RESUMEN
Transient blockade of glycine decarboxylase (GLDC) can restrict de novo pyrimidine synthesis, which is a well-described strategy for enhancing the host interferon response to viral infection and a target pathway for some licenced anti-inflammatory therapies. The aminothiol, cysteamine, is produced endogenously during the metabolism of coenzyme A, and is currently being investigated in a clinical trial as an intervention in community acquired pneumonia resulting from viral (influenza and SARS-CoV-2) and bacterial respiratory infection. Cysteamine is known to inhibit both bacterial and the eukaryotic host glycine cleavage systems via competitive inhibition of GLDC at concentrations, lower than those required for direct antimicrobial or antiviral activity. Here, we demonstrate for the first time that therapeutically achievable concentrations of cysteamine can inhibit glycine utilisation by epithelial cells and improve cell-mediated responses to infection with respiratory viruses, including human coronavirus 229E and Influenza A. Cysteamine reduces interleukin-6 (IL-6) and increases the interferon-λ (IFN-λ) response to viral challenge and in response to liposomal polyinosinic:polycytidylic acid (poly I:C) simulant of RNA viral infection.
Asunto(s)
COVID-19 , Gripe Humana , Virosis , Humanos , Cisteamina/farmacología , Gripe Humana/tratamiento farmacológico , SARS-CoV-2 , Virosis/tratamiento farmacológico , Inmunidad Innata , Células EpitelialesRESUMEN
Pseudomonas aeruginosa is a major opportunistic human pathogen which employs a myriad of virulence factors. In people with cystic fibrosis (CF) P. aeruginosa frequently colonises the lungs and becomes a chronic infection that evolves to become less virulent over time, but often adapts to favour persistence in the host with alginate-producing mucoid, slow-growing, and antibiotic resistant phenotypes emerging. Cysteamine is an endogenous aminothiol which has been shown to prevent biofilm formation, reduce phenazine production, and potentiate antibiotic activity against P. aeruginosa, and has been investigated in clinical trials as an adjunct therapy for pulmonary exacerbations of CF. Here we demonstrate (for the first time in a prokaryote) that cysteamine prevents glycine utilisation by P. aeruginosa in common with previously reported activity blocking the glycine cleavage system in human cells. Despite the clear inhibition of glycine metabolism, cysteamine also inhibits hydrogen cyanide (HCN) production by P. aeruginosa, suggesting a direct interference in the regulation of virulence factor synthesis. Cysteamine impaired chemotaxis, lowered pyocyanin, pyoverdine and exopolysaccharide production, and reduced the toxicity of P. aeruginosa secreted factors in a Galleria mellonella infection model. Thus, cysteamine has additional potent anti-virulence properties targeting P. aeruginosa, further supporting its therapeutic potential in CF and other infections.
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Infecciones por Pseudomonas , Pseudomonas aeruginosa , Biopelículas , Cisteamina , Glicina , Humanos , Infecciones por Pseudomonas/tratamiento farmacológico , VirulenciaRESUMEN
The impact of gender on assessments of leadership performance and leadership potential was examined through two clusters of leadership behaviors, one set related to traditional constructions of leadership labeled directing others and another associated with contemporary constructions of leadership labeled engaging others. Based on data collected from a sample of 91 senior leaders in one US financial services organization over a 3-year period prior to Covid-19, the results showed a negative relationship between directing others behaviors and leadership potential ratings for females and a positive relationship between these variables for males. A negative relationship between engaging others behaviors and performance assessments was also found for females. This study highlights the continuing bias in leadership assessments of women and explores the contradictions between the perception and the reality of women's leadership.
RESUMEN
The need for optimized as well as standardized test systems of novel antimicrobial peptides (AMPs) was discussed by experts in the field at the International Meeting on Antimicrobial Peptides (IMAP) 2017 and the 2019 Gordon Research Conference (GRC) on Antimicrobial Peptides, and a survey related to this topic was circulated to participants to collate opinions. The survey included questions ranging from the relevance of susceptibility testing for understanding the mode of action of AMPs, to the importance of optimization and a degree of standardization of test methods and their clinical relevance. Based on the survey results, suggestions for future improvements in the research field are made.
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Antiinfecciosos , Antiinfecciosos/farmacología , Humanos , Proteínas Citotóxicas Formadoras de PorosRESUMEN
Fungi cause disease in nearly one billion individuals worldwide. Only three classes of antifungal agents are currently available in mainstream clinical use. Emerging and drug-resistant fungi, toxicity, and drug-drug interactions compromise their efficacy and applicability. Consequently, new and improved antifungal therapies are urgently needed. In response to that need, we have developed NP339, a 2-kDa polyarginine peptide that is active against pathogenic fungi from the genera Candida, Aspergillus, and Cryptococcus, as well as others. NP339 was designed based on endogenous cationic human defense peptides, which are constituents of the cornerstone of immune defense against pathogenic microbes. NP339 specifically targets the fungal cell membrane through a charge-charge-initiated membrane interaction and therefore possesses a differentiated safety and toxicity profile to existing antifungal classes. NP339 is rapidly fungicidal and does not elicit resistance in target fungi upon extensive passaging in vitro. Preliminary analyses in murine models indicate scope for therapeutic application of NP339 against a range of systemic and mucocutaneous fungal infections. Collectively, these data indicate that NP339 can be developed into a highly differentiated, first-in-class antifungal candidate for poorly served invasive and other serious fungal diseases.
Asunto(s)
Antifúngicos , Micosis , Animales , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Candida , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Micosis/tratamiento farmacológico , Péptidos/farmacologíaRESUMEN
Antimicrobial therapies developed from immunology, specifically the primary function of the immune system in host defence against microbial pathogens, could offer some of the step-change strategies in drug design and development urgently required to generate much needed, truly novel interventions in infectious disease. The immune system is an as yet underexploited resource of novel molecules and the blueprints for new approaches to combating infection with non-antibiotic, directly antimicrobial strategies.
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Antiinfecciosos/uso terapéutico , Inmunoterapia , Infecciones/terapia , Farmacorresistencia Microbiana , Humanos , Inmunidad Innata , Infecciones/inmunología , InvencionesRESUMEN
BACKGROUND: Emerging data suggests a possible role for cysteamine as an adjunct treatment for pulmonary exacerbations of cystic fibrosis (CF) that continue to be a major clinical challenge. There are no studies investigating the use of cysteamine in pulmonary exacerbations of CF. This exploratory randomized clinical trial was conducted to answer the question: In future pivotal trials of cysteamine as an adjunct treatment in pulmonary exacerbations of CF, which candidate cysteamine dosing regimens should be tested and which are the most appropriate, clinically meaningful outcome measures to employ as endpoints? METHODS AND FINDINGS: Multicentre double-blind randomized clinical trial. Adults experiencing a pulmonary exacerbation of CF being treated with standard care that included aminoglycoside therapy were randomized equally to a concomitant 14-day course of placebo, or one of 5 dosing regimens of cysteamine. Outcomes were recorded on days 0, 7, 14 and 21 and included sputum bacterial load and the patient reported outcome measures (PROMs): Chronic Respiratory Infection Symptom Score (CRISS), the Cystic Fibrosis Questionnaire-Revised (CFQ-R); FEV1, blood leukocyte count, and inflammatory markers. Eighty nine participants in fifteen US and EU centres were randomized, 78 completed the 14-day treatment period. Cysteamine had no significant effect on sputum bacterial load, however technical difficulties limited interpretation. The most consistent findings were for cysteamine 450mg twice daily that had effects additional to that observed with placebo, with improved symptoms, CRISS additional 9.85 points (95% CI 0.02, 19.7) p = 0.05, reduced blood leukocyte count by 2.46x109 /l (95% CI 0.11, 4.80), p = 0.041 and reduced CRP by geometric mean 2.57 nmol/l (95% CI 0.15, 0.99), p = 0.049. CONCLUSION: In this exploratory study cysteamine appeared to be safe and well-tolerated. Future pivotal trials investigating the utility of cysteamine in pulmonary exacerbations of CF need to include the cysteamine 450mg doses and CRISS and blood leukocyte count as outcome measures. CLINICAL TRIAL REGISTRATION: NCT03000348; www.clinicaltrials.gov.
Asunto(s)
Cisteamina/administración & dosificación , Cisteamina/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Pulmón/efectos de los fármacos , Administración Oral , Adulto , Cisteamina/efectos adversos , Femenino , Humanos , Masculino , Cumplimiento de la Medicación , SeguridadRESUMEN
The purpose of this review is to describe antifungal therapeutic candidates in preclinical and clinical development derived from, or directly influenced by, the immune system, with a specific focus on antimicrobial peptides (AMP). Although the focus of this review is AMP with direct antimicrobial effects on fungi, we will also discuss compounds with direct antifungal activity, including monoclonal antibodies (mAb), as well as immunomodulatory molecules that can enhance the immune response to fungal infection, including immunomodulatory AMP, vaccines, checkpoint inhibitors, interferon and colony stimulating factors as well as immune cell therapies. The focus of this manuscript will be a non-exhaustive review of antifungal compounds in preclinical and clinical development that are based on the principles of immunology and the authors acknowledge the incredible amount of in vitro and in vivo work that has been conducted to develop such therapeutic candidates.
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Antifúngicos/uso terapéutico , Hongos/fisiología , Inmunoterapia/métodos , Micosis/terapia , Proteínas Citotóxicas Formadoras de Poros/uso terapéutico , Animales , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Humanos , Inmunidad InnataRESUMEN
During the development of antimicrobial peptides (AMP) as potential therapeutics, antimicrobial susceptibility testing (AST) stands as an essential part of the process in identification and optimisation of candidate AMP. Standard methods for AST, developed almost 60 years ago for testing conventional antibiotics, are not necessarily fit for purpose when it comes to determining the susceptibility of microorganisms to AMP. Without careful consideration of the parameters comprising AST there is a risk of failing to identify novel antimicrobials at a time when antimicrobial resistance (AMR) is leading the planet toward a post-antibiotic era. More physiologically/clinically relevant AST will allow better determination of the preclinical activity of drug candidates and allow the identification of lead compounds. An important consideration is the efficacy of AMP in biological matrices replicating sites of infection, e.g., blood/plasma/serum, lung bronchiolar lavage fluid/sputum, urine, biofilms, etc., as this will likely be more predictive of clinical efficacy. Additionally, specific AST for different target microorganisms may help to better predict efficacy of AMP in specific infections. In this manuscript, we describe what we believe are the key considerations for AST of AMP and hope that this information can better guide the preclinical development of AMP toward becoming a new generation of urgently needed antimicrobials.
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Antibacterianos , Antiinfecciosos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antiinfecciosos/farmacología , Biopelículas , Pruebas de Sensibilidad Microbiana , Proteínas Citotóxicas Formadoras de PorosRESUMEN
NP213 (Novexatin®) is a novel antifungal peptide specifically designed for the topical treatment of onychomycosis. NP213 was designed using host defense peptides (HDP), essential components of the innate immune response to infection, as a template. NP213 is a water-soluble cyclic fungicidal peptide that effectively penetrates human nail. NP213 demonstrated a promising preclinical and clinical safety profile, with no evidence of systemic exposure following topical application to the skin and nails. NP213 was efficacious in two phase IIa human trials with 43.3% of patients having no fungi detectable by culture of fragments from NP213-treated nails after 180 days in the first study and likewise 56.5% of patients were culture negative for dermatophytes after 360 days in the second phase IIa study. In both trials, NP213 was applied daily for only 28 days in marked contrast to other topical onychomycosis treatments that require application for up to 52 weeks. Patient reported outcomes from the phase IIa studies were positive with participants recording an improved appearance of their nails after only 14 days of application. All fungi identified in these studies were Trichophyton spp. NP213 (Novexatin®) is a promising, highly differentiated peptide-based candidate for the topical treatment of onychomycosis, addressing the infectious cause and cosmetic issues of this very common condition.
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Antifúngicos/uso terapéutico , Péptidos Catiónicos Antimicrobianos/uso terapéutico , Onicomicosis/tratamiento farmacológico , Péptidos Cíclicos/uso terapéutico , Administración Tópica , Antifúngicos/farmacocinética , Péptidos Catiónicos Antimicrobianos/farmacocinética , Ensayos Clínicos como Asunto , Humanos , Uñas/efectos de los fármacos , Uñas/microbiología , Onicomicosis/microbiología , Péptidos Cíclicos/farmacocinética , Resultado del TratamientoRESUMEN
Onychomycosis is a common, difficult-to-treat nail infection that is mainly caused by dermatophytes. Current therapies are not wholly effective and are associated with manifold side effects. The development of treatments for onychomycosis is challenging because standard in vitro tests are not predictive of antifungal efficacy within the nail. We have developed a new antifungal agent, NP213, for the treatment of onychomycosis. NP213 is based on endogenous host defense peptides produced within the nail. We compared the in vitro activity of NP213 and existing antifungal agents using conventional antimicrobial susceptibility test (AST) systems and more physiologically relevant models based on the human nail. We observed that the standard in vitro AST methodologies failed to predict the efficacy of antifungal agents within the nail. To address that, we present a more physiologically relevant modified AST method. This method, alongside other standard in vitro assessments of activity (including mechanism-of-action and time-of-kill studies), better reflected the activity of NP213 and other antifungal agents within the nail than standard in vitro AST methods. NP213 is a rapidly acting, fungicidal peptide that is superior to existing antifungal agents in vitro It penetrated the nail more effectively than other antifungals, as confirmed by using an optimized in vitro nail infection model. The data presented here support the current clinical development status of NP213 as a novel agent for treating onychomycosis. We propose that the modified tests developed and applied for NP213 characterization are the most relevant to use for screening any potential therapeutic candidates for onychomycosis.
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Antifúngicos/uso terapéutico , Onicomicosis/tratamiento farmacológico , Antifúngicos/farmacología , Arthrodermataceae/efectos de los fármacos , Arthrodermataceae/patogenicidad , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Microscopía Electroquímica de Rastreo , Uñas/microbiología , Onicomicosis/microbiología , Tiña/tratamiento farmacológico , Tiña/microbiologíaRESUMEN
Cysteamine is an endogenous aminothiol produced in mammalian cells as a consequence of coenzyme A metabolism through the activity of the vanin family of pantetheinase ectoenzymes. It is known to have a biological role in oxidative stress, inflammation, and cell migration. There have been several reports demonstrating anti-infective properties targeting viruses, bacteria, and even the malarial parasite. We and others have previously described broad-spectrum antimicrobial and antibiofilm activities of cysteamine. Here, we go further to demonstrate redox-dependent mechanisms of action for the compound and how its antimicrobial effects are, at least in part, due to undermining bacterial defenses against oxidative and nitrosative challenges. We demonstrate the therapeutic potentiation of antibiotic therapy against Pseudomonas aeruginosa in mouse models of infection. We also demonstrate potentiation of many different classes of antibiotics against a selection of priority antibiotic-resistant pathogens, including colistin (often considered an antibiotic of last resort), and we discuss how this endogenous antimicrobial component of innate immunity has a role in infectious disease that is beginning to be explored and is not yet fully understood.
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Cistamina/farmacología , Cisteamina/farmacología , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacos , Animales , Antibacterianos/farmacología , Farmacorresistencia Bacteriana , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Infecciones por Pseudomonas/microbiología , Especies de Nitrógeno Reactivo , Especies Reactivas de OxígenoRESUMEN
Staphylococcus aureus is a clinically significant human pathogen that causes infectious diseases ranging from skin and soft tissue infections (SSTI) and health care-associated infections (HAI) to potentially fatal bacteremia and endocarditis. Nasal carriage of S. aureus, especially for persistent carriage, is associated with an increased risk of subsequent infection, particularly nosocomial and surgical site infections (SSI), usually via autoinfection. NP108 is a cationic antimicrobial polymer composed of generally recognized as safe (GRAS) amino acid building blocks. NP108 is broad spectrum and rapidly bactericidal (3-log kill in ≤3 h), killing bacteria by membrane disruption and cell lysis. NP108, contrary to many antibiotics, shows equally effective antimicrobial activity against a variety of S. aureus (MIC100 = 8 to 500 mg/liter) and S. epidermidis (MIC100 = 4 to 8 mg/liter) isolates, whether exponentially growing or in stationary phase. NP108 is antimicrobially active under nutrient-limiting conditions similar to those found in the anterior nares (MIC100 = 8 mg/liter) and kills antibiotic-resilient small colony variants (MIC100 = 32 mg/liter) and S. aureus biofilms (prevention, MIC100 = 1 to 4 mg/liter; eradication, MIC100 ≥ 31.25 mg/liter). NP108 is active against isolates of S. aureus resistant to the current standard-of-care decolonization agent, mupirocin, with no significant increase in the MIC100 NP108 is water soluble and has been formulated into compatible aqueous gel vehicles for human use in which antimicrobial efficacy is retained (2.0% [wt/vol]). NP108 is a potential nonantibiotic antimicrobial alternative to antibiotics for the nasal decolonization of S. aureus, with clear advantages in its mechanism of action over the existing gold standard, mupirocin.
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Antibacterianos/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Meticilina/farmacología , Mupirocina/farmacología , Polímeros/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Portador Sano/tratamiento farmacológico , Portador Sano/microbiología , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/microbiología , Humanos , Nariz/microbiología , Infecciones Estafilocócicas/microbiología , Infección de la Herida Quirúrgica/tratamiento farmacológico , Infección de la Herida Quirúrgica/microbiologíaRESUMEN
There are no wholly successful chemotherapeutic strategies against Burkholderia cepacia complex (BCC) colonization in cystic fibrosis (CF). We assessed the impact of cysteamine (Lynovex) in combination with standard-of-care CF antibiotics in vitro against BCC CF isolates by the concentration at which 100% of bacteria were killed (MIC100) and checkerboard assays under CLSI standard conditions. Cysteamine facilitated the aminoglycoside-, fluoroquinolone- and folate pathway inhibitor-mediated killing of BCC organisms that were otherwise resistant or intermediately sensitive to these antibiotic classes. Slow-growing BCC strains are often recalcitrant to treatment and form biofilms. In assessing the impact of cysteamine on biofilms, we demonstrated inhibition of BCC biofilm formation at sub-MIC100s of cysteamine.
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Antibacterianos/farmacología , Complejo Burkholderia cepacia/efectos de los fármacos , Cisteamina/farmacología , Fibrosis Quística/microbiología , Biopelículas/efectos de los fármacos , Complejo Burkholderia cepacia/aislamiento & purificación , Humanos , Pruebas de Sensibilidad Microbiana , Tobramicina/farmacologíaRESUMEN
BACKGROUND AND OBJECTIVE: Cysteamine is licensed for use in nephropathic cystinosis but preclinical data suggest a role in managing cystic fibrosis (CF). This study aimed to determine whether oral cysteamine is absorbed in adult CF patients and enters the bronchial secretions. Tolerability outcomes were also explored. METHODS: Patients ≥18 years of age, weighing >50 kg with stable CF lung disease were commenced on oral cysteamine bitartrate (Cystagon(®)) 450 mg once daily, increased weekly to 450 mg four times daily. Serial plasma cysteamine concentrations were measured for 24 h after the first dose. Participants were reviewed every week for 6 weeks, except at 4 weeks. Plasma cysteamine concentrations were measured 8 h after dosing when reviewed at 1, 2 and 3 weeks and 6 h after dosing when reviewed at 5 weeks. Sputum cysteamine concentration was also quantified at the 5-week assessment. RESULTS: Seven of the ten participants reported adverse reactions typical of cysteamine, two participants discontinued intervention. Following the first 450-mg dose, mean (SD) maximum concentration (C max) was 2.86 (1.96) mg/l, the time corresponding to C max (T max) was 1.2 (0.7) h, the half-life (t ½) was 3.7 (1.7) h, clearance (CL/F) 89.9 (30.5) L/h and volume of distribution (V d/F) 427 (129) L. Cysteamine appeared to accumulate in sputum with a median (interquartile range) sputum:plasma cysteamine concentration ratio of 4.2 (0.98-8.84). CONCLUSION: Oral cysteamine is absorbed and enters the bronchial secretions in patients with CF. Although adverse reactions were common, the majority of patients continued with cysteamine. Further trials are required to establish the risk benefit ratio of cysteamine therapy in CF.
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Cisteamina/farmacocinética , Cisteamina/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Adulto , Área Bajo la Curva , Cisteamina/efectos adversos , Fibrosis Quística/metabolismo , Fibrosis Quística/microbiología , Cistinosis/tratamiento farmacológico , Femenino , Semivida , Humanos , Absorción Intestinal , Masculino , Esputo/metabolismo , Esputo/microbiología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Cysteamine has recently been shown to have in vitro properties potentially therapeutically beneficial in cystic fibrosis (CF). In this study we investigated the antimicrobial and mucolytic activity of cysteamine against the complex biologic matrix of CF sputum. METHODS: Sputum samples were obtained from 23 CF adults. Sputum polymicrobial content after in vitro exposure to cysteamine and standard CF antibiotics was assessed after a single exposure and after 14 days low-dose exposure. The effect of cysteamine on sputum spinnbarkeit was assessed. FINDINGS: Cysteamine reduced sputum polymicrobial burden by 3.18 (95% CI 2.30-4. 07, p < 0.001) log10 units after 24 h incubation. Combined cysteamine and tobramycin reduced polymicrobial burden by a further 3.75 (95% CI 2.63-5.07, p < 0 · 001) log10 units above that seen with tobramycin. Repeated low dosing with cysteamine reduced sputum polymicrobial load from day 10 onwards (p = 0.032). Cysteamine reduced CF sputum viscoelasticity, sputum spinnbarkeit cysteamine 11.1 mm/s (95% CI 3.95-18.2) vs DNAse 1.69 mm/s (95% CI 0.73-2.65), p = 0.016. Cysteamine was active against Mycobacterium abscessus as a monotherapy and also potentiated the effects of amikacin and azithromycin. CONCLUSION: Further investigation is required into the therapeutic potential of cysteamine in CF to treat emerging as well as established microbial pathogens and as a mucolytic agent.
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Antiinfecciosos/farmacología , Cisteamina/farmacología , Fibrosis Quística/complicaciones , Infecciones Oportunistas/complicaciones , Infecciones Oportunistas/microbiología , Adulto , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antiinfecciosos/uso terapéutico , Recuento de Colonia Microbiana , Cisteamina/uso terapéutico , Fibrosis Quística/genética , Fibrosis Quística/fisiopatología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Femenino , Genotipo , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Mutación , Micobacterias no Tuberculosas/efectos de los fármacos , Micobacterias no Tuberculosas/aislamiento & purificación , Infecciones Oportunistas/tratamiento farmacológico , Esputo/efectos de los fármacos , Esputo/microbiología , Adulto JovenRESUMEN
The purpose of this perspective article is to present the argument that authentic leadership is a gendered representation of leadership. We first provide a brief history of leadership theories and definitions of authentic leadership. We then critique authentic leadership and offer arguments to support the premise that authentic leadership is not gender-neutral and is especially challenging for women.
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In this Perspective article we propose that in order to pave the way for women's career advancement into the senior ranks of organizations, attention must be directed at the systemic norms and structures that drive the gendered nature of the workplace. A focus on individual level issues, i.e., women lacking confidence and women opting out, detracts from the work that must be done at the organizational level in order to dismantle the system of pervasive, structural disadvantage facing women seeking to advance to senior leadership positions.
RESUMEN
Cystic fibrosis (CF) is a heterogeneous multiorgan disease caused by mutations in the CFTR gene leading to misfolding (and other defects) and consequent dysfunction of CFTR protein. The majority of mutations cause a severe CF phenotype, and people with this condition will require a wide variety of medical interventions and therapies throughout their lives to address the symptoms of their condition. CF affects many different organ systems, but the most serious consequence of the disease is degeneration of lung function due to chronic respiratory infection and colonization of the airways with opportunistic microbial pathogens. Improvements in therapeutics, particularly the effective use of antibiotics, have led to significant gradual increases in life expectancy. There remains, however, a continuing need for newer, safer and more effective antimicrobials and mucolytic agents to maintain and improve our ability to combat CF lung infections before other curative approaches which target the root cause of the disease become available.