**6. Future treatments**

**5.2. Treatment of bacterial infections**

190 Cystic Fibrosis in the Light of New Research

While the buildup of mucus within the lungs is quite problematic, it is often not what leads to the overall mortality or morbidity of CF patients. Rather, this is due to secondary infections that arise from this buildup. As stated earlier, this mucus is a rich, largely immobile niche of complex nutrients that enmesh the bacteria. In healthy lungs, the cilia are functioning properly with a thin PCL and clearing most pathogens out of the lungs. However, with the thick mucus, this is not the case, as the cilia do not have enough physical force to push it upwards. As a result, bacteria begin to infect the area. However, the precise location in the lungs where the infection resides is important for the choice of treatment methods. In general, the lungs are divided into two zones. The first is the conductive zone, which includes many of the prelimi‐ nary branches of the bronchi and does not directly include the alveoli or any of the accompa‐ nying areas. The second is the respiratory zone, which includes many of the later branches of the airways and the alveoli. These differences are important due to the necessary changes for treatments. In the conductive zone, the tissue does not have quite as high a vascular exposure, but is much closer to the mouth. As such, infections in this area are often treated with aero‐ solized medicines. In contrast, the respiratory zone is much deeper into the lungs, but has much higher vascular exposure due to the presence of the alveoli in this zone. Treatments for this zone usually include oral or intravenous medications. While the mode of treatment is known, the actual ability to determine where the infection is occurring is dependent on a series of initial cultures from the patient, and the species present can change once treatment begins.

Once the type of treatment has been determined, the next step is determining what the effective antibiotic(s) is for the particular bacteria being targeted. This is dependent on the class of antibiotic and has to be administered in a patient-specific manner. In general, there are some that work more efficiently in certain patients than in others. For example, tobramycin, a potent aminoglycoside, has been approved by the FDA for clinical treatment of *PA* in CF patients. However, various reports have shown an impenetrability of tobramycin in biofilms, an effect that may be due to the lowered levels of oxygen within the biofilms. The ability of an antibiotic to be active on biofilm bacteria is of the utmost importance when selecting a treatment strategy [33]. As mentioned previously, biofilms generally develop more resistance to certain antibi‐ otics due to their differential metabolism, as well as penetration issues. Those at the surface of the biofilm are generally more metabolically active, while those in the middle of the biofilm projections and those at the base are generally far less active or even inactive. Ciofu et al. [63] showed that certain antibiotics will be more or less effective in these areas depending on their mode of action. Tobramycin is highly effective on the more oxygen-rich outer layer of metabolically active bacteria, but others such as colistin are better suited at dealing with the metabolically inactive bacteria further into the biofilm. In addition, both basic and clinical scientists are focusing better on the proper physiology of bacteria for treatment. This is

something that is case-dependent, and cannot necessarily be generalized.

However, the efficiency of the antibiotics for long-term treatment of *PA* infections has been worrisome, especially because of the development of multi-drug resistant *PA* (MRPA) [64]. Because of these issues, it is imperative to unravel new treatments that will work on bacteria that are growing under non-traditional conditions (e.g., anaerobic or microaerobic). That is

While advancements in medicine are not written in stone, there are trends that are observable that can dictate what advancements should be expected. Most of these trends are collected on the website for the CF Foundation [66], which monitors all forms of data related to CF research. In this case, they maintain a log of what is in the pipeline for research, as well as commonly available treatments for patients. In general, the medications available fall into six categories: CFTR modulators, anti-inflammatory drugs, anti-infective drugs, nutrition, mucus alteration, and airway surface restoration. Much of the research on medications has been focused on antiinflammatory and anti-infective medications. While most of the anti-infective compounds have been modifications of available antibiotics into inhalable forms (such as aerosolized amikacin and vancomycin), the developments in anti-inflammatory medications are slightly more unique. One such example is the development of a drug that is targeting the Type III Secretion System of *PA*. This is a humanized monoclonal antibody directed against one of the protein components of the T3SS. The study states that its goal is to develop an anti-inflamma‐ tory molecule, which this antibody serves to do. By interacting with the T3SS, it will hopefully reduce any inflammation caused by sensing this molecule, and potentially reduce the amount of molecules secreted by this system. However, as they note, this is not a means to kill *PA* [66]. The antibody does not serve that purpose, so it is not able to function as an antibiotic in infected patients.

Another field that seems to be growing with potential treatments is the area of CFTR modu‐ lators. This field of treatment is focused on finding drugs that change the defective behavior of mutant CFTR protein. Since one form of mutant CFTR is produced yet does not make it to the apical membrane of the cells, some thought has gone into making it possible for the protein to make it to the surface, and hopefully in that process, fold properly to allow for a functioning anion channel. All of these are experimental compounds, but have made it to Phase 2 clinical trials at the time of this publication [66]. The first is a "potentiator", a compound that suppos‐ edly will be able to open a defective CFTR once it has reached the surface. While this is not meant for all forms of the disease, it is possible that this will have a great impact. Next is a "corrector" that is meant to move the folded protein to the correct location in the cell. This can help with proteins that have misfolded and are sent for degradation or are sent to a different membrane of the cell (e.g., basolateral). Finally, a synthetic signaling molecule has been developed that is meant to supplement decreased levels of S-nitrosoglutathione (an NO generator) in the cells of CF patients. This signaling molecule has been found to be decreased in these patients, and already evidence from the trial has shown that by supplementing this signal, there is increased and proper folding of the CFTR and function of the channel once it is in the membrane.
