible >1agent in >3 antimicrobial categories were considered as multidrug resistant (MDR).[8]

As per CLSI recommendation, isolates producing a zone diameter <27 mm against cefotaxime (30 μg) or zone diameter <22 mm against ceftazidime (30 μg) were considered as presumptive ESBL producers. These isolates were confirmed by phenotypic confirmatory test. Ceftazidime/cefotaxime (30 μg) discs alone and in combination with clavulanic acid (ceftazidime/cefotaxime + clavulanic acid, 30/10 μg discs) were placed 30 mm apart center to center on a lawn culture of the test isolate on MHA plate and incubated for 18–24 h at 35°C. An increase of >5 mm in zone of inhibition of the combination discs in comparison with the ceftazidime/cefotaxime disc alone was considered to be ESBL producer.[7]

Statistical analyses

Statistical analysis was done using computer software primer. The qualitative data were expressed in proportion and percentages. The difference in proportion was analyzed using Chi-square test. Significance level for tests was determined as 95% (P < 0.05).

  Results Top

A total 145 E. coli isolates were included in the study. Out of these 70 (48.27%) were IPD patients and 75 (51.72%) were OPD patients. Majority of the isolates were in the age group 21–30 years accounting for 48.96% followed by age group of 31–40 years (14.48%). Among these isolates 91 (62.76%) were from male patients and 54 (37.24%) were from female patients [Table 1]. In this study, E. coli showed highest susceptibility toward fosfomycin (94.48%), tigecycline (87.59%), and nitrofurantoin (77.24%). Susceptibility toward cefotaxime, cefazolin, and levofloxacin was lowest [Table 2]. Multidrug resistance was observed in 85.51% isolates, out of which 53.84% were from IPD patients and 46.15% from OPD patients, difference was not statistically significant (P = 0.86). ESBL production was detected in 45.51% of isolates and all of them were MDR. Among fosfomycin susceptible strains, 84.82% were MDR and 42.06% were ESBL producers. All fosfomycin-resistant strains were MDR and 50.00% were ESBL producers. There was no statistical difference in susceptibility of MDR/non-MDR (P = 0.96) and ESBL/non-ESBL (P = 0.81) isolates toward fosfomycin [Table 2].
Table 1: Age and sex-wise distribution of uropathogenic Escherichia coli

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Table 2: Antibiotic susceptibility pattern of multi-drug resistant and extended spectrum β-lactamase producing Escherichia coli

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  Discussion Top

Treatment of UTIs is becoming increasingly difficult due to the emergence of multidrug resistance among uropathogenic E. coli. With only a few alternative drugs available for these resistant pathogens, testing for old and forgotten antibiotics such as fosfomycin is necessary in addition to the development of newer drugs. In our study, male patients showed a higher prevalence of 62.76% (91/145) compared to that of female patients 37.24% (54/145), whereas earlier studies have reported a higher prevalence in female patients.[1],[2],[9],[10],[11] This difference could be due to the fact that the samples were received from departments other than obstetrics and gynecology. Age group analysis revealed that 21–30 years was the most common presenting age group in both male and female patients. Our finding is in concordance with reports of Bakshi et al.[1] and Sardar et al.,[11] whereas Sundaramurthy et al.[2] reported higher prevalence in elderly group (61–70 years).

Evaluation of multidrug resistance pattern showed that 85.51% of the isolates were MDR. Similar pattern of multidrug resistance was also observed by Sreenivasan et al.[12] and Wagle et al.[13] In various other studies, prevalence of MDR isolates varied from 28.03% to 51.50%,[1],[3],[14],[15],[16] but in a study from Pune, Dalai et al.[17] reported a low prevalence of 14.80%. These variations are due to the differences in antibiotic usage and infection control measures in hospitals of different geographical areas.

In our study, 45.51% of the isolates were ESBL producers which is similar to the study results of Sreenivasan et al. (40.50%)[12] and Sahni et al. (47.6%).[15] However, previous studies have reported a high ESBL positivity rate of 65.30%[17] and 74.15%[12] and a low ESBL positivity rate of 14.8%.[11] All the ESBL producing isolates in our study were MDR. This correlation of ESBL producer and MDR resembles the study conducted by Das et al.,[14] Bakshi et al.,[1] whereas Sahni et al.[15] observed 76.80% of ESBL isolates to be MDR.

The notable finding in our study is 94.48% susceptibility of uropathogenic E. coli isolates to fosfomycin. Similar high susceptibility to fosfomycin was also observed by several recent studies.[12],[13],[14],[16],[18] Some of the authors have reported 100% susceptibility in their studies.[1],[2],[5],[9],[10],[11],[19] Sahni et al.[15] found susceptibility of 83.0% in their study. Fosfomycin susceptibility observed among MDR isolates was 84.82% which is in accordance with the findings of Dalai et al.[17] and Sreenivasan et al.[12] Gopichand et al.,[5] Bakshi et al.,[1] and Anand et al.[3] noted 100% susceptibility among ESBL-producing isolates; however, in the present study, a susceptibility of 92.42% was observed.

Apart from fosfomycin, very good susceptibility was observed towards tigecycline (87.58%) and nitrofurantoin (77.24%) in our study. Both these antibiotics were effective in MDR and ESBL-producing isolates. The Indian Council of Medical Research (ICMR), Antimicrobial Resistance Surveillance Network, 2018 data, reported 88.10% and 86.0% of the isolates were found to be sensitive to two old antibiotics, fosfomycin and nitrofurantoin, respectively.[20] Very good susceptibility towards nitrofurantoin has been observed in many studies,[1],[5],[9],[14],[18] but Anand et al.[3] and Patvardhan et al.[21] reported low sensitivity.

The Treatment Guidelines for Antimicrobial Use in Common Syndromes (2019) by ICMR recommends nitrofurantoin or fosfomycin as a drug of choice for empiric treatment of acute cystitis and co-trimoxazole, ertapenem, or amikacin as alternative choice.[22] We observed moderate susceptibility to Amikacin which was also noted by Gopichand et al.[5] while Bakshi et al.[1] and Das et al.[14] found very good susceptibility. Carbapenems had a good response in few studies,[1],[5],[14],[18] but we observed poor response. Oral antibiotics such as co-trimoxazole and fluoroquinolones which are advised as first-line against UTI showed a poor susceptibility in our study. This finding has been reported by many other researchers as well.[1],[3],[9],[14],[18],[21] This poor susceptibility to co-trimoxazole and fluoroquinolones may be due to the widespread misuse of these drugs for every outpatient and lack of implementation of adequate guidelines for prescribing antibiotics.

To conclude, in the present study, fosfomycin, nitrofurantoin, and tigecycline showed excellent in vitro activity against MDR and ESBL-producing isolates. Therefore, they can be a promising alternative to currently available first-line antibiotics for the treatment of UTI. Benefits of the use of fosfomycin are its low cost, availability in oral form and single dose administration, nontoxic, nonallergic, and tendency to display little cross-resistance to other antibiotics. As only few alternative drugs are available for the resistant uropathogens, it should be remembered that injudicious use of fosfomycin may also lead to the development of resistance to this drug. Therefore, it is necessary to know the antibiotic surveillance patterns in a particular health-care setup. This will not only prevent the emergence and spread of drug resistance but also help in preserving the few leftover antibiotics for future use.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Bakshi R, Sehgal VK, Kansal P, Kaur S. Detection of extended-spectrum beta lactamases and AmpC beta lactamases producing uropathogenic Escherichia coli in a tertiary care hospital. IJMDS 2019;8:1783-92.  Back to cited text no. 1
Sundaramurthy R, Tiruvanamalai R, Sivaraman TS, Arunagiri R, Charles J. Study on clinic-microbiological profile and antibiotic susceptibility pattern of urinary tract pathogens with special reference to susceptibility of Escherichia coli to fosfomycin. IJMR 2018;5:258-66.  Back to cited text no. 2
Anand M, Sahu C, Negi P, Singh A. In vitro Assessment of fosfomycin: A beacon of hope in drug resistant organisms causing urinary tract infections. JAMMR 2019;30:1-9.  Back to cited text no. 3
Li Y, Zheng B, Li Y, Zhu S, Xue F, Liu J. Antimicrobial susceptibility and molecular mechanisms of fosfomycin resistance in clinical Escherichia coli isolates in mainland China. PLoS One 2015;10:e0135269.  Back to cited text no. 4
Gopichand P, Agarwal G, Natarajan M, Mandal J, Deepanjali S, Parameswaran S, et al. In vitro effect of fosfomycin on multi-drug resistant gram-negative bacteria causing urinary tract infections. Infect Drug Resist 2019;12:2005-13.  Back to cited text no. 5
Procop WG, Church LD, Hall SG, Janda MW, Koneman WE, Shreckenberger CP, et al. Koneman's Color Atlas & Textbook of Diagnostic Microbiology. 7th ed. Philadelphia, USA: Lippincott Williams and Wilkins; 2016.  Back to cited text no. 6
Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty Nine Informational Supplement. Vol. 39. Wayne, PA, USA: Clinical and Laboratory Standards Institute (CLSI); 2019. p. M100-S29.  Back to cited text no. 7
Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrugresistant, extensively drugresistant and pandrugresistant bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012;18:26881.  Back to cited text no. 8
Kumar D, Das A, Purbey MK, Gupta N, Nath G. Susceptibility of uropathogenic multidrug-resistant Escherichia coli to fosfomycin. JACM 2017;19:101-4.  Back to cited text no. 9
Gupta V, Rani H, Singla N, Kaistha N, Chander J. Determination of extended-spectrum β-lactamases and ampC production in uropathogenic isolates of Escherichia coli and susceptibility to fosfomycin. JLP 2013;5:90-3.  Back to cited text no. 10
Sardar A, Basireddy SR, Navaz A, Singh M, Kabra V. Comparative evaluation of fosfomycin activity with other antimicrobial agents against E. coli Isolates from urinary tract infections. J Clin Diagn Res 2017;11:C26-9.  Back to cited text no. 11
Sreenivasan S, Kali A, Pravin Charles MV, Kunigal S. Evaluation of in vitro susceptibility of fosfomycin among Enterobacteriaceae isolates from urine cultures: A study from Puducherry. J Lab Physicians 2019;11:249-52.  Back to cited text no. 12
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Wagle S, Khanal BR, Tiwari BR. High susceptibility of fosfomycin to uropathogenic Escherichia coli isolated at tertiary care hospital of Nepal. JAMB 2018;13:1-8.  Back to cited text no. 13
Das B, Mittal N, Goswami R, Adhana D, Rathore N. Prevalence of multidrug resistance (MDR) and extended spectrum betalactamases (ESBLs) among uropathogenic Escherichia coli isolates from female patients in a tertiary care hospital in North India. Int J Reprod Contracept Obstet Gynecol 2018;7:5031-6.  Back to cited text no. 14
Sahni RD, Balaji V, Varghese R, John J, Tansarli GS, Falagas ME. Evaluation of fosfomycin activity against uropathogens in a fosfomycin-naive population in South India: A prospective study. Future Microbiol 2013;8:675-80.  Back to cited text no. 15
Pai KB, Rajagopalan B. Susceptibility of urinary Escherichia coli to fosfomycin and nitrofurantoin-re-exploration of old and forgotten oral antibiotics. JEMDS 2020;9:928-31.  Back to cited text no. 16
Dalai S, Modak M, Lahiri K. Fosfomycin susceptibility among uropathogenic E. coli and K.pneumoniae. IJSR 2019;8:282-4.  Back to cited text no. 17
Shilpa, Baveja KU, Govil D, Wadhwa T, Mehta Y. Susceptibility of multi-drug-resistant organisms (MDROs) isolated from cases of urinary tract infection to fosfomycin (The New Antibiotic) vis-a-vis other antimicrobial agents. J Commum Dis 2018;50:34-7.  Back to cited text no. 18
Khan IU, Mirza IA, Ikram A, Ali S, Hussain A, Ghafoor T. In vitro activity of fosfomycin tromethamine against extended spectrum beta-lactamase producing urinary tract bacteria. J Coll Physicians Surg Pak 2014;24:914-7.  Back to cited text no. 19
Bhargava B, Gopalkrishnan R, Ohri V, Walia K. Treatment Guidelines for Antimicrobial Use in Common Syndromes, 2nd ed. ICMR, New Delhi 2019. Available from: https://main.icmr.nic.in/guidelines. [Last accessed on 2020 Aug 05].  Back to cited text no. 20
Patvardhan V, Singh S. Fosfomycin for the treatment of drug Resistant urinarytract infections: Potential of an old drug not explored fully. Int Urol Nephrol 2017;49:1637-43.  Back to cited text no. 21
Bhargava B, Gopalkrishnan R, Ohri V, Walia K. Treatment Guidelines for Antimicrobial Use in Common Syndromes. 2nd ed. New Delhi: ICMR; 2019.  Back to cited text no. 22


  [Table 1], [Table 2]


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