Fosfomycin/Tobramycin for Inhalation in Patients with Cystic Fibrosis with <i>Pseudomonas</i> Airway Infection

Trapnell, Bruce C.; McColley, Susanna A.; Kissner, Dana G.; Rolfe, Mark W.; Rosen, Jonathan; McKevitt, Matthew; Moorehead, Lisa; Montgomery, A. Bruce; Geller, David E.

doi:10.1164/rccm.201105-0924oc

Cited by 111 publications

(65 citation statements)

References 23 publications

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“…Fosfomycin tobramycin (FTI) for inhalation has activity against anaerobic, gram-negative, and grampositive bacteria, including MRSA. In a clinical trial of FTI in patients with CF with P. aeruginosa infection, 29 patients with MRSA at baseline had significant decreases in the concentration of MRSA after 28 days of FTI (n = 19) compared with placebo (n = 10) (44). Current published experience with aerosolized vancomycin suggests that it is safe and well tolerated (45,46).…”

Section: Methicillin-resistant Staphylococcus Aureusmentioning

confidence: 99%

Antibiotic Management of Lung Infections in Cystic Fibrosis. I. The Microbiome, Methicillin-Resistant Staphylococcus aureus, Gram-Negative Bacteria, and Multiple Infections

et al. 2014

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Despite significant advances in treatment strategies targeting the underlying defect in cystic fibrosis (CF), airway infection remains an important cause of lung disease. In this two-part series, we review recent evidence related to the complexity of CF airway infection, explore data suggesting the relevance of individual microbial species, and discuss current and future treatment options. In Part I, the evidence with respect to the spectrum of bacteria present in the CF airway, known as the lung microbiome is discussed. Subsequently, the current approach to treat methicillin-resistant Staphylococcus aureus, gram-negative bacteria, as well as multiple coinfections is reviewed. Newer molecular techniques have demonstrated that the airway microbiome consists of a large number of microbes, and the balance between microbes, rather than the mere presence of a single species, may be relevant for disease pathophysiology. A better understanding of this complex environment could help define optimal treatment regimens that target pathogens without affecting others. Although relevance of these organisms is unclear, the pathologic consequences of methicillin-resistant S. aureus infection in patients with CF have been recently determined. New strategies for eradication and treatment of both acute and chronic infections are discussed. Pseudomonas aeruginosa plays a prominent role in CF lung disease, but many other nonfermenting gram-negative bacteria are also found in the CF airway. Many new inhaled antibiotics specifically targeting P. aeruginosa have become available with the hope that they will improve the quality of life for patients. Part I concludes with a discussion of how best to treat patients with multiple coinfections.

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Section: Methicillin-resistant Staphylococcus Aureusmentioning

confidence: 99%

Antibiotic Management of Lung Infections in Cystic Fibrosis. I. The Microbiome, Methicillin-Resistant Staphylococcus aureus, Gram-Negative Bacteria, and Multiple Infections

et al. 2014

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“…Current maintenance therapy of inhaled antibiotics is directed toward P. aeruginosa, but broader spectrum antibiotics could potentially be more beneficial by targeting other bacteria as well. One study assessed the effect of a combination of fosfomycin, an antipseudomonal antibiotic, with in vitro activity against staphylococci including MRSA as well as anaerobic bacteria, and tobramycin (fosfomycin/tobramycin for inhalation; FTI) in adult patients with CF (9). Lung function improved in both treatment groups during the run-in phase, in which all patients received inhaled aztreonam.…”

Section: Cystic Fibrosis Microbiologymentioning

confidence: 99%

Update in Cystic Fibrosis 2012

Goss

Ratjen

2013

Am J Respir Crit Care Med

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“…34 Later on, fosfomycin has been produced in a hydrosoluble form, fosfomycin-trometamol (also known as tromethamine or TRIS), and administrated orally for the treatment of uncomplicated urinary tract and gastrointestinal infections. 6,32 Due to its long mean half-life (5.7 -2.8 hr), low toxicity, and low side effects, this drug is used alone 25 or in combination with tobramycin 37 to treat chronic pulmonary infections caused by multidrug-resistant P. aeruginosa strains in cystic fibrosis patients. Fosfomycin has been efficiently used in combination with various antimicrobial agents and in some cases, synergetic effects have been reported.…”

Section: Introductionmentioning

confidence: 99%

Blocking Peptidoglycan Recycling in Pseudomonas aeruginosa Attenuates Intrinsic Resistance to Fosfomycin

Borisova

Gisin

Mayer

2014

Microbial Drug Resistance

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Gram-negative bacteria recycle as much as half of their cell wall per generation. Here we show that interference with cell wall recycling in Pseudomonas aeruginosa strains results in four-to eight-fold increased susceptibility to the antibiotic fosfomycin, pushing the minimal inhibitory concentration for strains PA14 and PA01 to therapeutically appropriate values of 2-4 and 8-16 mg/L, respectively. A newly discovered metabolic pathway that connects cell wall recycling with peptidoglycan de novo biosynthesis is responsible for the high intrinsic resistance of P. aeruginosa to fosfomycin. The pathway comprises an anomeric cell wall amino sugar kinase (AmgK) and an uridylyl transferase (MurU), which together convert N-acetylmuramic acid (MurNAc) through MurNAc a-1-phosphate to uridine diphosphate (UDP)-MurNAc, thereby bypassing the fosfomycinsensitive de novo synthesis of UDP-MurNAc. Thus, inhibition of peptidoglycan recycling can be applied as a new strategy for the combinatory therapy against multidrug-resistant P. aeruginosa strains.

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Fosfomycin/Tobramycin for Inhalation in Patients with Cystic Fibrosis with Pseudomonas Airway Infection

Abstract: FTI maintained the substantial improvements in FEV(1) % predicted achieved during the AZLI run-in and was well tolerated. FTI is a promising antipseudomonal therapy for patients with CF.

Cited by 111 publications

References 23 publications

Antibiotic Management of Lung Infections in Cystic Fibrosis. I. The Microbiome, Methicillin-Resistant Staphylococcus aureus, Gram-Negative Bacteria, and Multiple Infections

Antibiotic Management of Lung Infections in Cystic Fibrosis. I. The Microbiome, Methicillin-Resistant Staphylococcus aureus, Gram-Negative Bacteria, and Multiple Infections

Update in Cystic Fibrosis 2012

Blocking Peptidoglycan Recycling in Pseudomonas aeruginosa Attenuates Intrinsic Resistance to Fosfomycin

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