Antibiotic Management of Lung Infections in Cystic Fibrosis. I. The Microbiome, Methicillin-Resistant Staphylococcus aureus

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, butmany 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.</p

Antibiotic Management of Lung Infections in Cystic Fibrosis. II. Nontuberculous Mycobacteria, Anaerobic Bacteria, and Fungi

36 p.Airway infections are a key component of cystic fibrosis (CF) lung disease. Whereas the approach to common pathogens such as Pseudomonas aeruginosa is guided by a significant body of evidence, other infections often pose a considerable challenge to treating physicians. In Part I of this series on the antibiotic management of difficult lung infections, we discussed bacterial organisms including methicillin-resistant Staphylococcus aureus, gram-negative bacterial infections, and treatment of multiple bacterial pathogens. Here, we summarize the approach to infections with nontuberculous mycobacteria, anaerobic bacteria, and fungi. Nontuberculous mycobacteria can significantly impact the course of lung disease in patients with CF, but differentiation between colonization and infection is difficult clinically as coinfection with other micro-organisms is common. Treatment consists of different classes of antibiotics, varies in intensity, and is best guided by a team of specialized clinicians and microbiologists. The ability of anaerobic bacteria to contribute to CF lung disease is less clear, even though clinical relevance has been reported in individual patients. Anaerobes detected in CF sputum are often resistant to multiple drugs, and treatment has not yet been shown to positively affect patient outcome. Fungi have gained significant interest as potential CF pathogens. Although the role of Candida is largely unclear, there is mounting evidence that Scedosporium species and Aspergillus fumigatus, beyond the classical presentation of allergic bronchopulmonary aspergillosis, can be relevant in patients with CF and treatment should be considered. At present, however there remains limited information on how best to select patients who could benefit from antifungal therapy.Accepted versio

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

35 p.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.Accepted versio

Absolute and Normalized T1 Maps from Healthy Volunteers.

<p>Absolute (left column) and normalized (right column) T1 maps from each of five healthy non-CF control subjects. The absolute T1 maps exhibited visible subject-to-subject variation despite the absence of known lung disease. The normalized T1 maps were generated directly from the absolute T1 maps by dividing by the mean central T1 relaxation time for each subject and resulted in reduced subject-to-subject variation for the healthy control subjects. HV: healthy volunteer.</p

Mean Regional Normalized T1 Values as a Function of FEV₁% predicted.

<p>Mean regional normalized T1 (nT1) values as a function of FEV₁% predicted for all ten early-stage CF patients (black squares) and 5 healthy volunteers (open diamonds). (a) upper right lung region; (b) upper left lung region; (c) lower right lung region; (d) lower left lung region. Linear regression lines and Pearson Correlation coefficients for the CF patients (controls excluded) are also shown in each plot. The mean nT1 values in the upper left and right lung regions resulted in a significant linear correlation (p<0.05) with FEV₁% predicted despite the known variation in these spirometric results. As expected, the correlations for the mean normalized T1 assessments in the lower lung regions were not significant (p>0.1). Note also the consistently lower mean nT1 values in the upper right and left lung regions for the CF patients in comparison to healthy volunteers.</p

Comparison of mean regional nT1 values from the upper and lower lung regions for the CF patients and healthy volunteers.

<p>A significant reduction in mean (SD) nT1 (**p = 0.001) was observed in the upper right (UR) [.914 (.037)] and upper left (UL) [0.906 (.040)] lung regions (black bars) for the CF patients (n = 10) in comparison to the healthy control subjects (n = 5) UR [.983 (.003)] and UL [0.984 (.011)] lung regions (open bars). The mean nT1 in the lower right (LR) and lower left (LL) lung regions was also significantly reduced for the CF patients in comparison to healthy volunteers (*p<0.05). Importantly, these differences were observed despite normal spirometry in both groups.</p

Manual ROI Selection.

<p>(a) A representative absolute T1 relaxation time map from a healthy volunteer. (b) The same image with manual ROI's overlaid. (UR = upper right lung region, UL = upper left lung region, CR = central right lung region, CL = central left lung region, LR = lower right lung region, LL = lower left lung region).</p