ABSTRACT
Background:
Urinary tract Infection is one of the most prevalent clinical entities affecting people worldwide. The accelerating rate of antimicrobial resistance due to the unimpeded and rampant use of antimicrobials with over the counter availability of drugs has limited the therapeutic options for the treatment of UTI. Fosfomycin, an old broad spectrum antimicrobial with good pharmacokinetics have regained the importance for the treatment of multidrug resistant (MDR) isolates. The purpose of this study was to determine the in vitro Fosfomycin susceptibility of common uropathogens and to study the resistance pattern of these organisms against commonly prescribed antimicrobial agents.
Material and Methods:
A retrospective cross-sectional study was conducted in the Bacteriology section of the Microbiology laboratory at Adesh Institute of Medical Sciences and Research, Bathinda, Punjab, for duration of 6 months from Dec 2022 to May 2023 from urine samples received from all clinically suspected cases of UTI. Samples were processed immediately as per standard microbiological techniques, followed by culture by a semi-quantitative method. Kass criteria were followed for interpretation of significant bacteriuria according to which significant growth was considered if colony count was more than equal to 105 colony forming unit (CFU)/mL. Culture positives were analysed by gram staining and on the basis of colony characteristics, gram staining, final identification, and antimicrobial susceptibility were done via Vitek 2 compact system.
Results:
A total of 2292 urine samples received in the Microbiology laboratory were processed and cultured during the study period, which yielded 509 significant bacterial isolates, i.e. 509/2292 (22.2%) culture positivity. Among 509 culture positive samples, Escherichia coli 235/509 (46.1%) was the most common uropathogen isolated followed by Klebsiella pneumoniae 107/509 (21.1%), Enterococcus species 40/509 (7.8%). Fosfomycin depicted good in vitro susceptibility of minimum 94% in both gram negative and gram positive uropathogens as compared to nitrofurantoin that showed sensitivity of 74% and 85%, respectively. Maximum resistance was observed towards cephalosporins, i.e., ceftriaxone in Escherichia coli (60%) and Klebsiella pneumoniae (64%) respectively followed by 50% in Acinetobacter baumannii. Maximum resistance to ciprofloxacin (62%) was seen in case of Acinetobacter baumannii. 172/405 (42.4%) isolates of Enterobacteriaceae family were extended spectrum β lactamase (ESBL) producers with an average Fosfomycin susceptibility of 95.9%. Among the total isolated uropathogens, 135/509 (26.5%) were multidrug resistant, out of which 116/135 (85.9%) depicted Fosfomycin susceptibility. Metallobetalactamase (MBL) production was seen in 14.3% of the isolated gram negative uropathogens. 63/73 (86.3%) of the MBL producers were found susceptible to Fosfomycin.
Interpretation and Conclusion:
Fosfomycin has emerged as an effective alternative for the treatment of common uropathogens including the MDR’s, ESBL producers and the MBL’s in the era of increasing antimicrobial resistance. It has the potential to act as a promising oral agent for the treatment of UTI in both community and healthcare setups.
Keywords: ESBL’s, Fosfomycin, MBL’s, uropathogens, multidrug resistance
Introduction
Urinary tract infections (UTI) are one of the most common ailments associated with significant morbidity and mortality in both Community and healthcare setups.[1] Among a wide array of both gram positive and gram negative pathogens responsible for causing UTI, they are known to harbour multiple drug resistance either inherited or transmissible against the most routinely used antimicrobial agents, i.e. cotrimoxazole, norfloxacin, nitrofurantoin, cephalosporins, semisynthetic penicillins with beta lactamase inhibitors, etc., Rampant and uncontrolled use of antibiotics has drastically altered the resistance pattern of uropathogens thus leading to the treatment failure and increased prevalence of multidrug resistant uropathogens (MDRs). MDR’s are the organisms resistant to any three different classes of antibiotics.[2] Acquired antibiotic resistance can occur because of varied mechanisms like a) presence of active efflux pumps; b) altering cell membrane permeability and bypassing of metabolic pathway; c) alteration of the drug target; d) enzymatic inactivation and modification. The production of β-lactamases is the most important mechanism contributing to drug resistance.[3] Among the beta lactamases, extended spectrum β-lactamases (ESBL’s) are the plasmid mediated enzymes that have the capacity to hydrolyse many β-lactams antibiotics, including third-generation cephalosporins and monobactams[4] whereas metallo-betalactamases (MBL’s) are a diverse set of enzymes that catalyses the hydrolysis of a broad range of β-lactam drugs, including carbapenems (Imipenem, Meropenem, etc.).[5] In the scenario of emerging multidrug Resistance (MDR), the treatment options with oral drugs usually prescribed are becoming limited with the role of injectables in place thus increasing the inpatient hospital stay with increased financial burden even in uncomplicated UTI.
Overuse and misuse of antimicrobials have limited the therapeutic options for treatment of UTI which has led to increase in prevalence of multidrug resistant uropathogens. (MDRs). Meanwhile, Fosfomycin, a phosphonic acid derivative discovered in Spain in 1969, produced by Streptomyces spp., acts by inhibition of cell wall synthesis by causing inhibition of phosphoenol pyruvate, an old antibiotic has regained its value for the treatment of UTI in MDR uropathogens. Its oral regimen with maximum urinary concentration varying between 1053 mg/l and 3749 mg/l, 2 hours after administration of 3 gm oral preparation of Fosfomycin trometamol maintaining its level for 24 hours is an added advantage.[6] Approximately, 93-99% of above is excreted unchanged in urine with minimal binding to plasma proteins. It’s broad spectrum coverage including multidrug resistant strains and minimal cross resistance with other antibiotics is a privilege over other antibiotics. It has a tendency to achieve 80% microbiological eradication in cystitis in treated patients with 90% clinical healing in infections caused by ESBL strains. Even in asymptomatic bacteriuria in pregnancy, it can serve as a miracle drug. Moreover in paediatric population, its easy dosage, urinary concentration, minimal side effects and unalteration of intestinal flora are the additional advantages. Its synergistic effect in combination with other antibiotics like daptomycin and imipenem greater dissemination than other antibiotics through biofilms is useful in treating complex infections by multidrug resistant strains.[6] Thus with such clinical implications, Fosfomycin with single-time oral therapy, can serve as a wonder drug and a greater therapeutic option in case of uropathogens.[2] The potential for the emergence of resistance during therapy, causing selection of resistant mutants is an important consideration to be taken into account.[7] Keeping in mind the increasing resistance of uropathogens, the present study was undertaken to evaluate the in vitro antimicrobial activity of Fosfomycin among the multidrug resistant uropathogens in comparison to other antibiotics which can serve as an additional aid for healthcare providers in the treatment of the multidrug resistant superbugs.
Materials and Methods
A retrospective observational study was conducted in the Bacteriology section of Microbiology laboratory at Adesh Institute of Medical Sciences and Research, Bathinda, Punjab. The study period was 6 months for which data was collected (Dec 2022 to May 2023) and analysed. Institutional Research committee, Ethics committee for biomedical and health research, Adesh University permissions were taken before starting the study. Urine samples received in the laboratory with clinical suspicion of UTI whether midstream clean catch urine sample, surgically collected urine samples, and urine received from the catheter with proper surgical asepsis with needle and syringe were included in the study. All the non-duplicate urine samples received in the laboratory for urine culture and sensitivity were processed. Demographic details and clinical information was also collected
Inclusion criteria- All the non-duplicate bacterial isolates with significant bacteriuria were included in the study.
Exclusion criteria- Improper labelling of the urine samples with incomplete demographic details and clinical data
- Urine samples received from children <12 years.
- Urine samples with fungal isolates
- Repeat samples received for processing.
Study procedure
The samples were received in universal sterile containers appropriately labelled and analysed within two hours after collection. Routine microscopic examination of urine samples was done to look for pus cells, red blood cells, casts and epithelial cells. Urine culture was done by semi-quantitative method in which a loopful 0.001 mL of well mixed uncentrifuged urine was inoculated on blood agar and CLED (Cysteine Lactose Electrolyte Deficient medium) agar and incubated for 24-48 hours at 37°C aerobically to check for the bacterial growth. The plates were then examined macroscopically for bacterial growth. Kass criteria were followed for interpretation of significant bacteriuria according to which significant growth was considered if number of colony count was more than 105 CFU/mL.[8]
Culture positives were analysed by gram stain and on the basis of colony characteristics, gram staining, biochemical tests, final identification were done using Vitek 2 compact system. Out of the 2292 total urine samples received, 509 samples showed culture positivity. Isolates identified as multidrug resistant were further analysed for their susceptibility to Fosfomycin. For gram positive organisms GP card 628 was used and for gram negative GN card 405 and 406 was used. Fosfomycin susceptibility in gram positive bacteria and nitrofurantoin susceptibility in gram negative bacteria was done on Mueller Hinton Agar by Kirby Bauer disc diffusion method and zone diameter was interpreted according to the latest CLSI guidelines M100 published in 2022.[9] In addition to Vitek-2, the potential ESBL producers showing resistance to third-generation cephalosporins were also manually subjected to phenotypic confirmatory tests, a double-disk synergy test and a combined disk assay method. For MBL production, all gram negative isolates showing resistance to Imipenem and Meropenem antibiotic disks via Vitek-2 were subjected to phenotypic confirmatory tests, an Imipenem-ethylene diaminetetraacetic acid combined disk test, and an Imipenem-ethylenediamine tetraacetic acid double-disk synergy test.[4] Collected data was all compiled in the MS Excel sheet and applicable statically analysis was done. Data was analysed and effectiveness of Fosfomycin over other drugs was calculated in frequencies and percentages.
Results
A total of 2292 urine samples were received after fulfilling the inclusion criteria, out of which 509 (22.2%) samples yielded significant growth on culture. 276 (54.3%) were females, 233 (45.7%) were males as shown in Figure 1. Mean age of the patient was 38 years, representing the sexually active females. Most of the culture positive urine samples were from different IPD’s (47.1%), maximum from Obstetrics and Gynaecology, Medicine and Paediatric wards followed by OPD (39.2%) maximum from Urology and Medicine OPDs, and 7.3% were from Emergency and 6.4% were from ICU’s [Table 1].
Figure 1.
Pie chart depicting culture positive urine samples
Table 1.
Department-wise distribution of uropathogens
| Department | No of isolates | Percentage |
|---|---|---|
| OPD | 200 | 39.2 |
| IPD | 240 | 47.1 |
| Emergency | 37 | 7.3 |
| ICU | 32 | 6.4 |
Among the culture-positive samples, the most common uropathogens in the present study were members of Enterobacterales—E coli (46.1%), followed by K pneumoniae (21.1%) as shown in Figure 2
Figure 2.
Distribution (percentage) of isolated uropathogens
Among the gram negative isolates, lower rates of resistance were observed for Imipenem (14%), Tigecycline (13%) and Colistin (7%). Fosfomycin depicted a good in vitro activity of minimum 93% in Enterobacterales. Relatively Nitrofurantoin showed a susceptibility of 72% in Enterobacterales. Third-generation cephalosporins, i.e. Ceftriaxone in Escherichia coli and Klebsiella pneumoniae showed maximum resistance of 60% and 64% respectively followed by 50% in Acinetobacter baumannii. 55% and 58% isolates of Escherichia coli and Klebsiella pneumoniae were resistant to ciprofloxacin. Maximum resistance to ciprofloxacin (62%) was seen in case of Acinetobacter baumannii as shown in Figure 3
Figure 3.
Antimicrobial resistance (%) of the isolated gram negative uropathogens
Staphylococcus aureus showed maximum resistance towards BenzylPenicillin (60%) while Linezolid, Vancomycin, Teicoplanin showed excellent sensitivity of 96%, 96% and 97%, respectively.
Fosfomycin was effective in vitro against 94% and 100% of Staphylococcus aureus and Enterococcus spp. respectively as shown in Figure 4.
Figure 4.
Antimicrobial resistance (%) of isolated gram positive uropathogens
Maximum ESBL production was seen in Klebsiella pneumoniae (58.8%) with susceptibility for Fosfomycin for 90.9% as depicted in Figure 5.
Figure 5.
Fosfomycin susceptibility among ESBL producing isolates of Enterobacteriaceae
Figures 6 and 7 depict distribution (%) of MDR and MBL producing isolates and Fosfomycin susceptibility. Among all the isolated uropathogens, 26.5% were multidrug resistant out of which 85.9% depicted Fosfomycin susceptibility. MBL production was seen in 14.3% of the isolated gram negative uropathogens. 86.3% of MBL producers were found susceptible to Fosfomycin.
Figure 6.
Distribution (%) of MDR and MBL producing isolates
Figure 7.
Fosfomycin susceptibility among MDR and MBL producers
Discussion
Urinary tract infections are one of the primary ailments encountered in both community and healthcare setups. The emergence of resistance to regularly used antibiotics has left limited therapeutic options for UTI. Hence, there is an increasing need to develop and introduce new antimicrobials for this purpose. With the scarcity of availability of antimicrobials, the old and forgotten antibiotics have retrieved their importance for treatment of UTI. Hence, the present study was undertaken to look for Fosfomycin susceptibility among isolated uropathogens including the multidrug resistant strains. A total of 2292 urine samples were studied for a period of 6 months, (509) 22.2% of which depicted culture positivity [Figure 1]. Similar results were shown by studies done by Sharmin S et al.[10] reported the incidence of UTI as 17.3%. Lower rate of UTI was observed in Indian study conducted by Singh M.M et al.[11] that depicted the culture positivity of 4.2%. Females (54.3%) showed a higher preponderance than males (45.7%) which was consistent with the data shown by various studies.[10,12] This could be attributed to the shorter urethra and the close proximity of urethral meatus to anus in females leading to increased chances of UTI in females. Maximum culture positivity was seen from the samples received from the Obstetrics and Gynaecology patients as maximum urine samples were received from there followed by urology OPD. 6.4% of urine samples were from ICU’s mostly from the catheterized patients [Table 1].
Among 509 culture positive samples, most common uropathogens isolated was Escherichia coli 235/509 (46.1%) followed by Klebsiella pneumoniae107/509 (21.1%), Enterococcus species 40/509 (7.8%) [Figure 2]. Similar results were seen in a study done by Sharmin S[10] where members of the Enterobacterales-Escherichia coli (65.84%), followed by Klebsiella pneumoniae (16.49%) were the most common uropathogens isolated. Another study conducted by Sharlee R et al.[13] found that out of 103 gram negative bacilli, majority were Escherichia coli with 29.1% followed by Klebsiella pneumoniae 25.3%, Pseudomonas aeruginosa 3%, Acinetobacter 3%, Enterobacterales 1.9% and Citrobacter species 1.2%. Out of 59 gram positive cocci, majority were Staph. aureus with 22.2% followed by Coagulase negative Staphylococcus with 11.7% and Enterococcus species as 2.6%.
In the current study, among the isolated gram negative uropathogens, third-generation cephalosporins, i.e. ceftriaxone in Escherichia coli and Klebsiella pneumoniae showed maximum resistance of 60% and 64% respectively followed by 50% in Acinetobacter baumannii. 55% and 58% isolates of Escherichia coli and Klebsiella pneumoniae were resistant to Ciprofloxacin. Maximum resistance to Ciprofloxacin (62%) was seen in case of Acinetobacter baumannii. A fairly good sensitivity was seen in case of Fosfomycin in all gram negative isolates of minimum 93% as compared to nitrofurantoin with 72% susceptibility. Furthermore, Tigecycline and Colistin also showed a good pattern of sensitivity [Figure 3].
Similarly, among the isolated gram positive uropathogens, penicillins were the most resistant (60%) while Linezolid, Vancomycin, Teicoplanin showed excellent sensitivity of 96%, 96% and 97%, respectively. Fosfomycin showed excellent activity against both Staphylococcus aureus (94%) and Enterococcus (100%) [Figure 4].
In addition, on evaluation of ESBL production among the 405 isolates of Enterobacteriaceae family, 108/235 (45.9%) Escherichia coli, 55/107 (58.8%) of Klebsiella pneumoniae, 6/23 (26%) of Enterobacter aerogenes, 2/27 (7.4%), Proteus spp and 2/13 (15.3%) Citrobacter spp. was ESBL producers. Fosfomycin depicted a good in vitro activity against these ESBL producers as 106/108 (98.1%) of Escherichia coli, 50/55 (90.9%) of Klebsiella pneumoniae, 5/6 (83.3%) of Enterobacter aerogenes and both the ESBL producing isolates of Proteus and Citrobacter were found susceptible to Fosfomycin [Figure 5]. Gopichand et al.,[14] Bakshi et al.[15] and Anand et al.[16] noted 100% susceptibility of Fosfomycin among ESBL producing isolates.
Multidrug resistant (MDR) organisms are resistant to any three different classes of antibiotics as defined by the standard guidelines.[2] Among all the isolated uropathogens, 26.5% were multidrug resistant out of which 85.9% depicted Fosfomycin susceptibility [Figure 6, Figure 7]. Similar observation was seen in various other studies where prevalence of MDR isolates varied from 28.03% to51.50%.[15,16,17,18,19] Another study from Pune, Dalai et al.[20] reported a low prevalence of 14.80%. These variations are due to the different antibiotic usages and infection control measures in hospitals of different geographical areas.
Acquired MBLs have recently emerged as one of the most worrisome resistance mechanisms owing to their capacity to hydrolyse all β-lactams, including carbapenems. MBL production was seen in 14.3% of the isolated gram negative uropathogens. 86.3% of MBL producers were found susceptible to Fosfomycin [Figure 6, Figure 7]. In the present study, non-fermenter, i.e. P.aeruginosa and A.baumannii contributed to the maximum in cases of MBL production (25%) followed by K.pneumoniae (18.7%) and Enterobacter aerogenes (17.3%) [Figure 6]. Tellis et al.[21] recorded almost similar findings with P.aeruginosa, MBL isolates as 20.8%. However dissimilar results were obtained by study done by Kaur D C[22] that reported, 0% E coli, 75% K.pneumoniae, 50% isolates of P.aeruginosa as MBL producers. Due to the multiple drug resistance conferred by MBLs, their detection and control of spread by following stringent infection control practices alongside proper therapeutic regimens in both community and healthcare setup is need of the hour.
The notable finding in our study was 86.9% MDR isolates and 88.8% MBL producers of uropathogenic Escherichia coli exhibited good in vitro activity towards Fosfomycin followed by 87.8% MDR and 80% MBL producers of Klebsiella pneumoniae. All MDR isolates of Proteus and Citrobacter spp. were susceptible to Fosfomycin. In addition even the multidrug resistant and MBL producing strains of P.aeruginosa depicted 80% and 88.8% susceptibility towards Fosfomycin [Figure 7]. Sahni et al.[23] found susceptibility of 83.0% in their study, Jain et al.[19] depicted Fosfomycin susceptibility among MDR isolates as 84.82% which was concordant with the findings of Dalai et al.[20] and Sreenivasan et al.[1] In a study conducted by Banerjee et al.,[2] the susceptibility among carbapenem resistant Enterobacteriaceae was also found to be quite high. Thus such high susceptibility of Fosfomycin can serve as a boon and can have an added advantage in clinical day-to-day practice over the most commonly prescribed nephrotoxic Polymyxins as the salvage therapy for these cases.
Limitations
The limitation of our study was lacking clinical information regarding symptomatic or asymptomatic UTI, complicated or uncomplicated and distribution of patients based on the sources of infection like catheter-associated or community-acquired UTI.
Conclusion
This study confirmed the high in vitro susceptibility of Fosfomycin against both susceptible and MDR uropathogens including the ESBL and MBL producers. In the era of increasing antimicrobial resistance, Fosfomycin has a potential to emerge as an effective oral agent and a safe therapeutic option for empirical as well as definitive treatment of UTI in both community and healthcare setup. Moreover, its easy dosage and compliance, minimal toxicity with negligible cross-resistance to other antibiotics are the additional advantages leading to the regaining of its antibacterial activity against the bacterial pathogens.
Authors contribution
Jasleen Kaur has prepared, reviewed and supervised the manuscript. Priya Bhat has prepared and reviewed the manuscript, and Upasana Bhumbla is the corresponding author, who has reviewed and supervised the manuscript.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
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