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.

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.

Back to the Future: Intravenous Fosfomycin is Safe and Effective for the Treatment of Complicated Infections in Children.

BACKGROUND: Despite its broad spectrum and excellent safety profile, fosfomycin is still rarely used in pediatrics, with very limited experience from clinicians. METHODS: We retrospectively reviewed the medical records of all children admitted to Bambino Gesù Children's Hospital, IRCCS, Rome, Italy, and treated with fosfomycin for any serious infection. Children with immunodeficiency and oncologic diseases were excluded. Of each, we reported and analyzed demographic and clinical data. RESULTS: The clinical charts of 20 patients were reviewed and analyzed. The mean age was 10.2 years. Most children were males (85%). Most patients treated had an osteo-articular infection (65%). In our sample, 7 patients (35%) had an underlying comorbidity. The causative agent was isolated in 14 cases (70%). All patients were treated with a combination of 2-3 antibiotics, including fosfomycin. The average duration of antibiotic treatment was 18 days. After treatment, 8 patients (40%) experienced a mild adverse reaction, possibly correlated with the administration of fosfomycin. All patients were discharged in good clinical condition. CONCLUSIONS: The present study reports on a sample of pediatric patients with complicated infections where administration of fosfomycin led to eradication of the disease with little or no side effects. Role of the underlying condition and concomitant medication in causing the reaction could not be ruled out. These data suggest that fosfomycin is an effective and safe antibiotic in the pediatric population, particularly for deep-seated infections sustained by multi-drug resistant pathogens.

Fosfomycin in the pediatric SETTING: Evidence and potential indications / Fosfomicina en el ámbito pediátrico: Evidencia y posibles indicaciones

To date, there has been little experience in using fosfomycin in children. However, its broad spectrum of action and excellent safety profile have renewed interest in this antibiotic, especially for treating infections by multidrug-resistant bacteria. The main indication for fosfomycin in pediatrics is currently community-acquired lower urinary tract infection. Given its good activity against bacteria, fosfomycin can also be useful in urinary infections caused by extended-spectrum beta-lactamase-producing enterobacteria. Fosfomycin presents very good dissemination to tissues including bone and is therefore an option in the combined therapy of osteomyelitis, especially in cases produced by methicillin-resistant Staphylococcus aureus (MRSA) or in cases with beta-lactam allergies. Fosfomycin can also be employed in combination for multidrug-resistant Gram-negative bacteremia (especially carbapenemase-producing enterobacteria), S. aureus (if there is a high suspicion of MRSA or complicated infections) and vancomycin-resistant Enterococcus spp. Other infections in which fosfomycin could be part of a combined therapy include staphylococcal endocarditis (in case of beta-lactam allergy or MRSA), central nervous system infections (mainly by MRSA, S. epidermidis, Listeria and resistant pneumococcus), nosocomial pneumonia and infections associated with mechanical ventilation

Hasta la fecha existe poca experiencia en el uso de fosfomicina en niños. Sin embargo, su amplio espectro de acción y excelente perfil de seguridad han renovado el interés por este antibiótico, especialmente para el tratamiento de infecciones por bacterias multirresistentes. En la actualidad, su principal indicación en pediatría es la infección urinaria de vías bajas adquirida en la comunidad. Dada su buena actividad frente a enterobacterias puede ser también útil en infecciones urinarias producidas por bacterias productoras de β-lactamasas de espectro extendido. Fosfomicina presenta muy buena difusión a tejidos incluyendo hueso, por lo que es una alternativa en el tratamiento combinado de la osteomielitis, especialmente en casos producidos por Staphylococcus aureus resistente a meticilina (SARM) o pacientes alérgicos a β-lactámicos. También puede emplearse en combinación en bacteriemia por gramnegativos multirresistentes (especialmente enterobacterias productoras de carbapenemasas), S. aureus (si existe alta sospecha de SARM o infecciones complicadas) y Enterococcus spp. resistente a vancomicina. Otras infecciones en las que podría formar parte de un tratamiento combinado incluyen la endocarditis estafilocócica (en caso de alergia a β-lactámicos o SARM), infecciones del SNC (principalmente por SARM, S. epidermidis, neumococo resistente y Listeria) y neumonía nosocomial y asociada a ventilación mecánica

Emprego de fosfomicina trometamol em dose única para tratamento de infecçöes nåo complicadas do trato urinário em cardiopatas, gestantes e nåo-gestantes: estudo controlado / Fosfomycin trometanol single-dose in the treatment of uncomplicated urinary tract infections in cardiac pregnant or non pregnant women: a controlled study

Nas gestantes säo frequentes as infecçäoes do trato urinário, devendo ser diagnosticadas e tratadas antes da 16ª semana de gestaçäo, devido às suas repercussöes tardias como referido na literatura. Entre estas, a bacteriúrias assintomática que, se näo tratada, leva à pielonefrite em cerca de 25 por cento dos casos. Considerando as vantagens que oferece o tratamento em dose única, os autores realizaram um estudo 50 mulheres em idde fértil, gestantes ou näo, portadoras de cardiopatia, sem repercussäo hemodinâmica, de graus funcionais New York Heart Association (NYHA) I e II e com infecçäo dotrato urinário. A todas foi administrada fosfomicina trometamol em dose única de 3 g. Foram realizadas avaliaçöes clínicas, incluindo eletrocardiograma com 12 derivaçöes e as oportunas análises laboratoriais antes e após o tratamento. As pacientes gestantes foram acompanhadas até o termo, analisando-se os dados maternos de parto e puerpério e os dados dos recém-nascidos em relaçäo ao peso, comprimento e desenvolvimento. No grupo de 28 gestantes, 25 responderam positivamente ao tratamento (89,3 por cento); em três casos foi necessário o emprego de outras drogas, conforme indicaçäo do antibiograma. Em um caso de nova infecçäo foi repetido o tratamento com fosfomina trometamol com bom resultado. No grupo de 22 näo-gestantes, 21 pacientes responderam positivamente ao tratamento (95,5 por cento). Só um caso näo respondeu ao tratamento, sendo tratado com êxito com cefoxitina. A análise dos recém-nascidos mostrou que o tratamento com fosfomicina trometamol, em dose única de 3 g, näo influenciou o desenvolvimento dos conceptos, independentemente da idade gestacional em que a droga foi utilizada. Os efeitos colaterais limitaram-se a três casos de náuseas e um de vômito (no total, 8 por cento)