Fosfomycin Research Articles

This study was aimed to evaluate the antimicrobial resistance, biofilm formation and some type 1 fimbriae adhesion genes. A total of 120 urine specimens were obtained from different patients with UTIs during October 2022 to February 2023 from several Baghdad hospitals. Morphological, biochemical and molecular tests were utilized for identifying E. coli isolates. The results were shown that only 80 (66.7%) of isolates were identified as E. coli. Twelve antimicrobial discs were utilized for evaluate the ability of E. coli isolate to resistant these antimicrobials. The results revealed that 98.8% of isolates were resistant to Ampicillin (AMP), followed by 81.3, 77.5, 72.5, 70, 60 and 58.8 of isolates were resistant to Cefepime (FEP), Ceftazidime (CAZ), Tigecycline (TGC), Ciprofloxacin (CIP), Trimethoprim - Sulfamethoxazole (SXT) and Aztreonam (ATM), respectively. All isolates were sensitive to Fosfomycin (FOF) and Amikacin (AMK) as well as the majority of isolates (97.5, 72.5 and 43.8%) were sensitive to Imipenem (IMP), Nitrofurantoin (NIT) and Piperacillin- tazobactam (TZP). A 50 isolates were selected as multi-drug resistant isolates. The biofilm formation of E. coli was measured using microtiter plates. The majority of isolates (55%; n=44) were moderate biofilm producers, while 38.75% (n=31) were strong producers and 5 (6.25%) were weak producers. The molecular detections of fimH and fimA genes were performed with specific primers using PCR technique. The results indicated that all isolates carry both the fimH and fimA genes.

Urinary tract infection (UTI) is the second most common type of infection in the human body. It is one of the most prevalent conditions in medical practice, with approximately 150 million cases occurring globally each year. Approximately 50% of women will experience at least one episode of UTI during their lifetime, and between 20 and 40% will have recurrent episodes. The discovery of a broad-spectrum antibiotic, fosfomycin tromethamine, occurred in Spain in 1969 and is prominently used in the management of uncomplicated UTIs. As a phosphonic acid derivative, fosfomycin acts by disrupting bacterial cell wall synthesis by inhibiting the enzyme MurA, demonstrating effective activity against a wide variety of gram-negative and gram-positive pathogens, comprising multidrug-resistant strains such as Escherichia coli and Klebsiella pneumoniae. Fosfomycin is not metabolized and is predominantly excreted unchanged in the urine through glomerular filtration. Mean peak urinary concentrations of fosfomycin ranging from 1053 to 4415 mg/L occur within 4 hours of administration of a single oral dose of fosfomycin tromethamine correspondent to fosfomycin 3 gm. Urinary concentrations >128 mg/L, which are adequate to inhibit most urinary pathogens, are maintained for 24-48 hours following a single oral dose of fosfomycin tromethamine. This makes it particularly advantageous for uncomplicated UTIs, where it offers a convenient and effective single-dose treatment option. Clinical trials and observational studies have consistently shown high cure rates and patient compliance, attributing this to its minimal side effects and broad-spectrum efficacy. A single oral dose of fosfomycin tromethamine, equivalent to 3 gm of fosfomycin, is indicated for treating acute uncomplicated lower UTIs in adults. It is classified as pregnancy category B. Various clinical guidelines, such as the Infectious Diseases Society of America (IDSA), European Association of Urology (EAU), and National Institute for Health and Care Excellence (NICE), also recommend fosfomycin tromethamine for the treatment of UTI. In conclusion, fosfomycin tromethamine remains a robust and indispensable antibiotic in the management of uncomplicated UTIs, with a distinct pharmacological profile that ensures both efficacy and safety, and patient compliance due to its single-dose regimen.

Extensively drug-resistant (XDR) Acinetobacter baumannii infection has significant challenges due to limited treatment options. Although sulbactam (SUL) shows in vitro effectiveness against XDR A. baumannii, the efficacy of SUL-based combinations remains unclear. This investigation aimed to delineate the in vitro activity of SUL combined with various antimicrobial agents against XDR A. baumannii. Sixty-two clinical isolates of XDR A. baumannii were tested for minimal inhibitory concentrations (MICs) of SUL, amikacin (AMI), ciprofloxacin, colistin (COL), fosfomycin (FOS), gentamicin, meropenem (MER), rifampicin (RIF), sitafloxacin (SIT), and tigecycline (TIG) using broth microdilution. The checkerboard method, employing the fractional inhibitory concentration index, assessed in vitro synergy between the SUL-based combination. Time-kill analyses of selected isolates were conducted to measure log10 colony-forming unit per milliliter growth changes over 24 hours between individual and combined agents. The SUL MICs ranged from <4 to 256 mg/L, with an MIC50 of 64 mg/L. MIC ranges were lower for TIG (0.12-4.0 mg/L) and COL (0.5-2.0 mg/L), but higher for FOS (64->512 mg/L). Synergism was evident in the combinations of SUL/FOS (41.9%), SUL/AMI (19.3%), SUL/MER (17.7%), SUL/RIF (14.5%), SUL/TIG (12.9%), SUL/COL (6.5%), and SUL/SIT (4.8%). Only 1.6%-3.2% of the combinations exhibited antagonism. In the time-kill assays, a combination of SUL/FOS/AMI/MER exhibited sustained bactericidal activity at 24 hours against the two isolates, whereas two- and three-agent combinations showed varying degrees of synergism. Combining SUL with available antimicrobial agents had varying degrees of synergistic effect against XDR A. baumannii. Notably, the clinical utility of SUL-based combination therapy for XDR A. baumannii infections requires further exploration.IMPORTANCEThis study evaluated the in vitro effectiveness of SUL combined with other antibiotics against XDR Acinetobacter baumannii. Sixty-two clinical isolates were tested using broth microdilution and checkerboard methods. The SUL MIC50 was 64 mg/L, with tigecycline and colistin showing lower MIC ranges and higher fosfomycin. Synergistic activity was most notable with SUL/fosfomycin (41.9%), followed by SUL/amikacin (19.3%) and SUL/meropenem (17.7%). Antagonism was rare (1.6%-3.2%). Time-kill assays showed that the four-drug combination of SUL/fosfomycin/amikacin/meropenem had sustained bactericidal activity over 24 hours. While SUL-based combinations showed variable synergy, further studies are needed to determine their clinical potential.

This study elucidates potential genetic determinants and mechanisms involved in the synergistic effects of daptomycin (DAP) + fosfomycin (FOF) combination therapy. Among 33 clinically derived DAP-susceptible (S)/DAP-resistant (R) isogenic strain pairs, mutations in the mprF gene occurred in 30/33 DAP-R strains, including polymorphisms of L826F (33%) or T345A/L/I (15%). Strain variants of DAP-S CB1483 serially passaged in vitro for 10 days in DAP +/- FOF identified a key non-synonymous mutation in mprF (L826F) only in the DAP monotherapy arm. Interestingly, passage in FOF alone or DAP + FOF prevented the emergence of this mprF mutation following 10-day passage. This L826F mprF polymorphism, associated with a "gain-in-function" phenotype, exhibited increased amounts of lysyl-phosphatidylglycerol (L-PG) in the cell membrane (CM). Transcriptomics revealed a relatively modest number (~10) of distinct genes that were significantly up- or downregulated (≥2 log fold) in both the DAP-S and DAP-R strain pairs upon DAP + FOF exposures (vs. DAP or FOF alone). Of note, DAP + FOF decreased expression of lrgAB and sdrE and increased the expression level of fosB. In a rabbit infective endocarditis (IE) model, the DAP-R CB185 strain treated with DAP +/- FOF showed significantly reduced lrgB expression in vegetations compared with DAP treatment alone. Overall, these findings indicate that DAP + FOF therapy impacts MRSA through multiple specific mechanisms, enhancing bacterial clearance.

Fertilizer application is a necessary action in modernagricultureto meet the global food demand. Modern agriculture must enhance cropproduction while minimizing the amounts of used fertilizers to ensureenvironmental safety without compromising their effectiveness. Onepromising approach to achieve this ambitious goal is using controlled-releasefertilizers, which provide an effective amount of active ingredientsprolonged over time while reducing the losses caused by leaching intothe soil. In this work, a novel metal–organic framework (MOF)[Mg2(C3H7O5P)2(H2O)4]·H2O, named GR-MOF-27,basedon the antibacterial agent fosfomycin (FMC) and magnesium is reported.First, its crystal structure was determined by single-crystal X-raydiffraction, and then its stability in aqueous media was studied.The results showed a prolonged two-step release of Mg2+ ions (release rates of 26% in 4 h and 63% in 7 d), which fits topseudo-first-order kinetic (first 4 h) and pseudo-second-order (from4 h to 7 d) release models. Since the metal precursor (magnesium sulfate)is normally used as a fertilizer, the nutritional effects of GR-MOF-27and MgSO4 were evaluated and compared, obtaining the resultthat GR-MOF-27 improves plant growth by increasing shoot, root, anddried weight by 10.5, 11.0, and 13.1%, respectively. Additionally,plants treated with GR-MOF-27 showed an increase in the uptake ofimportant macronutrients, such as 64.9% of Mg and 57.4% of P, demonstratingthe benefits of using MOFs as slow-release fertilizers.

Fosfomycin (FOF) exhibits broad-spectrum antimicrobial activity, and is mainly used in combination therapy. Previous in vitro studies have shown synergistic effects of FOF in combination with flucloxacillin (FLX) against Staphylococcus aureus isolates. This study aims to validate these findings in vitro and investigate the synergistic effect in an in vivo Galleria mellonella model. Five methicillin- and FOF-susceptible isolates (ATCC-29213 & 4 clinical isolates); one methicillin- and FOF-resistant strain (DSMZ-23622) and four methicillin-resistant and FOF-susceptible strains (ATCC-33592 & 3 clinical isolates) were tested with checkerboard assays to assess synergism. Time-kill curves were generated for two MSSA (ATCC 29213 and 231/20) and two MRSA strains (ATCC 33592 and DSMZ 23622). The in vivo efficacy of FOF and/or FLX was evaluated by a G. mellonella survival assay and by determining the total bacterial count (TBC) in hemolymph. Checkerboard assays revealed additive or indifferent effects, with some indicating synergism. Time-kill curves demonstrated higher reduction in TBC with combination therapy compared to monotherapy. In vivo, the combination therapy showed the greatest reduction of TBC in larval haemolymph compared to monotherapy, and the survival assay showed highly synergistic activity of FLX plus FOF against MRSA (ATCC-33592) and MSSA (ATCC 6538), resulting in an average reduction in mortality of 48 and 40%, respectively, compared to monotherapies. Therefore, FOF plus FLX could be an alternative for the calculated or definitive treatment of S. aureus infections without antimicrobial susceptibility results or even for salvage therapy of MRSA infections after treatment failure or necessary discontinuation of classical MRSA drugs.Graphical abstract

Due to the involvement of biofilms in the pathogenesis of bone and joint infections (BJI), the treatment of these infections is often challenging, especially when multidrug- or extensively drug-resistant (MDR/XDR) pathogens are involved. Intravenous fosfomycin (FOS) is a phosphoenolpyruvate analogue with a unique mode of action and broad-spectrum activity against both Gram-positive (GP) and Gram-negative (GN) pathogens. It is used in various severe and deep-seated infections, including BJIs. This review article focuses on preclinical and clinical data surrounding the use of FOS for biofilm-related BJIs. Data from several in vitro and animal models of infection demonstrated that FOS, especially in combination with other antibiotics, is effective against biofilms of (methicillin-resistant) Staphylococcus spp., (vancomycin-resistant) Enterococcus spp., carbapenem-resistant and extended-spectrum beta-lactamase-producing Enterobacterales, and MDR Pseudomonas aeruginosa. Data from clinical studies, mostly retrospective observational studies and case reports/case series, revealed that FOS was typically used in combination with other antibiotics for the treatment of various BJI, including acute and chronic osteomyelitis, prosthetic joint infections, and fracture-related infections, in adult and pediatric patients. Success rates often exceeded 80%. FOS exhibits good and fast penetration into bone tissue and is generally well tolerated, with only a few adverse drug reactions, such as gastrointestinal disorders and electrolyte imbalances. Collectively, the data indicate that FOS is a valuable option as part of combination regimens for the treatment of BJIs caused by both GP and GN bacteria.

Fosfomycin (FOS) is a critical antibiotic for treating multi-drug resistant (MDR) Enterobacteriaceae infections, but its effectiveness is jeopardized by the dissemination of plasmids encoding enzymes that modify FOS. Despite the prohibition on its use in animal breeding in China, 100 strains of Escherichia coli (E. coli) exhibiting high resistance to FOS (MIC≥512 mg/L) were isolated from samples of waterfowl origin collected in Hainan, Sichuan, and Anhui. These strains commonly carried the fosA3 (88/100, 88.0%). In addition, 21 other antimicrobial resistance genes (ARGs) were detected in these strains, with high positivity rates for tetA, aphA1, sul2, folR, qnrS, and bla CTX-M. It is noteworthy that there was a significant positive correlation between the fosA3 and bla CTX-M (OR = 15.162, 95% CI: 1.875-122.635). The results of pulsed-field gel electrophoresis (PFGE) demonstrated the existence of multiple dispersed clonal clusters. Multilocus sequence typing (MLST) analysis identified 45 ST types, with ST48 and ST10 representing the most dominant clones. In the conjugation experiments, 53 fosA-like genes positive transconjugants were obtained with measurable conjugation frequency, which strongly demonstrated that these fosA3 may mainly locate on different types of plasmids possessing an efficient transmission ability. Whole genome sequencing (WGS) analysis further showed that the fosA3 was co-localized with the bla CTX-M on plasmids that showed a high degree of similarity in genetic structure. Of particular interest is the observation that the fosA3 is frequently accompanied by IS26 on either side of the gene. This structure may play a pivotal role in the horizontal transfer of the fosA3. The study revealed the alarming prevalence of FOS resistance in E. coli of waterfowl origin and delved deeply into the genetic characteristics and transmission mechanisms of the fosA3. The discovery of plasmid-mediated, transmissible FOS resistance in waterfowl E. coli poses a threat to "One Health". There's an urgent need for thorough monitoring and control measures against FOS resistance.

IntroductionIntravenous fosfomycin (FOS) is a broad-spectrum antibiotic primarily used in combination therapy to treat severe infections caused by both Gram-positive (GP) and Gram-negative (GN) pathogens, including multi-drug resistant (MDR) bacteria. The aim of this study, the largest to date, was to evaluate the effectiveness, safety, usage patterns, and patient characteristics of FOS in a real-world setting.MethodsInterim analysis of an ongoing, prospective, non-interventional, multicentre study in five European countries, involving centres in Germany, Italy, the United Kingdom, Greece, and Austria.ResultsA total of 716 patients were enrolled between January 2017 and November 2023 (mean age: 62.8 years, APACHE II: 18.3, SOFA: 6.7). Main indications for FOS were bacteraemia/sepsis (23.6%), complicated urinary tract infections (18.0%), and bone and joint infections (17.4%). Other indications included hospital-acquired/ventilator-associated pneumonia (11.0%), complicated skin and soft tissue infections (9.1%), bacterial meningitis/central nervous system (CNS) infections (7.8%), and infective endocarditis (6.4%). Most common pathogens identified were Staphylococcus aureus (31.4%, including methicillin-resistant S. aureus), Klebsiella spp. (including K. pneumoniae) (17.2%), Escherichia coli (14.2%), coagulase-negative staphylococci (12.9%), other Enterobacterales (10.9%), and Pseudomonas aeruginosa (8.4%). In 34.6% of patients, an MDR pathogen was involved. Carbapenem resistance (CR) was high in Klebsiella spp. infections (59/123, 48.0%). In most patients, FOS was used in combination therapy (90.2%). The median dose was 15 g/day. Overall, clinical success and clinical response were favourable with 75.3% and 83.4% at the end of FOS treatment. Clinical success rates in infections caused by MDR or CR pathogens were 78.0% and 81.8%, respectively. Microbiological cure was achieved in 82.4% of all patients. Electrolyte imbalances were the most frequently observed adverse drug reactions, while gastrointestinal disorders were rare.ConclusionThe results from this study suggest that FOS is a safe and effective option as combination partner in the treatment of patients with severe infections caused by both GP and GN pathogens, including deep-seated infections and/or involvement of MDR bacteria.Trial RegistrationClinicalTrials.gov identifier, NCT02979951.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-025-01125-2.

Dental infections can disrupt root development in immature permanent teeth, making traditional endodontic treatment challenging. Apexogenesis, a regenerative approach that promotes natural root development, offers a potential solution. However, issues related to disinfection and material biocompatibility still remain. The objective of this study was to evaluate the synergistic antimicrobial and antibiofilm properties of double and triple antibiotic combinations against common oral pathogens, and to incorporate the most effective combination into a thermosensitive hydrogel, to develop an alternative intracanal medication. Antibiotics were tested alone and in combination in planktonic and biofilm conditions of oral bacteria and Candida albicans. The antibiotic combinations with potential antimicrobial synergy were tested on Enterococcus faecalis biofilms in radicular dentin by confocal microscopy. Metronidazole (ME), ciprofloxacin (CI), and fosfomycin (FO) were incorporated into poly(N-vinylcaprolactam) (PNVCL) hydrogels, and their antibiofilm activity was compared to PNVCL hydrogels containing chlorhexidine (CHX) or calcium hydroxide (CH). The cytotoxicity of the hydrogels was assessed on MDPC-23 odontoblast-like cells using metiltetrazolium assays. A statistical analysis was performed using ANOVA followed by Tukey’s test (p &lt; 0.05). The combination of ME + CI + FO showed superior antibiofilm effects in mono- and dual-species biofilms and on biofilms inside dentinal tubules, comparable to CHX. PNVCL hydrogels with ME + CI + FO significantly reduced E. faecalis biofilms in dentinal tubules, exhibiting a higher efficacy than PNVCL + CH. Cytotoxicity tests revealed minimal effects on cell viability for both PNVCL hydrogels with and without antibiotics. In conclusion, ME + CI + FO showed potent antimicrobial synergy and, when loaded in thermosensitive PNVCL hydrogel, demonstrated significant antibiofilm activity and low cytotoxicity. These findings emphasize the potential of this formulation as an effective and biocompatible endodontic medication, especially for the treatment of immature permanent teeth.

The emergence of multidrug-resistant pathogens, particularly β-lactam, colistin, and fosfomycin-resistant Escherichia coli and Salmonella, is a significant public health concern. This study evaluated the in vitro synergistic effects of antimicrobial combinations against these resistant isolates. Ten isolates that originated from retail chicken meat, including five E. coli and five Salmonella isolates, were tested against cefotaxime (CTA), fosfomycin (FOS), and colistin (COL), both individually and in combinations. Antimicrobial susceptibility was assessed using the broth microdilution method, and synergistic interactions were evaluated using checkerboard and time-killing assays. All isolates were multidrug-resistant (MDR) and were resistant to CTA, COL, and FOS. The checkerboard assay showed varying levels of synergy: two out of five E. coli isolates exhibited synergy with FOS-COL, while one E. coli isolates out of four isolates showed synergy with CTA-COL. No E. coli isolates showed synergy with FOS-CTA. For Salmonella, two out of five isolates exhibited synergy with both FOS-CTA and FOS-COL, while three out of four isolates showed synergy with CTA-COL. The time-killing assay confirmed these results, with the FOS-COL combinations showing synergy against both E. coli and Salmonella strains. Notably, the FOS-COL combination demonstrated bactericidal effects against E. coli, and all three combinations were bactericidal against Salmonella. The study highlights the potential of antimicrobial combinations, particularly FOS-COL, in combating MDR E. coli and Salmonella. These findings support the use of combination therapy as a promising strategy to in effectively treating multi-drug-resistant foodborne infections, ensuring better medical outcomes and enhanced food safety, warranting further investigation into their mechanisms and clinical applications.

Introduction. Carbapenems are usually employed as first-line antimicrobials against bacteria harbouring extended-spectrum beta-lactamases (ESBLs). These enzymes confer resistance often to multiple classes of antimicrobials.Hypothesis/Gap Statement. This indiscriminate use of carbapenems and the inevitable development of carbapenem resistance have prompted the need for carbapenem-sparing strategies.Methodology. The non-carbapenem antimicrobial susceptibility patterns of 60 ESBL-producing Enterobacterales (ESBL-PE) isolates responsible for bloodstream infections, in 2022-2023 inclusive, processed at our institution were reviewed.Results. The non-carbapenem antimicrobial susceptibility patterns of 60 ESBL-PE isolates from bloodstream infections during the study period were determined. Escherichia coli was the most common species isolated (87%, n=52), with the majority of cases (73.3%, n=44) originating from a presumed urinary source. Temocillin (TMC), mecillinam (MEC), cefiderocol (FDC), amikacin and fosfomycin (FOS) displayed excellent activity against all ESBL-PE isolates tested, with susceptibility rates of≥85%. Ciprofloxacin and amoxicillin-clavulanic acid were the least efficacious agents, with susceptibility rates≤20%.Conclusions. TMC, MEC, FDC and FOS offer promising alternatives to carbapenems, demonstrating efficacy against ESBL-PE. The use of these agents not only broadens the therapeutic arsenal against ESBL-PE but also mitigates the potential for escalating carbapenem resistance, especially in regions where the incidence of carbapenem resistance is increasing.

Abstract Background Pseudomonas aeruginosa (Pae) is a significant pathogen causing up to 10% of hospital-acquired infections. Contributing to Pae’s multidrug-resistant (MDR) phenotype is the inducible Pseudomonas-derived cephalosporinase (PDC), low permeability outer membrane, multiple efflux systems, and loss of porins that yield resistant phenotypes. e.g. loss of OprD yields resistance to imipenem. Thus, the design of novel antibiotics or combination therapies that do not induce expression of blaPDC, are stable to PDC hydrolytic activity, bypass impermeability, and/or are not susceptible to efflux is essential for combating MDR Pae infections. Ceftazidime-avibactam (CZA), and imipenem/cilastatin/relebactam (I/R) were approved by the FDA for the treatment of infections caused by Pae; however, gaps in their efficacy against Pae remain. Previously, Winkler et al. analyzed a group of archived Pae and found that 20% of the isolates were resistant to CZA (PMID 25451057). By combining CZA with fosfomycin (FOS) and targeting multiple cell wall synthetic pathways, susceptibility was restored to most of the CZA resistant MDR Pae (PMID: 31099835). Based upon a similar mechanism of action, we propose that the combination of I/R+FOS will also restore susceptibility to I/R resistant Pae. Methods 149 isolates of Pae were used in this analysis. Minimum inhibitor concentrations (MICs) of IMI, I/R, and I/R+FOS against 150 P. aeruginosa isolates were determined following CLSI’s approved methods. To interpret the results better, genetic analysis of the resistomes was performed. Results The addition of FOS was found to shift the I/R MICs towards the susceptible range (Fig.1A). Moreover, the isolates tested with I/R+FOS possessed overall lower MICs (MIC50/90 I/R 8/256 mg/L vs. MIC50/90 I/R+FOS 8/64 mg/L) (Fig. 1B). The isolates have diverse resistance mechanisms including KPC-producers (3/149; 4.5%), VIM-producers (19/150; 28.3%), and isolates that carry mutations in ampR, ampD, oprD, and/or pbp genes. Conclusion I/R + FOS lowers MICs against MDR Pae. These results lead us to postulate that inhibiting MurA enzyme that catalyzes the first committed step in peptidoglycan synthesis with FOS adds to the potency of I/R even against VIM producers. Disclosures Robert Bonomo, MD, Merck: Grant/Research Support|Shionogi: Grant/Research Support Gauri G. Rao, PharmD, MS, Merck: Grant/Research Support

Abstract Background Gepotidacin (GEP) is a novel, bactericidal, first-in-class triazaacenaphthylene antibacterial that inhibits bacterial DNA replication by a unique mechanism of action, distinct binding site and provides well-balanced inhibition (for most uncomplicated urinary tract infections [uUTI] uropathogens and Neisseria gonorrhoeae) of two different type II topoisomerase enzymes GEP completed two phase 3 trials for treatment of uUTI This study reports the activity of GEP and other oral antibacterials against E. coli (EC), including molecularly characterized isolates carrying ESBL and carbapenemase genes collected from UTI patients in the US. Methods 3,995 EC collected from 52 US sites as part of the gepotidacin uropathogen global surveillance study were included (2019-2022). CLSI methods were used for susceptibility (S) testing and MIC interpretations. Isolates with aztreonam, ceftazidime, ceftriaxone or meropenem MIC of ≥2 mg/L were subjected to genome sequencing, and screening of β-lactamase genes and epidemiology typing (MLST, O:H, and fimH). Results A total of 86.2% (3,444/3,995) of EC did not meet the MIC criteria for molecular characterization (Table) and had GEP MIC50 and MIC90 values of 2 mg/L and 4 mg/L, respectively. Cefazolin (97.0%S), fosfomycin (FOS) (99.7%S), and nitrofurantoin (NIT) (98.7%S) had activity among oral comparator agents tested against this group. A total of 13.8% (551/3,995) of EC were screened for β-lactamase genes, and this group had GEP MIC50 and MIC90 values of 2 mg/L and 4 mg/L respectively. Other oral agents had limited activity, except for FOS (98.0%S) and NIT (92.7%S). In general, GEP retained activity with MIC50 and MIC90 values of 2 mg/L and 4 mg/L, respectively, against isolates carrying ESBL, AmpC and carbapenemase genes, and against clonal complex (CC) 131 and the resistant subset O25b:H4. Conclusion GEP showed generally consistent activity against UTI-causing EC in the US, including against isolates carrying ESBL, AmpC and/or carbapenemase genes. In addition, GEP had activity against the CC131 high-risk EC clone. These data support further clinical development of GEP as a potential treatment option for uUTI caused by EC including when other oral treatment options are limited due to drug resistance. Disclosures Rodrigo E. Mendes, PhD, GSK: Grant/Research Support Renuka Kapoor, PhD, GSK: Employee|GSK: Stocks/Bonds (Public Company) Didem Torumkuney, PhD, GSK: Employee|GSK: Stocks/Bonds (Public Company)

Sepsis, a life-threatening condition characterized by dysregulated host responses to infection, often leads to multi-organ dysfunction, including kidney injury. Kidney damage in sepsis can have severe consequences and is associated with high mortality rates. This study aimed to investigate the potential therapeutic effects of fosfomycin (FOS), a broad-spectrum antibiotic with immunomodulatory properties, on kidney damage induced by cecal ligation and puncture (CLP)-induced sepsis in a rodent model. In total, 24 rats were randomly divided into three groups. Group 1 (n = 8), the healthy control group (C), received a single dose of 0.9% NaCl (saline) solution via an intraperitoneal (i.p.) route. To group 2 (n = 8), the CLP group, CLP-induced sepsis was applied without medication, and a single dose of 0.9% NaCl (saline) solution was applied i.p. before induction. To group 3 (n = 8), the CLP + FOS (500 mg/kg) group, a single dose of 500 mg/kg FOS was administered i.p. before sepsis induction. The effects of fosfomycin on kidney function, histopathological changes, inflammatory markers, oxidative stress, and apoptosis were assessed. In the fosfomycin-treated group, the histological analysis results demonstrated reduction in kidney tissue damage and inflammation. Additionally, fosfomycin attenuated the upregulation of pro-inflammatory cytokines and reduced oxidative stress markers in kidney tissue. Furthermore, fosfomycin treatment was associated with a decrease in apoptotic cell death in the kidney. These findings suggest that fosfomycin may have a protective effect on kidney damage caused by CLP-induced sepsis. The potential mechanisms underlying this protection include the modulation of inflammation, reduction of oxidative stress, and inhibition of apoptosis.

Background: Fosfomycin (FOS) is an older antimicrobial agent newly rediscovered as a possible treatment for infections with limited therapeutic options (e.g., Gram-negative bacteria with difficult-to-treat resistance, DTR), especially in intravenous form. However, for correct usage of FOS, it is necessary to have a reliable susceptibility testing method suitable for routine practice and robust interpretation criteria. Results: The results were interpreted according to 2023 interpretation criteria provided by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). DTR Gram-negatives were more likely to be resistant to FOS (45% in Enterobacterales and 20% in P. aeruginosa) than non-DTR (10% and 6.7%, resp.). All isolates of S. aureus were susceptible to FOS. In Gram-negatives, all agreement values were unacceptable. Etest® performed better in the DTR cohort (categorical agreement, CA, 80%) than in the non-DTR cohort (CA 45.7%). There were no very major errors (VREs) observed in P. aeruginosa. S. aureus had surprisingly low essential agreement (EA) rates (53% for MRSA and 47% for MSSA) for Etest®, but categorical agreement was 100%. Methods: A total of 130 bacterial isolates were tested and compared using the disc diffusion method (DD) and gradient strip method (Etest®) with the reference method (agar dilution, AD). The spectrum of isolates tested was as follows: 40 Enterobacterales (20 DTR vs. 20 non-DTR), 30 Pseudomonas aeruginosa (15 DTR vs. 15 non-DTR), and 60 Staphylococcus aureus (30 methicillin-susceptible, MSSA, vs. 30 methicillin-resistant, MRSA). Conclusions: Neither one of the tested methods was identified as a suitable alternative to AD. It would be beneficial to define more interpretation criteria, at least in some instances.

ObjectivesThe aim of this study was to identify the synergistic effect and mechanisms of fosfomycin (FM) combined with colistin (COL) against KPC-producing Klebsiella pneumoniae (KPC-Kp).MethodsThe bactericidal effects, induced drug resistance and cytotoxicity of FM combined with COL were evaluated by time-kill assays and mutation rate test. Time-kill assays and transcriptomics analysis were used to further clarify the mechanism of FM combined with COL. The bacteria were taken from different points in time-kill assays, reactive oxygen species (ROS), nitric oxide and redox related enzymes were detected. The mechanism of synergistic bactericidal action was analyzed by transcriptome.ResultsThe bactericidal effect of FM combined with COL was better than that of monotherapy. The mutation frequency of FM alone at low dose (8 mg/L) was higher than that at high dose (64 mg/L). COL induced resistant isolates resulted in FM and COL resistance, while FM alone or combined with COL only resulted in FM resistance. The survival rate of Thp-1 cells in FM combined with COL against K. pneumoniae was higher than that of monotherapy. The intracellular nitric oxide, activities of total superoxide dismutase and catalase were increased along with the increase of FM concentration against KPC-Kp. FM combined with COL induced ROS accumulation and antioxidant capacity increase. Transcriptome analysis showed FM combined with COL could regulate the levels of soxRS and oxidative phosphorylation, in order to clear ROS and repair damage. In addition, FM combined with COL could result in synergetic bactericidal efficacy by inhibiting ribosomal transcription.ConclusionsFM combined with COL mediated synergistic bactericidal effect by regulating ROS accumulation and inhibiting ribosomal protein transcription, resulting in lower resistance and cytotoxicity.

The objective of this study was to assess the impact of the vehicle of administration and the prandial state of post weaning piglets on the indices of therapeutic efficacy for different broad-spectrum antibiotic/pathogen combinations. Pharmacokinetic data were retrieved from previous studies, in which we orally administered oxytetracycline (OTC), fosfomycin (FOS), or amoxicillin (AMX) according to the following treatments: dissolved in soft water to fasted or non-fasted piglets, dissolved in hard water to fasted or non-fasted piglets, and mixed with feed. Minimum inhibitory concentration (MIC) values for susceptible strains of bacteria causing swine diseases were obtained from the database of European Committee on Antimicrobial Susceptibility Testing (EUCAST) for each antibiotic. Pharmacokinetic/pharmacodynamic (PK/PD) indices of therapeutic efficacy-drug exposure over the dosing interval (fAUC/MIC) for OTC and FOS; time that free drug concentration remains above MIC (%fT>MIC) for AMX-were calculated for each antibiotic/pathogen combination under each treatment. After all OTC and in-feed FOS and AMX treatments, the indices of therapeutic efficacy were below the target value for all the study microorganisms. When FOS or AMX were delivered dissolved in soft or hard water, the indices were above the target value over which therapeutic efficacy would be expected for Escherichia coli treated with FOS and, Glaesserella parasuis, Pasteurella multocida, and Actinobacillus pleuropneumoniae treated with AMX. The prandial state of piglets showed no influence on the indices of therapeutic efficacy. Pharmacokinetic profiles of broad-spectrum antibiotics, specifically the ability to achieve target concentrations, may be largely reduced due to drug interactions with components present in feed or water resulting in a discrepancy with PK/PD principles of prudent and responsible use of antibiotics.

DFT studies on the performance of BN nanocage (B12N12) as adsorbent and sensor for fosfomycin

Fosfomycin (FOS) is an effective antibiotic against multidrug-resistant Enterobacterales, but its effectiveness is reducing. Little is known on the current prevalence of FosA enzymes in low-risk pathogens, such as Citrobacter freundii. The aim of the study was the molecular characterization of a carbapenemase- and FosA-producing C. freundii collected in Italy. AK867, collected in 2023, showed an XDR profile, retaining susceptibility only to colistin. AK867 showed a FOS MIC >128 mg/L by ADM. Based on WGS, AK867 belonged to ST116 and owned a wide resistome, including fosA3, blaKPC-2, and blaVIM-1. fosA3 was carried by a conjugative pKPC-CAV1312 plasmid of 320,480 bp, on a novel composite transposon (12,907 bp). FosA3 transposon shared similarities with other fosA3-harboring pKPC-CAV1312 plasmids among Citrobacter spp. We report the first case of FosA3 production in clinical carbapenemase-producing C.freundii ST116. The incidence of FosA3 enzymes is increasing among Enterobacterales, affecting even low-virulence pathogens, as C. freundii.