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Rev Esp Quimioter 2019; 32(3):208-216

From a pathogen’s genome to an effective vaccine: the four-component meningococcal serogroup B vaccine

RAQUEL ABAD, FEDERICO MARTINÓN-TORRES, MARIA ELENA SANTOLAYA, ANGELIKA BANZHOFF, CARMEN GONZÁLEZ-INCHAUSTI, MARIA GABRIELA GRAÑA, JULIO A. VÁZQUEZ

Invasive meningococcal disease (IMD), caused by the bacterium Neisseria meningitidis, entails significant mortality and morbidity. Disease incidence is highest in infants <1 year and young children globally. In Europe, N. meningitidis serogroup B is responsible for over 50% of overall IMD cases, whereas the majority of IMD cases in Latin America is caused either by serogroup B or C. The development of an effective vaccine against serogroup B has challenged the researchers for over half a century. Serogroup B capsular polysaccharide was an inappropriate vaccine antigen, and the success of outer membrane vesicle (OMV) vaccines was restricted to homologous bacterial strains. Reverse vaccinology led to the development of a 4-component meningococcal vaccine including three novel antigens, and OMVs (4CMenB). Each vaccine component has a different target. 4CMenB has been authorised based on its immunogenicity and safety data because the low disease incidence precluded formal clinical efficacy studies. Human serum bactericidal antibody (hSBA) assay tests functional antibodies in the serum of vaccinated individuals (i.e. the vaccine immunogenicity), and is the accepted correlate of protection. Vaccine strain coverage has been assessed both through hSBA assays and a more conservative method named Meningococcal Antigen Typing System (MATS). Effectiveness data of 4CMenB have been collected in the field since 2013. The vaccine proved effective in outbreak control in North America, and recent data from the introduction of the vaccine in the United Kingdom infant national immunisation programme reveal a vaccine effectiveness of 82.9% for the first two doses, with an acceptable safety profile.

Rev Esp Quimioter 2019; 32(3):208-216 [Texto completo PDF]

[Vídeo presentación] 

 

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Rev Esp Quimioter 2019; 32(Suppl.1):25-29


New evidence on the use of fosfomycin for bacteremia and infectious endocarditis

JAVIER VEGANZONES, ANA MONTERO, EMILIO MASEDA

There is growing concern regarding the increased resistance rates of numerous pathogens and the limited availability of new antibiotics against these pathogens. In this context, fosfomycin is of considerable interest due to its activity against a wide spectrum of these microorganisms. We will review the encouraging data on this issue regarding the use of fosfomycin in treating Gram-negative bacterial infections. We will also cover fosfomycin’s role against 2 of the main causal agents of bacteremia and endocarditis worldwide (nosocomial and community-acquired): enterococci, whose growing resistance to glycopeptides and aminoglycosides represents a serious threat, and methicillin-resistant Staphylococcus aureus, whose infection, despite efforts, continues to be associated with high morbidity and mortality and a high risk of complications. Thanks also to its considerable synergistic capacity with various antibiotics, fosfomycin is a tool for extending the therapeutic arsenal against these types of infections.

Rev Esp Quimioter 2019; 32(Suppl.1):25-29 [Texto completo PDF ESPAÑOL] [Full-text PDF ENGLISH]

 

 

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Rev Esp Quimioter 2019; 32(Suppl.1):62-66

Fosfomycin in antimicrobial stewardship programs

ELENA MÚÑEZ RUBIO, ANTONIO RAMOS MARTÍNEZ, ANA FERNÁNDEZ CRUZ

Due to the increase in antimicrobial resistance, strategies such as antimicrobial stewardship programs (ASP) have been developed to improve the clinical results, decrease the adverse effects and the development of resistances and ensure cost-effective therapies. Fosfomycin has a unique mechanism of action against Gram-positive and Gram-negative bacteria. Cross-resistance is uncommon; however, fosfomycin should be used in combination in severe infections to avoid selecting resistant mutations. Fosfomycin’s oral formulation facilitates sequential treatment, has low toxicity and high tissue penetration, even in the central nervous system and bone. Fosfomycin is active against resistant Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin- resistant enterococci and penicillin-resistant Streptococcus pneumoniae, as well as against resistant Gram-negative bacteria such as extended-spectrum beta-lactamase-producing and carbapenemase-producing enterobacteria. Fosfomycin is therefore useful for cases of persistent bacteremia, skin and soft tissue infections, as a glycopeptide-sparing and carbapenem-sparing drug for healthcare-associated infections and for polymicrobial infections. Published studies have demonstrated the synergy between fosfomycin and beta-lactams, daptomycin and glycopeptides against MSSA and MRSA; with linezolid in biofilm-associated infections and with aminoglycosides and colistin against Gram-negative bacteria, providing a nephroprotective effect.

Rev Esp Quimioter 2019; 32(Suppl.1):62-66 [Texto completo PDF ESPAÑOL] [Full-text PDF ENGLISH]

 

 

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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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