Adverse events during intravenous fosfomycin therapy in a real-life scenario. Risk factors and the potential role of therapeutic drug monitoring.

BACKGROUND: Intravenous fosfomycin (IVFOF) is gaining interest in severe infections. Its use may be limited by adverse events (AEs). Little experience exists on IVFOF therapeutic drug monitoring (TDM) in real-life setting. PATIENTS AND METHODS: Retrospective study of patients receiving IVFOF for > 48 h at Policlinico Hospital (Milan, Italy) from 01/01/2019 to 01/01/2023. AEs associated to IVFOF graded CTCAE ≥ II were considered. Demographic and clinical risk factors for IVFOF-related AEs were analysed with simple and multivariable regression models. The determination of IVFOF TDM was made by a rapid ultraperformance liquid chromatography mass spectrometry method (LC-MS/MS) on plasma samples. The performance of TDM (trough levels (Cmin) in intermittent infusion, steady state levels (Css) in continuous infusion) in predicting AEs ≤ 5 days after its assessment was evaluated. RESULTS: Two hundred and twenty-four patients were included. At IVFOF initiation, 81/224 (36.2%) patients were in ICU and 35/224 (15.7%) had septic shock. The most frequent infection site was the low respiratory tract (124/224, 55.4%). Ninety-five patients (42.4%) experienced ≥ 1AEs, with median time of 4.0 (2.0-7.0) days from IVFOF initiation. Hypernatremia was the most frequent AE (53/224, 23.7%). Therapy discontinuation due to AEs occurred in 38/224 (17.0%). ICU setting, low respiratory tract infections and septic shock resulted associated with AEs (RRadjusted 1.59 (95%CI:1.09-2.31), 1.46 (95%CI:1.03-2.07) and 1.73 (95%CI:1.27-2.37), respectively), while IVFOF daily dose did not. Of the 68 patients undergone IVFOF TDM, TDM values predicted overall AEs and hypernatremia with AUROC of 0.65 (95%CI:0.44-0.86) and 0.91 (95%CI:0.79-1.0) respectively for Cmin, 0.67 (95%CI:0.39-0.95) and 0.76 (95%CI:0.52-1.0) respectively for Css. CONCLUSIONS: We provided real world data on the use of IVFOF-based regimens and associated AEs. IVFOF TDM deserves further research as it may represent a valid tool to predict AEs. KEY POINTS: Real world data on intravenous fosfomycin for severe bacterial infections. AEs occurred in over 40% (therapy discontinuation in 17%) and were related to baseline clinical severity but not to fosfomycin dose. TDM showed promising results in predicting AEs.

Effect of ceftazidime-avibactam combined with different antimicrobials against carbapenem-resistant Klebsiella pneumoniae.

This study aimed to assess the in vitro efficacy of ceftazidime-avibactam (CZA) in combination with various antimicrobial agents against carbapenem-resistant Klebsiella pneumoniae (CRKP). We selected 59 clinical CRKP isolates containing distinct drug resistance mechanisms. The minimum inhibitory concentrations (MICs) of meropenem (MEM), colistin (COL), eravacycline (ERA), amikacin (AK), fosfomycin (FOS), and aztreonam (ATM), both individually and in combination with CZA, were tested using the checkerboard method. The interactions of antimicrobial agent combinations were assessed by fractional inhibitory concentration index (FICI) and susceptible breakpoint index (SBPI). The time-kill curve assay was employed to dynamically evaluate the effects of these drugs alone and in combination format. In the checkerboard assay, the combination of CZA+MEM showed the highest level of synergistic effect against both KPC-producing and carbapenemase-non-producing isolates, with synergy rates of 91.3% and 100%, respectively. Following closely was the combination of FOS+CZA . For metallo-beta-lactamases (MBLs) producing strains, ATM+CZA displayed complete synergy, while the combination of MEM+CZA showed a synergy rate of only 57.14% for NDM-producing strains and 91.67% for IMP-producing strains. In the time-kill assay, MEM+CZA also demonstrated significant synergistic effects against the two KPC-2-producing isolates (Y070 and L70), the two carbapenemase-non-producing isolates (Y083 and L093), and the NDM-1-producing strain L13, with reductions in log10 CFU/mL exceeding 10 compared to the control. Against the IMP-producing strain Y047, ATM+CZA exhibited the highest synergistic effect, resulting in a log10 CFU/mL reduction of 10.43 compared to the control. The combination of CZA and MEM exhibited good synergistic effects against KPC-producing and non-enzyme-producing strains, followed by the FOS+CZA combination. Among MBL-producing strains, ATM+CZA demonstrated the most pronounced synergistic effect. However, the combinations of CZA with ERA, AK, and COL show irrelevant effects against the tested clinical isolates. IMPORTANCE: Our study confirmed the efficacy of the combination CZA+MEM against KPC-producing and non-carbapenemase-producing strains. For metalloenzyme-producing strains, CZA+ATM demonstrated the most significant synergy. Additionally, CZA exhibited a notable synergy effect when combined with FOS. These combination therapies present promising new options for the treatment of CRKP infection.

FosA8-producing E. coli ST131: clinical cases in Italy, February 2023.

Fosfomycin-resistant FosA8-producing Enterobacterales are uncommon strains with extremely low incidence in Europe, based on only three reports in the literature. We detected FosA8-producing Escherichia coli ST131 in clinical isolates from two patients admitted in February 2023 to a rehabilitation unit in Italy. The occurrence of rare fosA-like genes in the high-risk clone ST131 is of clinical relevance. The dissemination of FosA-producing E. coli, although still at low levels, should be continuously monitored.

Intravenous fosfomycin for treatment of severe infections caused by carbapenem-resistant Acinetobacter baumannii: A multi-centre clinical experience.

BACKGROUND: Severe infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) have been reported increasingly over the past few years. Many in-vivo and in-vitro studies have suggested a possible role of intravenous fosfomycin for the treatment of CRAB infections. METHODS: This multi-centre, retrospective study included patients treated with intravenous fosfomycin for severe infections caused by CRAB admitted consecutively to four hospitals in Italy from December 2017 to December 2022. The primary goal of the study was to evaluate the risk factors associated with 30-day mortality in the study population. A propensity score matched analysis was added to the model. RESULTS: One hundred and two patients with severe infections caused by CRAB treated with an intravenous fosfomycin-containing regimen were enrolled in this study. Ventilator-associated pneumonia (VAP) was diagnosed in 59% of patients, primary bacteraemia in 22% of patients, and central-venous-catheter-related infection in 16% of patients. All patients were treated with a regimen containing intravenous fosfomycin, mainly in combination with cefiderocol (n=54), colistin (n=48) or ampicillin/sulbactam (n=18). Forty-eight (47%) patients died within 30 days. Fifty-eight (57%) patients experienced clinical therapeutic failure. Cox regression analysis showed that diabetes, primary bacteraemia and a colistin-containing regimen were independently associated with 30-day mortality, whereas adequate source control of infection, early 24-h active in-vitro therapy, and a cefiderocol-containing regimen were associated with survival. A colistin-based regimen, A. baumannii colonization and primary bacteraemia were independently associated with clinical failure. Conversely, adequate source control of infection, a cefiderocol-containing regimen, and early 24-h active in-vitro therapy were associated with clinical success. CONCLUSIONS: Different antibiotic regimens containing fosfomycin in combination can be used for treatment of severe infections caused by CRAB.

Selective bacteriophages reduce the emergence of resistant bacteria in bacteriophage-antibiotic combination therapy.

Escherichia coli O157:H7 is a globally important foodborne pathogen with implications for food safety. Antibiotic treatment for O157 may potentially contribute to the exacerbation of hemolytic uremic syndrome, and the increasing prevalence of antibiotic-resistant strains necessitates the development of new treatment strategies. In this study, the bactericidal effects and resistance development of antibiotic and bacteriophage monotherapy were compared with those of combination therapy against O157. Experiments involving continuous exposure of O157 to phages and antibiotics, along with genetic deletion studies, revealed that the deletion of glpT and uhpT significantly increased resistance to fosfomycin. Furthermore, we found that OmpC functions as a receptor for the PP01 phage, which infects O157, and FhuA functions as a receptor for the newly isolated SP15 phage, targeting O157. In the glpT and uhpT deletion mutants, additional deletion in ompC, the receptor for the PP01 phage, increased resistance to fosfomycin. These findings suggest that specific phages may contribute to antibiotic resistance by selecting the emergence of gene mutations responsible for both phage and antibiotic resistance. While combination therapy with phages and antibiotics holds promise for the treatment of bacterial infections, careful consideration of phage selection is necessary.IMPORTANCEThe combination treatment of fosfomycin and bacteriophages against Escherichia coli O157 demonstrated superior bactericidal efficacy compared to monotherapy, effectively suppressing the emergence of resistance. However, mutations selected by phage PP01 led to enhanced resistance not only to the phage but also to fosfomycin. These findings underscore the importance of exercising caution in selecting phages for combination therapy, as resistance selected by specific phages may increase the risk of developing antibiotic resistance.

Comparison of ciprofloxacin versus fosfomycin versus fosfomycin plus trimethoprim/sulfamethoxazole for preventing infections after transrectal prostate biopsy.

BACKGROUND: To evaluate antibiotic prophylaxis in transrectal prostate biopsies due to the recommendation of the European Medicines Agency (EMA): We describe our single center experience switching from ciprofloxacin to fosfomycin trometamol (FMT) alone and to an augmented prophylaxis combining fosfomycin and trimethoprim/sulfamethoxazole (TMP/SMX). METHODS: Between 01/2019 and 12/2020 we compared three different regimes. The primary endpoint was the clinical diagnosis of an infection within 4 weeks after biopsy. We enrolled 822 men, 398 (48%) of whom received ciprofloxacin (group-C), 136 (16.5%) received FMT (group-F) and 288 (35%) received the combination of TMP/SMX and FMT (group-BF). RESULTS: Baseline characteristics were similar between groups. In total 37/398 (5%) postinterventional infections were detected, of which 13/398 (3%) vs 18/136 (13.2%) vs 6/288 (2.1%) were detected in group-C, group-F and group-BF respectively. The relative risk of infectious complication was 1.3 (CI 0.7-2.6) for group-C vs. group-BF and 2.8 (CI 1.4-5.7) for group-F vs. group-BF respectively. CONCLUSION: The replacement of ciprofloxacin by fosfomycin alone resulted in a significant increase of postinterventional infections, while the combination of FMT and TMP/SMX had a comparable infection rate to FQ without apparent adverse events. Therefore, this combined regimen of FMT and TMP/SMX is recommended.

Assessment of three antibiotic combination regimens against Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries.

Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria.

Identification of the novel fosfomycin resistance gene fosSC in Staphylococcus capitis.

OBJECTIVES: Fosfomycin has regained attention for treating infections caused by methicillin-resistant Staphylococcus aureus and multidrug-resistant coagulase-negative staphylococci. In this research, our objective was to investigate the mechanisms underlying fosfomycin resistance in Staphylococcus capitis. METHODS: The minimum inhibitory concentrations (MICs) of fosfomycin were assessed in 109 clinical S. capitis isolates by the agar dilution method. By cloning the fos-like genes into the shuttle vector, pTSSCm-Pcap, and observing the change in fosfomycin MICs, the gene function was verified. Core genome multilocus sequence typing and comparative genomics analysis were conducted to determine the population characteristics of S. capitis isolates and analyse the genetic environment of the fos-like genes. RESULTS: We identified a novel fosfomycin resistance gene, fosSC, on the chromosome in 58 out of 109 (53.2%) S. capitis isolates. The deduced products of the fosSC genes shared 67.15-67.88% amino acid sequence identity with FosB. The RN-pT-fosSC transformants carrying fosSC showed a 512-fold increase in the fosfomycin MICs. The fosSC gene was embedded in a conserved genetic context, but IS431mec was located to the left of the fosSC gene in cluster L due to the insertion of staphylococcal cassette chromosome mec. CONCLUSIONS: The chromosomal fosSC genes in some lineages of S. capitis explained their high-level fosfomycin resistance. Ongoing surveillance is crucial for monitoring the potential threat of horizontal transfer, which could be facilitated by the presence of mobile genetic elements surrounding the fosSC gene.

Treatment of infections caused by multidrug-resistant Gram-negative bacilli: A practical approach by the Italian (SIMIT) and French (SPILF) Societies of Infectious Diseases.

INTRODUCTION: The emergence of multidrug-resistant Gram-negative bacilli and the development of new antibiotics have complicated the selection of optimal regimens. International guidelines are valuable tools, but are limited by the scarcity of high-quality randomized trials in many situations. METHODS: A panel of experts from the French and Italian Societies of Infectious Diseases aimed to address unresolved issues in clinical practice based on their experience, an updated literature review and open discussions. RESULTS: The panel reached consensus for the following 'first choices': (i) cefepime for ventilator-acquired pneumonia due to AmpC ß-lactamase-producing Enterobacterales; (ii) the ß-lactam/ß-lactamase inhibitor combination most active in vitro, or cefiderocol combined with fosfomycin, and aerosolized colistin or aminoglycosides, for severe pneumonia due to Pseudomonas aeruginosa resistant to ceftolozane-tazobactam; (iii) high-dose piperacillin-tazobactam (including loading dose and continuous infusion) for complicated urinary tract infections (cUTIs) caused by extended-spectrum ß-lactamase-producing Enterobacterales with piperacillin-tazobactam minimum inhibitory concentration (MIC) ≤8 mg/L; (iv) high-dose cefepime for cUTIs due to AmpC ß-lactamase-producing Enterobacterales other than Enterobacter spp. if cefepime MIC ≤2 mg/L; (v) ceftolozane-tazobactam or ceftazidime-avibactam plus metronidazole for intra-abdominal infections (IAIs) due to third-generation cephalosporin-resistant Enterobacterales; (vi) ceftazidime-avibactam plus aztreonam plus metronidazole for IAIs due to metallo-ß-lactamase-producing Enterobacterales; (vii) ampicillin-sulbactam plus colistin for bloodstream infections (BSIs) caused by carbapenem-resistant Acinetobacter baumannii; (viii) meropenem-vaborbactam for BSIs caused by Klebsiella pneumoniae carbapenemase-producing Enterobacterales; and (ix) ceftazidime-avibactam plus fosfomycin for neurological infections caused by carbapenem-resistant P. aeruginosa. CONCLUSIONS: These expert choices were based on the necessary balance between antimicrobial stewardship principles and the need to provide optimal treatment for individual patients in each situation.

Change in Tissue Microbiome and Related Human Beta Defensin Levels Induced by Antibiotic Use in Bladder Carcinoma.

It is now generally accepted that the success of antitumor therapy can be impaired by concurrent antibiotic therapy, the presence of certain bacteria, and elevated defensin levels around the tumor tissue. The aim of our current investigation was to identify the underlying changes in microbiome and defensin levels in the tumor tissue induced by different antibiotics, as well as the duration of this modification. The microbiome of the tumor tissues was significantly different from that of healthy volunteers. Comparing only the tumor samples, no significant difference was confirmed between the untreated group and the group treated with antibiotics more than 3 months earlier. However, antibiotic treatment within 3 months of analysis resulted in a significantly modified microbiome composition. Irrespective of whether Fosfomycin, Fluoroquinolone or Beta-lactam treatment was used, the abundance of Bacteroides decreased, and Staphylococcus abundance increased. Large amounts of the genus Acinetobacter were observed in the Fluoroquinolone-treated group. Regardless of the antibiotic treatment, hBD1 expression of the tumor cells consistently doubled. The increase in hBD2 and hBD3 expression was the highest in the Beta-lactam treated group. Apparently, antibiotic treatment within 3 months of sample analysis induced microbiome changes and defensin expression levels, depending on the identity of the applied antibiotic.

Small Molecule IITR08367 Potentiates Antibacterial Efficacy of Fosfomycin against Acinetobacter baumannii by Efflux Pump Inhibition.

Fosfomycin is a broad-spectrum single-dose therapy approved for treating lower urinary tract infections. Acinetobacter baumannii, one of the five major UTI-causing pathogens, is intrinsically resistant to fosfomycin. Reduced uptake and active efflux are major reasons for this intrinsic resistance. AbaF, a major facilitator superfamily class of transporter in A. baumannii, is responsible for fosfomycin efflux and biofilm formation. This study describes the identification and validation of a novel small-molecule efflux pump inhibitor that potentiates fosfomycin efficacy against A. baumannii. An AbaF inhibitor screening was performed against Escherichia coli KAM32/pUC18_abaF, using the noninhibitory concentration of 24 putative efflux pump inhibitors. The inhibitory activity of IITR08367 [bis(4-methylbenzyl) disufide] against fosfomycin/H+ antiport was validated using ethidium bromide efflux, quinacrine-based proton-sensitive fluorescence, and membrane depolarization assays. IITR08367 inhibits fosfomycin/H+ antiport activity by perturbing the transmembrane proton gradient. IITR08367 is a nontoxic molecule that potentiates fosfomycin activity against clinical strains of A. baumannii and prevents biofilm formation by inhibiting efflux pump (AbaF). The IITR08367-fosfomycin combination reduced bacterial burden by > 3 log10 in kidney and bladder tissue in the murine UTI model. Overall, fosfomycin, in combination with IITR08367, holds the potential to treat urinary tract infections caused by A. baumannii.

Reverse N-Substituted Hydroxamic Acid Derivatives of Fosmidomycin Target a Previously Unknown Subpocket of 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase (DXR).

Reverse analogs of the phosphonohydroxamic acid antibiotic fosmidomycin are potent inhibitors of the nonmevalonate isoprenoid biosynthesis enzyme 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR, IspC) of Plasmodium falciparum. Some novel analogs with large phenylalkyl substituents at the hydroxamic acid nitrogen exhibit nanomolar PfDXR inhibition and potent in vitro growth inhibition of P. falciparum parasites coupled with good parasite selectivity. X-ray crystallographic studies demonstrated that the N-phenylpropyl substituent of the newly developed lead compound 13e is accommodated in a subpocket within the DXR catalytic domain but does not reach the NADPH binding pocket of the N-terminal domain. As shown for reverse carba and thia analogs, PfDXR selectively binds the S-enantiomer of the new lead compound. In addition, some representatives of the novel inhibitor subclass are nanomolar Escherichia coli DXR inhibitors, whereas the inhibition of Mycobacterium tuberculosis DXR is considerably weaker.

[Investigation of the Antibacterial Synergistic Activity of Fosfomycin-Teicoplanin Combination in Methicillin-Resistant Staphylococcus aureus Strains Isolated from Various Clinical Sample]. / Çesitli Klinik Örneklerden Elde Edilen Metisiline Dirençli Staphylococcus aureus Izolatlarinda Fosfomisin-Teikoplanin Kombinasyonunun Antibakteriyel Sinerjistik Etkinliginin Arastirilmasi.

The aim of this study was to investigate the detection of teicoplanin and fosfomycin antibiotic susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) strains by different methods and to evaluate the antibacterial synergistic effect of teicoplanin-fosfomycin combination by using checkerboard assay and time kill curve assay. Forty-five MRSA strains isolated from clinical samples in routine medical microbiology laboratory of Göztepe Prof. Dr. Süleyman Yalçin City Hospital were included in the study. In the first stage of the combination study, minimum inhibitory concentrations (MIC) were investigated by broth microdilution for teicoplanin and by both broth microdilution and agar dilution methods for fosfomycin. The combination of teicoplanin and fosfomycin was tested by the checkerboard method in 45 MRSA strains and combination effect was determined according to fractional inhibitory concentration index (ΣFIC) calculation. The synergistic effect and bactericidal activity of antibiotic combination were studied against a randomly selected strain from the strains used in the study by using time-kill method for 24 hours. As a result of teicoplanin and fosfomycin antibiotic susceptibility studies, all isolates were found to be susceptible to both antibiotics according to the susceptibility breakpoints determined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). A synergistic effect was found in 22 (49%), additive effect in 22 (49%) and indifferent effect in one (2%) of the 45 strains studied with the checkerboard method. The mean ΣFIC of 45 isolates was found to be 0.5. In the combination study of the antibiotics of the isolate that was studied with time-kill method, synergism was detected for 1/8 MIC concentrations at 12th hour and 24th hour and synergism at 1/4 MIC concentration at sixth hour, 12th hour and 24th hour. In the combination study of 1/4 MIC concentrations of antibiotics, bactericidal effect was detected at sixth hour and this effect was observed to disappear at 12th and 24th hours. High rate of synergistic antibacterial effect of teicoplanin-fosfomycin combination on MRSA isolates was demonstrated as a result of in vitro tests. Such studies conducted on antibiotic-resistant bacterial infections will provide clinicians different treatment options and will contribute to increasing survival. As a result of this study, provided that it is supported by future clinical studies, it can be stated that the teicoplanin-fosfomycin combination may be an effective treatment option in community and hospital-acquired infections caused by MRSA.

[Antibacterial prophylaxis with fosfomycin at the time of the urethral catheter removal after radical prostatectomy (prospective randomized trial)].

AIM: To evaluate the effect of antibacterial prophylaxis using oral fosfomycin during the removal of a urethral catheter after radical prostatectomy on the development of urinary tract infection, severity of leukocyturia and bacteriuria, as well as the severity of lower urinary tract symptoms. MATERIALS AND METHODS: A single-center, non-blind, prospective, randomized controlled trial was carried out. The main group included 40 patients, and the control group included 37 patients. In the group 1, patients received two doses of oral fosfomycin, 3 g, namely in the evening on the day of catheter removal (the first dose) and 48 hours after catheter removal (the second dose). In the group 2, patients did not receive any antibacterial prophylaxis after urethral catheter removal. The endpoints of the study were confirmed episodes of urinary tract infection within 1 month after removal of the urethral catheter, leukocyturia and bacteriuria in urinalysis/urine culture) and severity of the lower urinary tract symptoms assessed by IPSS questionnaire. RESULTS: In the group 2, urinary tract infection was noted in 17.1%, while in the group 2 only in 2.6% of patients (p=0.032). Leukocyturia and bacteriuria were significantly less common in the group receiving antibacterial prophylaxis with fosfomycin (18.4% vs. 48.6%, respectively; p=0.006). Positive urine culture was observed in 7.9% vs. 25.7%, respectively (p=0.035). Four weeks after removal of the urethral catheter, the average IPSS score was significantly higher in the group 2 (13.2 vs. 9.5 points; p=0.002). There were no cases of allergic reaction and pseudomembranous colitis associated with C. difficile in both groups. Diarrhea cured with sorbents was noted in 2 patients (5.2%) in fosfomycin group. CONCLUSION: Antibacterial prophylaxis using two oral doses of fosfomycin 3 g on the day of urethral catheter removal and 48 hours after catheter removal after radical prostatectomy appears to be an effective scheme that reduces the incidence of urinary tract infection and the severity of lower urinary tract symptoms, and is characterized by a minimal risk of adverse events. It is necessary to carried out further research and develop clear recommendations for antibacterial prevention in urological interventions requiring prolonged urethral catheterization.

Population pharmacokinetic/pharmacodynamic target attainment analysis of IV fosfomycin for the treatment of MDR Gram-negative bacterial infections.

BACKGROUND: IV fosfomycin is used against MDR Gram-negative bacilli (GNB) but has dose-limiting side effects, especially in patients with impaired kidney function. OBJECTIVES: To determine the optimal dosage of IV fosfomycin for patients with varying degrees of kidney function. METHODS: Adult patients receiving IV fosfomycin for treatment of GNB were eligible. Five serial blood samples were collected after at least three doses of fosfomycin; plasma was assayed by LC-MS/MS and modelled by population pharmacokinetic analysis. The PTA for AUC24/MIC of 98.9 for Escherichia coli and Klebsiella pneumoniae, and 40.8 for Pseudomonas aeruginosa were computed by Monte Carlo simulations. Cumulative fractions of response (CFR) were analysed for each pathogen using EUCAST MIC distributions. RESULTS: A total of 24 patients were included. Creatinine clearance (CLCR) and gender significantly influenced fosfomycin clearance. The kidney function-adjusted dosing regimens are proposed by using the lowest dose that can achieve ≥90% PTA for AUC24/MIC of 98.9 at an MIC of ≤32 mg/L (EUCAST v.13 susceptibility breakpoint for Enterobacterales). For patients with normal kidney function (CLCR 91-120 mL/min), a dosage of 15 g/day is suggested. This regimen achieved 97.1% CFR against E. coli, whereas CFR was 72.9% for K. pneumoniae and 76.7% for P. aeruginosa. CONCLUSIONS: A fosfomycin dosage of 15 g/day with adjustment according to kidney function provided high PTA and CFR when treating E. coli. This dosage is lower than that used in current practice and may improve tolerability. Higher dosages may be needed for P. aeruginosa; however, safety data are limited.

Bacteriological profile, antimicrobial susceptibility, and factors associated with urinary tract infection in pregnant women.

INTRODUCTION: Urinary tract infection (UTI) is a common bacterial complication in pregnancy. The study aimed to estimate the prevalence, risk factors, and bacterial etiology of UTI during pregnancy and determine the efficacy of antimicrobial drugs in treating UTIs. METHODOLOGY: Urine specimens and clinical data were collected from pregnant women who attended primary health centers in Erbil, Iraq. All specimens were cultured on appropriate media and identified by standard microbiological methods. The pregnant women were grouped into symptomatic UTI group, asymptomatic bacteriuria group, and the control group. The agar dilution method was used to determine antimicrobial susceptibility. RESULTS: Among the 5,042 pregnant women included in this study, significant bacteriuria was found in 625 (12.40%) of the cases, and 198 (31.68%) had symptomatic UTI, of which 43.59% were diagnosed during the third trimester. Out of the 643 bacteria isolated, 33.28% were symptomatic UTI, of which 43.59% developed during the third trimester. There was a significant difference in the bacterial etiology between symptomatic UTI and asymptomatic bacteriuria (p = 0.002), as well as between cystitis and pyelonephritis (p = 0.017). The most common bacterial species isolated was Escherichia coli, which was susceptible to fosfomycin (100%), meropenem (99.45%), and nitrofurantoin (97.8%). CONCLUSIONS: Pregnant women are more likely to develop UTI in the third trimester. Escherichia coli is the predominant pathogen. The study suggests the use of fosfomycin, meropenem, and nitrofurantoin for the treatment of UTI. No Gram-positive isolates were resistant to daptomycin.

Antibiotics efficacy in clinical and microbiological cure of uncomplicated urinary tract infection: a systematic review and network meta-analysis.

PURPOSE: Fosfomycin has been used more frequently in managing uncomplicated urinary tract infections (UTIs) due to decreased compliance and increased multidrug-resistant bacteria. The aim of this network meta-analysis was to assess the efficacy of Fosfomycin compared to Nitrofurantoin, Trimethoprim-Sulfamethoxazole (TMP-SMX), and Ciprofloxacin in terms of clinical and microbiological cure alongside with other measurements. MATERIALS AND METHODS: We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). We included randomized control trials (RCTs) with uncomplicated UTI patients who received Fosfomycin, Nitrofurantoin, TMP-SMX, or Ciprofloxacin and reported the clinical or microbiological cure. We used Cochrane Risk of Bias Assessment Tool to assess the included studies' quality. R-software was used for all statistical analysis. We ranked all antibiotics using the netrank function which yielded P scores. Frequentist network meta-analysis was used to assess the efficacy of all outcomes. RESULTS: We included 13 RCTs with a total number of 3856 patients that showed Fosfomycin ranked the highest among the other antibiotics with respect to clinical cure (P-score = 0.99) and microbiological cure (P-score = 0.99) while Ciprofloxacin ranked the lowest (P-score = 0.11 and 0.02, respectively). Moreover, Ciprofloxacin yielded the highest relapse rate (P-score = 1), whereas TMP-SMX had the lowest relapse rate (P-score = 0.07). As for the adverse events, Ciprofloxacin demonstrated the highest adverse events as opposed to Fosfomycin (P-score = 0.98 and 0.05, respectively). CONCLUSION: The network meta-analysis demonstrated that Fosfomycin is the most effective antibiotic in treating uncomplicated UTIs with respect to clinical cure, microbiological cure, and adverse events profile.

Comparative effectiveness and mortality of colistin monotherapy versus colistin-fosfomycin combination therapy for the treatment of carbapenem-resistant Enterobacteriaceae (CRE) infections: A propensity score analysis.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) infections pose a significant threat to global health due to limited treatment options and high mortality rates. Colistin-based regimens have emerged as a primary treatment approach, but the effectiveness and mortality outcomes of colistin monotherapy versus colistin-fosfomycin combination therapy remain uncertain. This study aims to compare the effectiveness and mortality of colistin monotherapy and colistin-fosfomycin combination therapy for CRE infections. Notably, our study is the first to undertake a comprehensive examination of the effectiveness and mortality outcomes between colistin monotherapy and colistin-fosfomycin combination therapy in the context of CRE infections. METHODS: A retrospective cohort study was conducted using data from patients diagnosed with carbapenem-resistant Enterobacteriaceae (CRE) infections at Nakornping Hospital during 2015 to 2022. Inverse probability weighting (IPW) was employed to create balanced cohorts of patients receiving either colistin monotherapy or colistin-fosfomycin combination therapy. The primary outcome measure was treatment effectiveness, assessed by 30-day mortality. Secondary outcome measures included clinical response, mortality at the end of treatment, and microbiologic response. Univariate and multivariate logistic regression analysis were employed after applying propensity score weighting using inverse probability of weighting (IPW). RESULTS: A total of 220 patients were included in the analysis, with 67 receiving colistin monotherapy and 153 receiving colistin-fosfomycin combination therapy. Propensity score weighting using IPW balanced the baseline characteristics between the two groups. The effectiveness of treatment, as measured by 30-day mortality, was not significantly different between the colistin monotherapy group and the colistin-fosfomycin combination therapy group (adjusted odds ratio [aOR] = 1.51, 95% confidence interval [CI]: 0.60-3.78, p = 0.383). Similarly, no significant difference was observed in the mortality at the end of treatment between the two groups (aOR = 1.26, 95% CI: 0.55-2.90, p = 0.576). The clinical response (aOR = 1.48, 95% CI: 0.61-3.59, p = 0.383) and microbiologic response (aOR = 0.66, 95% CI: 0.18-2.38, p = 0.527) were similar between the colistin monotherapy and colistin-fosfomycin combination therapy groups. CONCLUSION: The propensity score analysis among 220 matched patients showed comparable treatment effectiveness and mortality between colistin monotherapy and colistin-fosfomycin combination therapy for CRE infections. These results suggest that colistin monotherapy may be as effective as combination therapy. More prospective randomized controlled trials are needed to confirm these findings and establish optimal CRE treatment strategies.

Bacterial Persistence in Urinary Tract Infection Among Postmenopausal Population.

IMPORTANCE: Urinary tract infections (UTIs) are common in older-aged women. Our study examined bacterial persistence with commonly prescribed antibiotics. Bacterial growth was demonstrated despite antibiotic treatment. OBJECTIVES: The aims of this study were to quantify the bacterial persister phenotype in urine collected from postmenopausal women with acute and recurrent UTI and to determine the capabilities of first-line antibiotics to effectively treat persister cells. STUDY DESIGN: This was an institutional review board-approved cross-sectional analysis within a large academic referral center. Uropathogens were cultured from postmenopausal women with acute or recurrent UTI and screened for persister cells using persistence assays. Demographic and clinical variables were collected and analyzed. The entire experimental process was repeated in triplicate. Data were analyzed for significance (P < 0.05) between the persister culture and antibiotic treatments using a 1-way analysis of variance with multiple comparisons in Prism 9.3.0. RESULTS: Forty participants were included: 62.5% White, 22.5% Black, 3% Asian, and 2% Hispanic with a mean age of 72.3 ± 11.62 years. The persister phenotype was demonstrated in all of Escherichia coli isolates. Treatment with fosfomycin demonstrated reduced colony-forming units per milliliter compared with control (P < 0.01). Among recurrent isolates, there was a statistically significant decrease in colony-forming units per milliliter after antibiotic treatment with all 4 antibiotics (P < 0.05). CONCLUSIONS: This study demonstrated in vitro bacterial persistence in uropathogens from urogynecology patients despite treatment with commonly prescribed antibiotics. Fosfomycin generated the least amount of persister cells. Results suggest that persistence may be one bacterial defense mechanism involved in UTIs. Further research is needed to understand the clinical implications.