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Rev Esp Quimioter 2019; 32(Suppl.1):55-61


Fosfomycin in the pediatric setting: Evidence and potential indications

FERNANDO BAQUERO-ARTIGAO, TERESA DEL ROSAL RABES

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.

Rev Esp Quimioter 2019; 32(Suppl.1):55-61 [Texto completo PDF ESPAÑOL] [Full-text PDF ENGLISH]

 

 

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Rev Esp Quimioter 2019; 32(Suppl.1):45-54


Fosfomycin in infections caused by multidrug-resistant Gram-negative pathogens

JESÚS RUIZ RAMOS, MIGUEL SALAVERT LLETÍ

The alarming increase in antibiotic resistance rates reported for various pathogens has resulted in the use of alternative treatment policies. Given the fairly limited availability of new antimicrobial drugs, the reassessment of older antibiotics is now an interesting option. Fosfomycin, a bactericidal analog of phosphoenolpyruvate that has been previously been employed as an oral treatment for uncomplicated urinary tract infection, has recently raised interest among physicians worldwide. In general, the advanced resistance described in Gram-negative bacteria suggests that fosfomycin can be an appropriate treatment option for patients with highly resistant microbial infections. This review, which refers to key available data, focuses on the possibility of extending the use of fosfomycin beyond urinary tract infections and against multidrug-resistant Gram-negative bacteria.

Rev Esp Quimioter 2019; 32(Suppl.1):45-54 [Texto completo PDF ESPAÑOL] [Full-text PDF ENGLISH]

 

 

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Rev Esp Quimioter 2019; 32(Suppl.1):37-44

Oral and intravenous fosfomycin in complicated urinary tract infections

INMACULADA LÓPEZ-MONTESINOS, JUAN P. HORCAJADA

Urinary tract infections are one of the most common health problems and entail a high consumption of health system resources. Due to the increase in global antibiotic resistances in recent years, it is increasingly common to find uropathogens with multiple resistance mechanisms, including quinolone-resistant bacteria, broad-spectrum β-lactamase producers and carbapenemase producers. In this scenario, the role of fosfomycin has gained considerable importance, given its spectrum of activity against multidrug resistant microorganisms (Gram-positive and Gram-negative), becoming an attractive alternative therapy. Regarding the use of fosfomycin in complicated urinary tract infections, there is increasing clinical experience with patients with infections caused by multidrug resistant bacteria, those with recurrent urinary tract infection and special populations such as those with kidney transplants. Randomized comparative studies and series are underway, which will provide greater evidence. Nevertheless, more studies are needed to confirm the enormous potential of fosfomycin in complicated urinary tract infection in the era of multiresistance.

Rev Esp Quimioter 2019; 32(Suppl.1):37-44 [Texto completo PDF ESPAÑOL] [Full-text PDF ENGLISH]

 

 

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Rev Esp Quimioter 2019; 32(Suppl.1):30-36

The role of fosfomycin in osteoarticular infection

LAURA MORATA, ALEX SORIANO

Osteoarticular infections include septic arthritis and osteomyelitis, with Gram-positive microorganisms isolated most frequently. In recent years, there has been an increase in the number of resistant strains in this type of infection, which complicates the treatment. Fosfomycin is active against a large percentage of Gram-positive and Gram-negative pathogens, including multidrug-resistant strains, and its properties include low protein binding, low molecular weight and good bone dissemination. In this article, we discuss fosfomycin’s activity in vitro, its pharmacokinetic and pharmacodynamic parameters of interest in osteoarticular infections, the experimental models of osteomyelitis and foreign body infection and the clinical experience with these types of infections.

Rev Esp Quimioter 2019; 32(Suppl.1):30-36 [Texto completo PDF ESPAÑOL] [Full-text PDF ENGLISH]

 

 

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Rev Esp Quimioter 2019; 32(Suppl.1):19-24


Deciphering pharmacokinetics and pharmacodynamics of fosfomycin

ALICIA RODRÍGUEZ-GASCÓN, ANDRÉS CANUT-BLASCO

Fosfomycin, a low molecular weight and hydrophilic drug with negligible protein binding, is eliminated almost exclusively by glomerular filtration, whose clearance is subject to patient renal function. The volume of distribution approximates to the extracellular body water (about 0.3 L/Kg) in healthy volunteers, but it is increased in critically ill patients with bacterial infections. Fosfomycin presents a high ability to distribute into many tissues, including inflamed tissues and abscess fluids. Based on PK/PD analysis and Monte Carlo simulations, we have evaluated different fosfomycin dosing regimen to optimize the treatment of septic patients due to Enterobacterales and Pseudomonas aeruginosa. As PK/PD targets, we selected %T>MIC > 70% for all pathogens, and AUC24/MIC > 24 and AUC24/MIC > 15 for net stasis of Enterobacterales and P. aeruginosa, respectively. Pharmacokinetic parameters in critically ill patients were obtained from the literature. Several dosing regimens were studied in patients with normal renal function: fosfomycin 2-8 g given every 6-12 hours, infused over 30 minutes- 24 hours. At the susceptibility EUCAST breakpoint for Enterobacterales and Staphylococcus spp. (MIC ≤ 32 mg/L), fosfomycin 4 g/8h or higher infused over 30 minutes achieved a probability of target attainment (PTA) > 90%, based in both %T>MIC and AUC24/MIC. For MIC of 64 mg/L, fosfomycin 6 g/6h in 30-minute infusion and 8 g/ 8h in 30-minute and 6 hours infusions also achieved PTA values higher than 90%. No fosfomycin monotherapy regimen was able to achieve PK/PD targets related to antimicrobial efficacy for P. aeruginosa with MICs of 256-512 mg/L.

Rev Esp Quimioter 2019; 32(Suppl.1):19-24 [Texto completo PDF ESPAÑOL] [Full-text PDF ENGLISH]

 

 

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Rev Esp Quimioter 2019; 32(Suppl.1):08-18


New microbiological aspects of fosfomycin

MARÍA DÍEZ-AGUILAR, RAFAEL CANTÓN

The discovery of fosfomycin more than 40 years ago was an important milestone in antibiotic therapy. The antibiotic’s usefulness, alone or in combination, for treating infections caused by multidrug-resistant microorganisms is clearer than ever. Both the European Medicines Agency and the US Food and Drug Administration have open processes for reviewing the accumulated information on the use of fosfomycin and the information from new clinical trials on this compound. The agencies’ objectives are to establish common usage criteria for Europe and authorize the sale of fosfomycin in the US, respectively. Fosfomycin’s single mechanism of action results in no cross-resistance with other antibiotics. However, various fosfomycin-resistance mechanisms have been described, the most important of which, from the epidemiological standpoint, is enzymatic inactivation, which is essentially associated with a gene carrying a fosA3-harboring plasmid. Fosfomycin has been found more frequently in Asia in extended-spectrum beta-lactamase-producing and carbapenemase-producing Enterobacterales. Although fosfomycin presents lower intrinsic activity against Pseudomonas aeruginosa compared with that presented against Escherichia coli, fosfomycin’s activity has been demonstrated in biofilms, especially in combination with aminoglycosides. The current positioning of fosfomycin in the therapeutic arsenal for the treatment of infections caused by multidrug-resistant microorganisms requires new efforts to deepen our understanding of this compound, including those related to the laboratory methods employed in the antimicrobial susceptibility testing study.

Rev Esp Quimioter 2019; 32(Suppl.1):08-18 [Texto completo PDF ESPAÑOL] [Full-text PDF ENGLISH]

 

 

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Rev Esp Quimioter 2019; 32(Suppl.1):01-07


New perspectives for reassessing fosfomycin: applicability in current clinical practice

FRANCISCO JAVIER CANDEL, MAYRA MATESANZ DAVID, JOSÉ BARBERÁN LÓPEZ

Fosfomycin is a bactericidal antibiotic that interferes with cell wall synthesis. The drug therefore has a broad spectrum of activity against a wide range of Gram-positive and Gram-negative bacteria. Both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have started review processes of the accumulated information on the use of fosfomycin and on information from new clinical trials. The intent is to establish usage terms in Europe and to authorize the sale of fosfomycin in the US. This monograph reviews the most current aspects of the compound. From the microbiological point of view, fosfomycin’s single mechanism of action can provide a synergistic effect to other classes of antibiotics, including β-lactams, aminoglycosides, lipopeptides and fluoroquinolones. The resistance mechanisms include the reduced intracellular transport of the antibiotic, the change in target and the direct inactivation of the antibiotic by metalloenzymes and kinases; however, the clinical impact of some of these mechanisms has not yet been elucidated. The lack of agreement in determining the sensitivity cutoffs between the Clinical and Laboratory Standards Institute (CLSI) (≤64 mg/L) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (≤32 mg/L), the fact that a number of microorganisms require a higher MIC (Klebsiella spp., Enterobacter spp., Serratia spp., Pseudomonas aeruginosa) and the drug’s different effective concentrations against Gram-positive and Gram-negative bacteria have resulted in recommended dosages for treating multiresistant microorganism infections that vary between 8 and 12 g/day for Gram-positive bacteria and 16 and 24 g/day for Gram-negative bacteria. Fosfomycin has 3 presentations (intravenous with disodium salt, oral with calcium salt and combined with tromethamine),has good distribution in tissues and abscesses and is well tolerated. The pharmacodynamic ratio of dosage production for fosfomycin is AUC/MIC. However, the pharmacokinetics/pharmacodynamic ratio could be optimized in daily practice based on the pathogen, the patient’s clinical profile or the infection model. Fosfomycin is the treatment of choice for cystitis in immunocompetent patients, patients with transplants, pregnant women and in pediatric settings. The drug is especially useful due to its microbiological activity and oral posology in cystitis caused by ESBL bacteria. Administer intravenously at high doses and combined with other antimicrobial agents. Fosfomycin has been useful in treating infections by multiresistant Gram-negative bacteria, such as Enterobacteriaceae, carbapenemase carriers and P. aeruginosa, extensively resistant or panresistant in urinary infections and in skin and soft tissue. Fosfomycin has also been shown active in combination with daptomycin or imipenem in osteoarticular infections by methicillin-resistant Staphylococcus aureus. Fosfomycin is an old antibiotic that still has much to reveal.

Rev Esp Quimioter 2019; 32(Suppl.1)01-07 [Texto completo PDF ESPAÑOL ] [Full-text PDF ENGLISH]

 

 

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Rev Esp Quimioter 2019; 32(3):246-253


Meningitis/Encephalitis diagnosis in ICU using Multiplex PCR system: Is it time of change?

LUCÍA LÓPEZ-AMOR, DOLORES ESCUDERO, JAVIER FERNÁNDEZ, LORENA MARTÍN-IGLESIAS, LUCÍA VIÑA, JONATHAN FERNÁNDEZ-SUÁREZ, ÁLVARO LEAL-NEGREDO, BLANCA LEOZ, LAURA ÁLVAREZ-GARCÍA, CRISTIAN CASTELLÓ-ABIETAR, JOSÉ ANTONIO BOGA, FERNANDO VÁZQUEZ

Objetive. To evaluate the clinical impact of Meningitis/Encephalitis FilmArray® panel for the diagnosis of cerebral nervous system infection and to compare the results (including time for diagnosis) with those obtained by conventional microbiological techniques.
Patients and methods. A prospective observational study in an Intensive Care Unit of adults from a tertiary hospital was carried out. Cerebrospinal fluid from all patients was taken by lumbar puncture and assessed by the meningitis/encephalitis FilmArray® panel ME, cytochemical study, Gram, and conventional microbiological cultures.
Results. A total of 21 patients admitted with suspicion of Meningitis/Encephalitis. Median age of patients was 58.4 years (RIQ 38.1-67.3), median APACHE II 18 (RIQ 12-24). Median stay in ICU and median hospital stay was 4 (RIQ 2-6) and 17 days (RIQ 14-28), respectively. The overall mortality was 14.3%. A final clinical diagnosis of meningitis or encephalitis was established in 16 patients, obtaining the etiological diagnosis in 12 of them (75%). The most frequent etiology was Streptococcus pneumoniae (8 cases). FilmArray® allowed etiological diagnosis in 3 cases in which the culture had been negative, and the results led to changes in the empirical antimicrobial therapy in 7 of 16 cases (43.8%). FilmArray® yielded a global sensitivity and specificity of 100% and 90%, respectively. The median time to obtain results from the latter and conventional culture (including antibiogram) was 2.9 hours (RIQ 2.1-3.8) and 45.1 hours (RIQ 38.9-58.7), respectively.
Conclusions. The Meningitis/Encephalitis FilmArray® panel was able to establish the etiologic diagnosis faster than conventional methods. Also, it achieved a better sensitivity and led to prompt targeted antimicrobial therapy.

Rev Esp Quimioter 2019; 32(3):246-253 [Texto completo PDF]

 

 

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Rev Esp Quimioter 2019; 32(3):238-245


Initial clinical outcomes and prognostic variables in the implementation of a Code Sepsis in a high complexity University Hospital

FERNANDO RAMASCO, ANGELS FIGUEROLA, ROSA MENDEZ, DIEGO RODRÍGUEZ SERRANO, ANDRÉS VON WERNITZ, ANA HERNÁNDEZ-ACEITUNO, CARMEN SÁEZ, LAURA CARDEÑOSO, ELENA MARTIN, NIEVES GARCÍA-VÁZQUEZ, CARMEN DE LAS CUEVAS, NATALIA PASCUAL, AZUCENA BAUTISTA, DAVID JIMÉNEZ, GUILLERMO FERNÁNDEZ, ANA LEAL, MERCEDES VINUESA, ALBERTO PIZARRO, MARCELLO DI MARTINO, LOURDES DEL CAMPO, IÑIGO GARCÍA SANZ, MARTA CHICOT, ANA BARRIOS, MARÍA JOSÉ RUBIO, THE MEMBERS OF DE CODE SEPSIS H.U DE LA PRINCESA

Objectives. To assess the impact of the first months of application of a Code Sepsis in a high complexity hospital, analyzing patient´s epidemiological and clinical characteristics and prognostic factors.
Materials and methods. A long-term observational study was carried out throughout a consecutive period of seven months (February 2015 – September 2015). The relationship with mortality of risk factors, and analytic values was analyzed using uni- and multivariate analyses.
Results. A total of 237 patients were included. The in-hospital mortality was 24% at 30 days and 27% at 60 days. The mortality of patients admitted to Critical Care Units was 30%. Significant differences were found between the patients who died and those who survived in mean levels of creatinine (2.30 vs 1.46 mg/dL, p <0.05), lactic acid (6.10 vs 2.62 mmol/L, p <0.05) and procalcitonin (23.27 vs 12.73 mg/dL, p<0.05). A statistically significant linear trend was found between SOFA scale rating and mortality (p<0.05). In the multivariate analysis additional independent risk factors associated with death were identified: age > 65 years (OR 5.33, p <0.05), lactic acid > 3 mmol/L (OR 5,85, p <0,05), creatinine > 1,2 mgr /dL (OR 4,54, p <0,05) and shock (OR 6,57, P <0,05).
Conclusions. The epidemiological, clinical and mortality characteristics of the patients in our series are similar to the best published in the literature. The study has identified several markers that could be useful at a local level to estimate risk of death in septic patients. Studies like this one are necessary to make improvements in the Code Sepsis programs.

Rev Esp Quimioter 2019; 32(3):238-245 [Full-text PDF]

 

 

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Rev Esp Quimioter 2019; 32(3):254-262


Description of carbapenemase-producing Enterobacteriaceae isolates in a Spanish tertiary hospital. Epidemiological analysis and clinical impact

LAURA LÓPEZ-GONZÁLEZ, JOSÉ MANUEL VIÑUELA-PRIETO, ICÍAR RODRIGUEZ-AVIAL, ROCÍO MANZANO, FRANCISCO JAVIER CANDEL

Objectives. The aim of the study was to carry out an epidemiological analysis of patients with carbapenemase-producing Enterobacteriaceae (CPE) isolations in our hospital as well as to perform a description of the genotypic temporal evolution of CPE isolated.
Material and methods. An observational prospective cohort study was performed involving all patients with CPE isolates from clinical samples during November 2014 to November 2016 in a Spanish teaching hospital. Patients were clinically evaluated and classified either as infected or colonized. Information on the consumption of carbapenems in the hospital during the study period was also analyzed. PCR was used for identification of the carbapenemase genes blaKPC, blaVIM, and blaOXA-48.
Results. A total of 301 CPE isolates were obtained (107 in 2014, 89 in 2015 and 105 in 2016). Klebsiella pneumoniae (73.4%) was the most prevalent microorganism. Hundred and seventy (56.7%) of carbapenemases detected were blaOXA-48, 73 (24.3%) were blaKPC and 57 (19%) were blaVIM. In year 2014 KPC was predominant while in 2016 OXA-48 predominated. In 2014 we observed a significant association between the medical wards and the ICU with a higher prevalence of OXA-48 (OR 4.15; P<0.001) and VIM (OR 7.40; P<0.001) in the univariate analysis, in the following years there was no association. Regarding the clinical significance of microbiological results after assessing our patients, 60% of isolates represented infection and 40% behaved as colonizers. One third of hospitalized patients with CPE isolation died within 30 days, regardless of whether they were colonized or infected.
Conclusions. We have observed an epidemiological change in the genotypes of our isolates along the study period. A thorough knowledge of the CPE’s epidemiological distribution in each hospital is fundamental for optimizing antimicrobial chemotherapy.

Rev Esp Quimioter 2019; 32(3):254-262 [Full-text PDF]

 

 

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