Assuntos
Antibacterianos , Ciprofloxacina , Fosfomicina , Próstata , Combinação Trimetoprima e Sulfametoxazol , Humanos , Masculino , Ciprofloxacina/uso terapêutico , Ciprofloxacina/administração & dosagem , Fosfomicina/uso terapêutico , Fosfomicina/administração & dosagem , Próstata/patologia , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Combinação Trimetoprima e Sulfametoxazol/administração & dosagem , Antibioticoprofilaxia/métodos , Quimioterapia Combinada , Biópsia/métodos , Biópsia/efeitos adversosRESUMO
BACKGROUND: The role of intravenous fosfomycin (iv-FOS) as a part of combination therapy for Gram-negative bacteria bloodstream infections (GNB-BSI) needs to be evaluated in clinical practice, as in vitro data show potential efficacy. METHODS: All consecutive patients with a GNB-BSI from 01 January 2021 to 01 April 2023 were included. Primary outcome was 30-day mortality. A Cox regression analysis was used to identify predictors of mortality; an inverse-probability of treatment-weighting (IPTW) analysis was also performed. RESULTS: Overall, 363 patients were enrolled: 211 (58%) males, with a median (q1-q3) age of 68 (57-78) years, and a median Charlson comorbidity index of 5 (3-7). At GNB-BSI onset, the median SOFA score was 5 (2-7) and 122 patients (34%) presented with septic shock. Pathogens were principally Klebsiella pneumoniae (42%), Escherichia coli (28%) and Pseudomonas aeruginosa (17%); of them, 36% were carbapenem-resistant. The therapy included carbapenems (40%), cephalosporins (37%) and beta-lactams/beta-lactamases-inhibitors (19%); a combination with iv-FOS was used in 98 (27%) cases at a median dosage of 16 (16-18) g/daily. The use of iv-FOS was not associated with reduced crude mortality (21% vs 29%, P = 0.147). However, on multivariable Cox-regression, combination therapy with iv-FOS resulted in protection for mortality (aHR 0.51, 95% CI 0.28-0.92), but not other combo-therapies (HR 0.69, 95% CI 0.44-1.16). This result was also confirmed with the IPTW-adjusted Cox model (aHR 0.52, 95% CI 0.31-0.91). Subgroup analysis suggested a benefit in severe infections (SOFA > 6, PITT ≥ 4) and when iv-FOS was initiated within 24 hours of GNB-BSI onset. CONCLUSIONS: Fosfomycin in combination therapy for GNB-BSI may have a role in improving survival. These results justify the development of further clinical trials.
Assuntos
Administração Intravenosa , Antibacterianos , Bacteriemia , Fosfomicina , Infecções por Bactérias Gram-Negativas , Pontuação de Propensão , Humanos , Fosfomicina/uso terapêutico , Fosfomicina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Estudos Retrospectivos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/mortalidade , Infecções por Bactérias Gram-Negativas/microbiologia , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Bacteriemia/mortalidade , Bactérias Gram-Negativas/efeitos dos fármacos , Quimioterapia CombinadaRESUMO
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.
Assuntos
Antibacterianos , Monitoramento de Medicamentos , Fosfomicina , Humanos , Fosfomicina/efeitos adversos , Fosfomicina/administração & dosagem , Fosfomicina/uso terapêutico , Feminino , Masculino , Estudos Retrospectivos , Antibacterianos/efeitos adversos , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Pessoa de Meia-Idade , Fatores de Risco , Idoso , Administração Intravenosa , Itália , Adulto , Espectrometria de Massas em TandemRESUMO
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.
Assuntos
Antibacterianos , Antibioticoprofilaxia , Ciprofloxacina , Quimioterapia Combinada , Fosfomicina , Próstata , Combinação Trimetoprima e Sulfametoxazol , Humanos , Masculino , Fosfomicina/uso terapêutico , Fosfomicina/administração & dosagem , Ciprofloxacina/uso terapêutico , Ciprofloxacina/administração & dosagem , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Combinação Trimetoprima e Sulfametoxazol/administração & dosagem , Antibioticoprofilaxia/métodos , Idoso , Pessoa de Meia-Idade , Próstata/patologia , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Biópsia/métodos , Biópsia/efeitos adversos , Estudos Retrospectivos , Reto , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/epidemiologiaRESUMO
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.
Assuntos
Infecções por Acinetobacter , Acinetobacter baumannii , Administração Intravenosa , Antibacterianos , Carbapenêmicos , Fosfomicina , Pneumonia Associada à Ventilação Mecânica , Sulbactam , Humanos , Fosfomicina/uso terapêutico , Fosfomicina/administração & dosagem , Acinetobacter baumannii/efeitos dos fármacos , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/mortalidade , Infecções por Acinetobacter/microbiologia , Estudos Retrospectivos , Masculino , Feminino , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Idoso , Pessoa de Meia-Idade , Carbapenêmicos/uso terapêutico , Sulbactam/uso terapêutico , Sulbactam/administração & dosagem , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Pneumonia Associada à Ventilação Mecânica/microbiologia , Pneumonia Associada à Ventilação Mecânica/mortalidade , Colistina/uso terapêutico , Colistina/administração & dosagem , Itália , Ampicilina/uso terapêutico , Ampicilina/administração & dosagem , Cefiderocol , Idoso de 80 Anos ou mais , Quimioterapia Combinada , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Bacteriemia/mortalidade , Farmacorresistência Bacteriana MúltiplaRESUMO
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.
Assuntos
Antibacterianos , Farmacorresistência Bacteriana Múltipla , Fosfomicina , Infecções por Bactérias Gram-Negativas , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa , Humanos , Fosfomicina/farmacocinética , Fosfomicina/administração & dosagem , Fosfomicina/farmacologia , Fosfomicina/efeitos adversos , Feminino , Masculino , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Pessoa de Meia-Idade , Idoso , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Adulto , Klebsiella pneumoniae/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Idoso de 80 Anos ou mais , Administração Intravenosa , Método de Monte Carlo , Espectrometria de Massas em Tandem , Bactérias Gram-Negativas/efeitos dos fármacosRESUMO
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.
Assuntos
Antibacterianos , Antibioticoprofilaxia , Fosfomicina , Prostatectomia , Cateteres Urinários , Infecções Urinárias , Humanos , Fosfomicina/administração & dosagem , Fosfomicina/uso terapêutico , Masculino , Prostatectomia/efeitos adversos , Prostatectomia/métodos , Pessoa de Meia-Idade , Infecções Urinárias/prevenção & controle , Idoso , Estudos Prospectivos , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Cateteres Urinários/efeitos adversos , Antibioticoprofilaxia/métodos , Cateterismo Urinário/efeitos adversos , Remoção de DispositivoRESUMO
AIM: To investigate the efficacy of intravenous (IV) fosfomycin as combination therapy for treatment of difficult-to-treat (DTT) acute and subacute infections with multi-drug-resistant (MDR) Gram-negative bacteria (GNB), and risk factors associated with 90-day mortality. METHODS: A retrospective, observational, monocentric study enrolled patients treated with IV fosfomycin in combination regimens (≥72 h) for proven DTT-MDR-GNB infection. Multi-variate regression analysis identified independent risk factors for 90-day mortality. A propensity score for receiving fosfomycin was performed to control for confounding factors. RESULTS: In total, 70 patients were included in this study: 54.3% had carbapenem-resistant isolates, 31.4% had ceftazidime/avibactam-resistant isolates and 28.6% had ceftolozane/tazobactam-resistant isolates. The main pathogens were Pseudomonas aeruginosa (57.1%) and Klebsiella pneumoniae (22.9%). The most prevalent infections were nosocomial pneumonia (42.9%), osteomyelitis (17.1%) and intra-abdominal infections. All-cause 30- and 90-day mortality were 15.7% and 31.4%, respectively (18.9% and 50% considering acute DTT-MDR-GNB infections alone). Relapse at 30 days occurred in 22.9% of cases (29% with emergence of fosfomycin resistance). Mortality at 90 days was independently associated with septic shock and ceftolozane/tazobactam resistance. The relationship between resistance to ceftolozane/tazobactam and 90-day mortality was confirmed to be significant after adjustment by propensity score analysis (hazard ratio 5.84, 95% confidence interval 1.65-20.68; P=0.006). CONCLUSIONS: Fosfomycin seems to be a promising salvage, combination treatment in DTT-MDR-GNB infections. Resistance to ceftolozane/tazobactam seems to be independently associated with treatment failure. Randomized clinical trials focusing on pathogen and infection sites are needed urgently to demonstrate the superiority of fosfomycin in combination with other agents for the resolution of DTT-MDR-GNB infections.
Assuntos
Administração Intravenosa , Antibacterianos , Cefalosporinas , Farmacorresistência Bacteriana Múltipla , Quimioterapia Combinada , Fosfomicina , Infecções por Bactérias Gram-Negativas , Fosfomicina/uso terapêutico , Fosfomicina/administração & dosagem , Humanos , Estudos Retrospectivos , Masculino , Feminino , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Negativas/mortalidade , Idoso , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Pessoa de Meia-Idade , Bactérias Gram-Negativas/efeitos dos fármacos , Resultado do Tratamento , Idoso de 80 Anos ou mais , Tazobactam/uso terapêutico , Adulto , Combinação de Medicamentos , Pseudomonas aeruginosa/efeitos dos fármacos , Fatores de RiscoRESUMO
OBJECTIVE: A case of post-neurosurgical ventriculitis caused by a KPC-producing Klebsiella pneumoniae (KPC-Kp) with a ceftazidime/avibactam-resistant, meropenem-susceptible phenotype is reported. METHODS AND RESULTS: The patient had a concomitant bloodstream infection with a wild-type KPC-Kp with a ceftazidime/avibactam-susceptible, meropenem-resistant phenotype. Prolonged treatment with intravenous fosfomycin and meropenem/vaborbactam achieved clinical success. Therapeutic drug monitoring performed during the first days of treatment showed for the first time that vaborbactam efficiently penetrates cerebrospinal fluid. In contrast, meropenem was undetectable in cerebrospinal fluid at each sampling, suggesting that additional doses of meropenem may be required to appropriately prescribe meropenem/vaborbactam for central nervous system infections. Plasma and cerebrospinal fluid levels of fosfomycin were adequate, confirming the potential of this agent possibly even in the fight against multidrug-resistant organisms. CONCLUSIONS: This case highlights the need for therapeutic drug monitoring as a crucial tool for optimizing treatment in complicated cases where the pharmacokinetic behaviour of antibiotics is difficult to predict.
Assuntos
Antibacterianos , Bacteriemia , Ácidos Borônicos , Ventriculite Cerebral , Fosfomicina , Infecções por Klebsiella , Klebsiella pneumoniae , Meropeném , Humanos , Fosfomicina/uso terapêutico , Fosfomicina/administração & dosagem , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/enzimologia , Meropeném/administração & dosagem , Meropeném/uso terapêutico , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/microbiologia , Ventriculite Cerebral/tratamento farmacológico , Ventriculite Cerebral/microbiologia , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Ácidos Borônicos/administração & dosagem , Testes de Sensibilidade Microbiana , Masculino , beta-Lactamases/metabolismo , Farmacorresistência Bacteriana Múltipla , Pessoa de Meia-Idade , Combinação de Medicamentos , Feminino , Procedimentos Neurocirúrgicos , Resultado do Tratamento , Compostos Heterocíclicos com 1 AnelRESUMO
Individualization of fosfomycin dosing based on therapeutic drug monitoring (TDM) of plasma concentrations could reduce drug-related adverse events and improve clinical outcome in complex clinical conditions. Quantification of fosfomycin in plasma samples was performed by a rapid ultraperformance liquid chromatography mass spectrometry method. Sample preparation involved protein precipitation with [13C3]-fosfomycin benzylamine salt as internal standard. The calibration curve ranged from 2 to 800 mg/L. Within- and between-day precision and accuracy, sensitivity, selectivity, dilution integrity, recovery were investigated and the results met the acceptance criteria. In patients, multiple drug dosing (every 6 or 8 hours) or in continuous administration were adopted, resulting in a large interpatient variability in drug concentrations (from 7.4 mg/L and 644.6 mg/L; CV: 91.1%). In critical care patient setting TDM can represent an important tool to identify the best fosfomycin dosing in single patients, taking into consideration clinical characteristics, infection sites and susceptibility of the treated pathogens.
Assuntos
Antibacterianos/sangue , Monitoramento de Medicamentos/métodos , Fosfomicina/sangue , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Cromatografia Líquida de Alta Pressão , Fosfomicina/administração & dosagem , Fosfomicina/efeitos adversos , Humanos , Espectrometria de Massas em Tandem , Fatores de TempoRESUMO
BACKGROUND: The aim of this study was to determine the in vitro efficacy of intravenous (IV) fosfomycin against extensively drug-resistant Enterobacterales strains and the effect of glucose 6-phosphate (G6-P) on sensitivity results. MATERIAL METHOD: Thirty-two extensively drug-resistant Klebsiella pneumonia strains were included in the study. Detection of the carbapenemase genes was performed using the Gene-Xpert® System Carba R® kit. Susceptibility of IV fosfomycin was assessed using the agar dilution method. The agar dilution method was repeated using Muller-Hinton Agar medium without G6-P to assess the effect of G6-P on sensitivity results. RESULTS: All strains in the study produced carbapenemases and were resistant to all drugs tested, including carbapenems, piperacillin-tazobactam, ceftriaxone, and ceftazidime. Fosfomycin resistance was detected in 3 (9.3%) strains. When the sensitivity test was repeated without G6-P, fosfomycin resistance was detected in 82.7% of the fosfomycin-susceptible strains. The Gene-Xpert® System showed NDM-1 in 46.8%, OXA-48 in 18.7%, KPC in 3.1%, and NDM-1 + OXA-48 in 21.8% of the strains. OXA-48 was detected in one of the resistant strains, and none of the viable genes were detected in two of the resistant strains. CONCLUSION: This study shows that IV fosfomycin is a potentially important treatment alternative for infections caused by common resistant strains. Accurate results may not be obtained unless G6-P is used in the agar dilution method for in vitro susceptibility studies of fosfomycin.
Assuntos
Antibacterianos/uso terapêutico , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Fosfomicina/uso terapêutico , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/genética , Administração Intravenosa , Antibacterianos/administração & dosagem , Fosfomicina/administração & dosagem , Variação Genética , Genótipo , Glucose-6-Fosfato/metabolismo , HumanosRESUMO
El síndrome de intolerancia a múltiples medicamentos (MDIS, por sus siglas en inglés) se caracteriza por la intolerancia a dos o más medicamentos no relacionados. Tiene una prevalencia baja y es común en pacientes con polifarmacia. A pesar de que las reacciones adversas a los medicamentos son muy frecuentes, es raro que los pacientes debuten con este síndrome, el cual tiene implicaciones clínicas de leves a graves que afectan su vida; de acuerdo con esto varían el abordaje y su manejo. La sintomatología presentada varía desde síntomas gastrointestinales como reflujo gastroesofágico, dolores musculares y cefalea, hasta síntomas cutáneos; estos son los más frecuentes, tales como urticaria y erupciones maculopapulares o presentaciones menos comunes como el síndrome de Stevens-Johnson. El MDIS es causado por una amplia variedad de fármacos; por ello el conocimiento del síndrome, así como un adecuado interrogatorio de los antecedentes del paciente, es necesario para realizar un diagnóstico oportuno e instaurar un manejo adecuado y preventivo, evitando reacciones adversas que pongan en riesgo su vida. Con los hallazgos del cuadro clínico en la paciente, y basados en los antecedentes alérgicos presentados anteriormente a diferentes medicamentos no relacionados entre ellos, más la presentación de un rash maculopapular generalizado posterior a la administración de trimetoprim/sulfametoxazol se realiza el diagnóstico de MDIS. Se decide cambiar de medicamento por fosfomicina, con una consecuente evolución favorable. (AU)
Assuntos
Humanos , Feminino , Adulto , Toxidermias/diagnóstico , Síndrome de Hipersensibilidade a Medicamentos/diagnóstico , Síndrome de Hipersensibilidade a Medicamentos/fisiopatologia , Combinação Trimetoprima e Sulfametoxazol/efeitos adversos , Loratadina/administração & dosagem , Polimedicação , Fosfomicina/administração & dosagemRESUMO
INTRODUCTION: Fosfomycin has re-emerged as a possible therapeutic alternative for the treatment of resistant bacterial pathogens. Its main mechanism of action is the inhibition of the initial step of cell wall synthesis and is active against both Gram-positive and Gram-negative bacteria. However, its clinical effectiveness against multidrug resistant bacteria remains largely unknown. Therefore, we aim to evaluate the clinical and microbiological effectiveness of intravenous fosfomycin as well as its safety in a tertiary care teaching hospital in Lebanon. METHODOLOGY: This is a retrospective chart review of adult patients who had presented to the hospital and were treated with intravenous fosfomycin for at least 24 hours for any type of infection between 2014 and 2019. RESULTS: Among 31 episodes treated with intravenous fosfomycin, 68% had an overall favorable clinical response. In 84% of the episodes, fosfomycin was administered in combination with other antibiotics, commonly tigecycline. Of those with available cultures at end of therapy, 73% achieved microbiological success. No relapse was documented within 30 days of completion of therapy. In the episodes secondary to resistant pathogens, the rates of favorable clinical outcome and microbiological success at the end of therapy were 71% and 73%, respectively. Fosfomycin resistance developed in two cases and mild adverse events occurred in 65% of the episodes during the course of treatment. CONCLUSIONS: Fosfomycin is a safe and effective option in the treatment of multi-drug resistant infections. Nevertheless, careful stewardship is important to maintain its efficacy and to reduce the risk of selection of antimicrobial resistance.
Assuntos
Antibacterianos/uso terapêutico , Fosfomicina/uso terapêutico , Infecções por Bactérias Gram-Negativas/epidemiologia , Infecções por Bactérias Gram-Positivas/epidemiologia , Administração Intravenosa , Adolescente , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Feminino , Fosfomicina/administração & dosagem , Fosfomicina/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Bactérias Gram-Positivas/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Líbano/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Centros de Atenção Terciária , Adulto JovemRESUMO
Antibiotics are essential molecules for the treatment and prophylaxis of many infectious diseases. However, drugs that combat microbial infections can become a human health threat due to their high and often indiscriminate consumption, considered one of the factors of antimicrobial resistance (AMR) emergence. The AMR crisis, the decrease in new drug development by the pharmaceutical industry, and reduced economic incentives for research have all reduced the options for treating infections, and new strategies are necessary, including the return of some traditional but "forgotten" antibiotics. However, prescriptions for these older drugs including nitrofurantoin and oral fosfomycin, have been based on the results of pioneer studies, and the limited knowledge generated 50-70 years ago may not be enough. To avoid harming patients and further increasing multidrug resistance, systematic evaluation is required, mainly for the drugs prescribed for community-acquired infections, such as urinary tract infections (UTI). Therefore, this review has the objective of reporting the use of two classic drugs from the nitrofuran and phosphonic acid classes for UTI control nowadays. Furthermore, we also explore new approaches used for these antibiotics, including new combination regimes for spectral amplification, and the prospects for reducing bacterial resistance in the fight against bacteria responsible for UTI.
Assuntos
Antibacterianos/farmacologia , Fosfomicina/farmacologia , Nitrofurantoína/farmacologia , Antibacterianos/administração & dosagem , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , Desenvolvimento de Medicamentos/tendências , Indústria Farmacêutica/tendências , Farmacorresistência Bacteriana Múltipla , Fosfomicina/administração & dosagem , Humanos , Nitrofurantoína/administração & dosagem , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologiaRESUMO
To assess fosfomycin (FOS) elimination in patients with sepsis and acute kidney injury (AKI) undergoing slow-extended daily dialysis (SLEDD) with the Genius system in a prospective observational study. After ethics committee approval ten patients with sepsis and AKI stage 3 underwent daily SLEDD sessions of eight hours. FOS was applied i.v. at doses of 3 × 5 g per day. FOS serum levels were measured pre- and post hemofilter before, during, and after SLEDD sessions, and instantaneous clearance was calculated. In five of the patients, we analyzed FOS levels after the first dose, in the other five patients serum levels were measured during ongoing therapy. FOS was eliminated rapidly via the hemofilter. FOS clearance decreased from 152 ± 10 mL/min (start of SLEED session) to 43 ± 38 mL/min (end of SLEDD session). In 3/5 first-dose patients after 4-6 h of SLEDD the FOS serum level fell below the EUCAST breakpoint of 32 mg/L for Enterobacterales and Staphylococcus species. In all patients with ongoing fosfomycin therapy serum levels were high and above the breakpoint at all times. FOS toxicity or adverse effects were not observed. FOS serum concentrations exhibit wide variability in critically ill patients with sepsis and AKI. FOS is eliminated rapidly during SLEDD. A loading dose of 5 g is not sufficient to achieve serum levels above the EUCAST breakpoint for common bacteria in all patients, considering that T > MIC > 70% of the dosing interval indicates sufficient plasma levels. We thus recommend a loading dose of 8 g followed by a maintenance dose of 5 g after a SLEDD session in anuric patients. We strongly recommend therapeutic drug monitoring of FOS levels in critically ill patients with AKI and dialysis therapy.
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Injúria Renal Aguda/terapia , Fosfomicina/administração & dosagem , Fosfomicina/efeitos adversos , Sepse/terapia , Injúria Renal Aguda/complicações , Idoso , Estado Terminal , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Enterobacter , Feminino , Hemodinâmica , Hemofiltração , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Diálise Renal , Sepse/complicaçõesRESUMO
Thermosensitive chitosan hydrogels-renewable, biocompatible materials-have many applications as injectable biomaterials for localized drug delivery in the treatment of a variety of diseases. To combat infections such as Staphylococcus aureus osteomyelitis, localized antibiotic delivery would allow for higher doses at the site of infection without the risks associated with traditional antibiotic regimens. Fosfomycin, a small antibiotic in its own class, was loaded into a chitosan hydrogel system with varied beta-glycerol phosphate (ß-GP) and fosfomycin (FOS) concentrations. The purpose of this study was to elucidate the interactions between FOS and chitosan hydrogel. The Kirby Bauer assay revealed an unexpected concentration-dependent inhibition of S. aureus, with reduced efficacy at the high FOS concentration but only at the low ß-GP concentration. No effect of FOS concentration was observed for the planktonic assay. Rheological testing revealed that increasing ß-GP concentration increased the storage modulus while decreasing gelation temperature. NMR showed that FOS was removed from the liquid portion of the hydrogel by reaction over 12 h. SEM and FTIR confirmed gels degraded and released organophosphates over 5 days. This work provides insight into the physicochemical interactions between fosfomycin and chitosan hydrogel systems and informs selection of biomaterial components for improving infection treatment.
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Antibacterianos/administração & dosagem , Quitosana/química , Fosfomicina/administração & dosagem , Glicerofosfatos/química , Antibacterianos/química , Antibacterianos/farmacologia , Sistemas de Liberação de Medicamentos , Fosfomicina/química , Fosfomicina/farmacologia , Hidrogéis , Reologia , Staphylococcus aureus/efeitos dos fármacos , Temperatura , Fatores de TempoAssuntos
Antibacterianos/farmacologia , Ácidos Borônicos/farmacologia , Fosfomicina/farmacologia , Compostos Heterocíclicos com 1 Anel/farmacologia , Klebsiella pneumoniae/efeitos dos fármacos , Meropeném/farmacologia , Antibacterianos/administração & dosagem , Compostos Azabicíclicos/farmacologia , Ácidos Borônicos/administração & dosagem , Ceftazidima/farmacologia , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla/genética , Fosfomicina/administração & dosagem , Genes Bacterianos , Genótipo , Compostos Heterocíclicos com 1 Anel/administração & dosagem , Meropeném/administração & dosagemRESUMO
Fosfomycin (FOS) administered intravenously has been recently rediscovered for the treatment of systemic infections due to multidrug-resistant bacteria. Its pharmacokinetic properties suggest a time-dependent dosing schedule with more clinical benefits from prolonged (PI) or continuous infusion (CI) than from intermittent infusion. We revised literature concerning PI and CI FOS to identify the best dosing regimen based on current evidence. We performed a MEDLINE/PubMed search. Ninety-one studies and their pertinent references were screened. Seventeen studies were included in the present review. The activity of FOS against Gram-negative and Gram-positive bacteria was evaluated in fourteen and five studies, respectively. Six studies evaluated FOS activity in combination with another antibiotic. Daily dosing of 12, 16, 18 or 24 g, administered with different schedules, were investigated. These regimens resulted active against the tested isolates in most cases. Emergence of resistant isolates has been shown to be preventable through the coadministration of another active antibiotic. FOS is a promising option to treat systemic infections caused by multidrug-resistant bacteria. Coadministration with another active molecule is required to prevent the emergence of resistant bacterial strains. The results of our review suggest that a therapeutic regimen including a loading dose of FOS 8 g followed by a daily dose of 16 g or 24 g CI could be the best therapeutic approach for patients with normal renal function. The dosing regimens in patients with renal insufficiency and CI or PI superiority compared with intermittent infusion in clinical settings should be further investigated.
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Antibacterianos/administração & dosagem , Infecções Bacterianas/tratamento farmacológico , Fosfomicina/administração & dosagem , Antibacterianos/farmacocinética , Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Infecções Bacterianas/microbiologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Farmacorresistência Bacteriana Múltipla , Fosfomicina/farmacocinética , Humanos , Infusões Intravenosas , Fatores de TempoRESUMO
Mounting antimicrobial resistance to carbapenemase-producing Klebsiella pneumoniae (CPKP) highlights the need to optimize currently available treatment options. The objective of this study was to explore alternative dosing strategies that limit the emergence of resistance to preserve the utility of last-line antibiotics by: (i) evaluating the pharmacodynamic (PD) killing activity of simulated humanized exposures to monotherapy and two-drug and three-drug combinations against CPKP bacterial isolates with different resistance mechanisms; and (ii) optimizing polymyxin B (PMB) exposure simulated in the three-drug combination regimens to maximize the killing activity. Two CPKP clinical isolates (BAA2146 (NDM-1) and BRKP76 (KPC-2)) were evaluated over 168 hours using a hollow-fiber infection model simulating clinically relevant PMB, fosfomycin, and meropenem dosing regimens. PMB-based three-drug combinations were further optimized by varying the initial exposure (0-24 hours) or maintenance dose received over the duration of treatment. The area under the bacterial load-versus-time curve (AUCFU) was used to determine PD activity. Overall reductions in PMB exposure ranged from 2 to 84%. BAA2146 and BRKP76 had median (range) AUCFUs of 11.0 (10.6-11.6) log10 CFU hour/mL and 7.08 (7.04-11.9) log10 CFU hour/mL, respectively. The PMB "front loaded" 2.5 mg/kg/day + 0.5 mg/kg maintenance dose in combination with meropenem and fosfomycin was a promising regimen against BRKP76, with an overall reduction in PMB exposure of 56% while still eradicating the bacteria. Tailored triple-combination therapy allows for the optimization of dose and treatment duration of last-line agents like PMB to achieve adequate drug exposure and appropriate PD activity while minimizing the emergence of resistance.
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Antibacterianos/farmacologia , Proteínas de Bactérias/biossíntese , Fosfomicina/farmacologia , Klebsiella pneumoniae/efeitos dos fármacos , Meropeném/farmacologia , Polimixina B/farmacologia , beta-Lactamases/biossíntese , Antibacterianos/administração & dosagem , Técnicas Bacteriológicas , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla , Sinergismo Farmacológico , Fosfomicina/administração & dosagem , Humanos , Meropeném/administração & dosagem , Polimixina B/administração & dosagemRESUMO
Background and Objective: Combination therapy may be a treatment option against carbapenem-resistant Acinetobacter baumannii (CR-AB) infections. In this study, we explored the utility of fosfomycin in combination with meropenem (FOS/MEM) against CR-AB isolates. Materials and Methods: Screening of synergistic activity of FOS/MEM was performed using the checkerboard assay. A pharmacokinetic/pharmacodynamic analysis was performed for various FOS/MEM regimens using Monte Carlo simulations. Results: The minimum inhibitory concentration (MIC) required to inhibit the growth of 50% of the isolates (MIC50) and MIC required to inhibit the growth of 90% of the isolates (MIC90) of FOS and MEM were reduced fourfold and twofold, respectively. The combination was synergistic against 14/50 isolates. No antagonism was observed. Sixteen out of fifty isolates had MEM MICs of ≤8 mg/L when subjected to combination therapy, compared to none with monotherapy. Forty-one out of 50 isolates had FOS MICs of ≤128 mg/L when subjected to combination therapy, compared to 17/50 isolates with monotherapy. The cumulative fraction response for MEM and FOS improved from 0% to 40% and 40% to 80%, with combination therapy, respectively. Conclusions: Addition of MEM improved the in vitro activity of FOS against the CR-AB isolates. FOS/MEM could be a plausible option to treat CR-AB for a small fraction of isolates.