The future of antimicrobial therapy in the era of antibiotic resistance in cystic fibrosis pulmonary infection

McCaughey, Gerard; Gilpin, D.F.; Elborn, J. Stuart; Tunney, Michael

doi:10.1586/17476348.2013.814411

Cited by 13 publications

(11 citation statements)

References 110 publications

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“…However, increased acquisition of antibiotic resistance mechanisms is presenting a significant challenge for future treatment options [62]. Many are turning towards cationic antimicrobial peptides as a promising alternative for developing antimicrobials, as they are thought to be relatively insusceptible to the development of resistance mechanisms by mutations [63].…”

Section: Resultsmentioning

confidence: 99%

Cationic Antimicrobial Peptides Promote Microbial Mutagenesis and Pathoadaptation in Chronic Infections

et al. 2014

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Acquisition of adaptive mutations is essential for microbial persistence during chronic infections. This is particularly evident during chronic Pseudomonas aeruginosa lung infections in cystic fibrosis (CF) patients. Thus far, mutagenesis has been attributed to the generation of reactive species by polymorphonucleocytes (PMN) and antibiotic treatment. However, our current studies of mutagenesis leading to P. aeruginosa mucoid conversion have revealed a potential new mutagen. Our findings confirmed the current view that reactive oxygen species can promote mucoidy in vitro, but revealed PMNs are proficient at inducing mucoid conversion in the absence of an oxidative burst. This led to the discovery that cationic antimicrobial peptides can be mutagenic and promote mucoidy. Of specific interest was the human cathelicidin LL-37, canonically known to disrupt bacterial membranes leading to cell death. An alternative role was revealed at sub-inhibitory concentrations, where LL-37 was found to induce mutations within the mucA gene encoding a negative regulator of mucoidy and to promote rifampin resistance in both P. aeruginosa and Escherichia coli. The mechanism of mutagenesis was found to be dependent upon sub-inhibitory concentrations of LL-37 entering the bacterial cytosol and binding to DNA. LL-37/DNA interactions then promote translesion DNA synthesis by the polymerase DinB, whose error-prone replication potentiates the mutations. A model of LL-37 bound to DNA was generated, which reveals amino termini α-helices of dimerized LL-37 bind the major groove of DNA, with numerous DNA contacts made by LL-37 basic residues. This demonstrates a mutagenic role for antimicrobials previously thought to be insusceptible to resistance by mutation, highlighting a need to further investigate their role in evolution and pathoadaptation in chronic infections.

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Section: Resultsmentioning

confidence: 99%

Cationic Antimicrobial Peptides Promote Microbial Mutagenesis and Pathoadaptation in Chronic Infections

et al. 2014

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“…Cystic fibrosis (CF) patients may be at greater risk for developing multidrug-resistant infections than any other patient population (19). Organisms such as Pseudomonas aeruginosa, Burkholderia cepacia, and Stenotrophomonas maltophilia are common pathogens in these patients and are often extremely resistant, leaving few or no therapeutic options.…”

Section: Cystic Fibrosis and Synergy Testingmentioning

confidence: 99%

When Does 2 Plus 2 Equal 5? A Review of Antimicrobial Synergy Testing

2014

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In this age of emerging antibiotic resistance, limited therapeutic options exist for treating multidrug-resistant organisms. Combination therapy is commonly employed to manage these infections despite little laboratory guidance as to the efficacy of this approach. Synergy testing methods have been used to assess the interaction of antibiotic combinations in vitro. This review will discuss the four primary methods used to assess synergy, as well as the data that exist for testing of cystic fibrosis. In the final analysis, this review concludes that there is not enough evidence to endorse synergy testing for routine clinical use.

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“…Extended culture methods identify a much wider range of bacteria, which include more difficult to culture bacteria, such as anaerobic bacteria (4,15,23). At present, there is no readily available methodology to identify all of these organisms in a way that makes this information valuable for clinical treatment (77). Studies are under way to develop technologies to allow molecular identification without prior culture (78).…”

Section: Treating Multiple Infectionsmentioning

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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The future of antimicrobial therapy in the era of antibiotic resistance in cystic fibrosis pulmonary infection

Cited by 13 publications

References 110 publications

Cationic Antimicrobial Peptides Promote Microbial Mutagenesis and Pathoadaptation in Chronic Infections

Cationic Antimicrobial Peptides Promote Microbial Mutagenesis and Pathoadaptation in Chronic Infections

When Does 2 Plus 2 Equal 5? A Review of Antimicrobial Synergy Testing

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

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