Nitrofurantoin and Fosfomycin, effective oral empirical treatment options against multidrug resistant Escherichia coli

Objective: The present study is designed to monitor the antibiotic susceptibility pattern of Escherichia coli to assist in forecasting empirical therapy of urinary tract infection. Materials and Methods: It is a retrospective cross-sectional study. It was carried out at Dow Diagnostic Research and Reference Laboratory for a period of 3 months from February 2017 to April 2017. Data of a total of 5000 urine culture and sensitivity test reports were taken from the medical record. The data were analyzed by SPSS version


Introduction
Urinary tract infection (UTI) is among the most common bacterial infections affecting all age groups. 1 It has been estimated that UTIs cause around 8.1 million visits to health care personnel annually presenting as one of the major reasons for global economic burden. 2 Prevalence of UTI is affected by multiple factors such as old age, poor personal hygiene, pregnancy, urinary catheterization, genitourinary tract abnormalities, and co-morbidities like diabetes, HIV infection. 3 UTIs affect both genders but it is more common in the female population. It has been assessed that more than 50% of all women experience at least one UTI during their lifetime, with 20-30% presenting with recurrent UTI due to their anatomy and reproductive physiology. 4 Clinically UTI may present as asymptomatic, acute, chronic, complicated, or uncomplicated depending upon the type of infectious agent, part of urinary tract involved, and patient's immune response. 5 Most UTIs are treated empirically based on the culture and sensitivity pattern generated by regional microbiology laboratories.
The spectrum of antimicrobial susceptibility of UTI pathogens varies from time to time and in different geographic areas. Therefore regular monitoring of the antibiotic susceptibility pattern of uropathogens is very important. However, due to the indiscriminate use of antibiotics, there is high emergence of antibiotic resistance among urinary pathogens making it a major public health problem. 6 At present, new antibiotics that have been approved, are mostly for parental use, so for oral empirical treatment, we have very limited options. Literature search shows that multidrug-resistant Escherichia coli (E. coli) still retains susceptibility to two oral antibiotics are Nitrofurantoin and Fosfomycin. Both maintain high urinary concentration and minimal toxicity in comparison to newer antibiotics and have been considered as safe and effective drugs for the treatment of uncomplicated urinary tract infection in women. 7 With this background, a study is designed to determine the antibiotic susceptibility pattern of E. coli which may help in prescribing effective empirical treatment of urinary tract infection.

Materials and Methods
This retrospective cross-sectional study was conducted in the Microbiology section of DDRRL. Urine culture and sensitivity reports were collected from medical records of the Microbiology section of DDRRL after taking approval from Institutional Review Board (IRB) having Reference No. IRB-1794/DUHS/Approval/2021. This retrospective data record is maintained by the database of LIS (Laboratory Information System) under the supervision of Director DDRRL. The data contains information about the patient's age, gender, isolated organism, and antibiotic susceptibility pattern. The culture reports included samples from both inpatient and outpatient departments during a period from February 2017 to April 2017. A sample size of 5000 subjects was taken which achieved 98% power to detect a difference of 3.9% between two diagnostic tests (Fosfomycin & Nitrofurantoin) whose sensitivities were 95.8% and 91.9% respectively. This procedure used PASS version 15 software, a two-sided McNemar test with a 95% confidence interval. The prevalence of disease in the population was 73.2%. The proportion of discordant pairs was 35.1%. All samples having information regarding the patient's age, gender, and isolated organism were included in the study. However antibiotic susceptibility of antibiotics against only E. coli is included in the study. Samples having a lack of the above-mentioned information were excluded from the study as well as antibiotic susceptibility against organisms other than E. coli is excluded from the study. Urine culture samples were processed as per standard microbiological procedures and antibiotic susceptibility testing by Disk Diffusion method was performed according to CLSI guidelines 2021. 8 The antibiotic discs used for susceptibility testing against E. coli included Amoxicillin / Clavulanic acid 30g, Ampicillin 10g, Amikacin 30g, Meropenem 10g, Piperacillin / Tazobactam 110g, Gentamicin 10g, Ceftriaxone 30g, Cefuroxime 30g, Ciprofloxacin 5g, Cotrimaxazole 25g, Cefixime 5g, Nitrofurantoin 300g and Fosfomycin 200g. The data was entered in SPSS version 16 and statistical analysis was done. Descriptive statistics were measured in percentages.

Results
In the present study, a total of 5000 urine culture and sensitivity test report data was taken from medical records for a period of 3 months from Feb 2017 to April 2017. Out of them, 1565 (31.3%) urine samples were found positive for bacterial growth. Amongst these, 3303 (66%) samples were of female patients and 1697 (34%) samples were of male patients. The frequency of significant bacterial growth was much greater in the patients between 51-60 years of age followed by 21-30 years of age as compared to other age groups. (Figure 1) Among the isolated microorganisms, Gram-negative bacteria 1282 (81%) were more than Gram-positive bacteria 283 (18%). Of the gram-negative bacteria, the most frequent isolate was E. coli 938 (73%). (Table 1) E. coli was found highly sensitive to Meropenem, Amikacin, Fosfomycin, and Nitrofurantoin respectively. (Table 1) * Showing a high percentage of uropathogens in age groups Figure 1: Age-wise distribution of uropathogens in %

Discussion
This study has emphasized on antimicrobial susceptibility pattern of E. coli. This may help physicians in the appropriate selection of antibiotics for empirical treatment of patients suffering from UTI. The prevalence of UTI in our study was found to be 31.3% which is similar to the results of the study done in Rawalpindi by Khan MI. 9 Out of positive bacterial growth samples, 38% were females and 24% were males. Increased prevalence of UTI in females was also found in a research study done by Ullah A. in Kohat Teaching Hospital. 10 Moreover, patients of age group 51-60 years (18%) and 21-30 years (17.5%) were the most commonly affected age group which was consistent with data presented by Bitew A. in 2017. 11 In the present study, out of 1565 (14 species), bacterial isolates were recovered, Gram-negative bacteria constituted (81%) major portion as compared to Gram-positive bacteria (18%). This is in accordance with the study findings by Yadav M. 12 The most prevalent isolated bacteria were found to be E. coli (73.2%), also reported in a study conducted by Khan MI. 9 In the present study, E. coli was found to be highly sensitive to Meropenem, Amikacin, Fosfomycin, and Nitrofurantoin consistent with the results published in studies by Khan IU., Al-Zahrani J. and Pouladfar G. [13][14][15] However it was found resistant to Ampicillin 86%, Cephalosporin 73%, Ciprofloxacin 63% and Cotrimoxazole 69%. A similar pattern was documented in many studies. 9,16,17 Literature shows that Nitrofurantoin is an active drug against E. coli, the most common pathogen of urinary tract infection and overall resistance to it is uncommon and many multidrug-resistant pathogens are still found susceptible to it. Therefore Nitrofurantoin can be prescribed as a first-line antimicrobial option for the empirical therapy of suspected acute uncomplicated cystitis. 18 Susceptibility of Fosfomycin was also found highly effective in multidrug-resistant E. coli in UTI in comparison to other available antibiotics. Similar results were found in many related studies 19,20 which have shown that Fosfomycin is can an effective antibacterial drug for empirical treatment of UTI patients. 21 The Carbapenem group of antibiotics is still a reliable option for parental treatment of urinary tract infection as low resistance has also been observed in other studies. 16,22 Moreover, our study displayed low resistance against Amikacin, compatible findings are noted in other studies as well done in India and Turkey. 12,16 Therefore it can also be preferred as a parental drug for empirical therapy of UTI. As most physicians prefer broad-spectrum antibiotics for the treatment of outpatient UTIs therefore Ciprofloxacin had remained one of the most frequently prescribed antibiotics for UTI treatment. 23 However, a significant increase in antimicrobial resistance to ciprofloxacin has been noticed over a time period. 24 In our study, E. coli showed 63% resistance to ciprofloxacin. Similarly, high Cephalosporin resistance has been recorded in multiple studies due to its unchecked prescription practices. 17 They should be used with caution for empirical treatment in hospitalized patients due to their high resistance rates. Furthermore, high resistance rates of Ampicillin have also been noticed in other related studies by Bitew A. and Demir M. 11,16 Therefore, it is not appropriate to use it as a single agent in empirical treatment.
Cotrimoxazole resistance was also found high in our study which is in agreement with the studies done in 2019 and 2020 respectively. 16,25 Hence, it should not be considered a suitable option for empirical treatment in UTI. The high emergence of antibiotic resistance is mainly due to unchecked doctor practices, self-medication, and non-compliance of the patients. 26 The limitation of the study is that the data was retrospective therefore it was not known whether the patient was symptomatic, asymptomatic, or critically ill. Likewise, the source of the urine samples could not also be identified whether it was midstream urine or taken from a urine bag or catheter. Similarly, the data did not sort out inpatients and outpatients separately. Moreover, patients submitting more than one sample with complaints of recurrent UTI or colonization could not be identified.

Conclusion
The present study revealed that Fosfomycin and Nitrofurantoin are very effective oral antibiotic options for empirical treatment against E. coli causing urinary tract infection. They should be prescribed cautiously by the physicians to avoid the emergence of antibiotic resistance.