Pseudomonas infections and a new type of antifungal drug


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Aspergillosis patients support meeting. Speakers Pippa Newton and Graham Atherton

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Pseudomonas infections and a new type of antifungal drug

  2. 2. Programme  1.30 Graham   New generation of antifungal medication Itraconazole – anticancer drug?  2.00 Tea & Coffee  2.30 Pippa Newton (NAC Senior Consultant)  Pseudomonas – what is it, why does it make us ill?  3.00 Q & A from the floor or online
  3. 3. Targets for attack Targets to attack in the fungus MUST be only present in the fungus, otherwise the drug would attack the patient as much as it attacks the fungus Different classes of drugs target the plasma membrane, sterol biosynthesis, DNA biosynthesis, and β-glucan biosynthesis
  4. 4. Fungal Cell Structure
  5. 5. What drugs do we have now? Target Antifungal Sterol (Direct binding - Cell membrane) Polyene group: Amphotericin B Interfere with ergosterol synthesis (Cell membrane) Azole group: Itraconazole, Voriconazole, Posaconazole Allylamine group: terbinafine Cell Wall Glucan synthesis inhibitors: Echinocandins:Caspofunfin, Micafungin, Anidulafungin DNA Inhibits DNA synthesis: Flucytosine
  6. 6. Summary We have already exploited 4 different targets to attack fungi Still a need to develop new drugs      Some against new targets Some with better distribution Lower toxicity Fungicidal (more deadly) Cheaper!!!
  7. 7. Great Progress Macromolecular antimicrobial agents (Nanomolecules)
  8. 8. Research Group Fukushima et. al. 2013 (December) Broad based research: US, China, Japan, Singapore Research paper
  9. 9. History of this substance Known for some time to be antimicrobial – works a little like amphotericin B (Ambisome).
  10. 10. Toxicity Just like amphotericin these new chemicals are known to be toxic and lack specificity They will attack human cell membranes just as much as they attack microbial & fungal cell membranes No good!
  11. 11. Polyene Binds sterol – (membrane) Specificity - amphotericin
  12. 12. New form of molecule Shows high specificity for fungal & bacterial cells Leaves human cells alone! Forms self aggregating assembly in water and targets microbial cell membranes Low toxicity to mammalian cells Biodegradable CHEAP to make in large quantities!!
  13. 13. Self aggregation
  14. 14. Disrupts cell membrane
  15. 15. Does it work in the lab?
  16. 16. Does it work on real infections? Sections of eye infected with fungus (Keratitis) and treated with: Water Amphotericin New drug – note lack of toxicity
  17. 17. Human treatment? Next phase is to test in humans – mainly as topical treatment at first Promising to provide a whole new class of drugs, very difficult to develop resistance against NB there is still little resistance to amphotericin after 55 years.
  18. 18. What is Pseudomonas ? Dr Pippa Newton
  19. 19. Pseudomonas related bacteria    Bacteria Present in soil, plants and ground water Several groups of Pseudomonas related bacteria that cause disease in humans including - Pseudomonas aeruginosa - Stenotrophomonas - Burkholderia species  About 50% of the organisms grown produce a blue-green pigment (pyocyan)  Detecting the bacteria in a clinical sample does not necessarily mean there is an infection present
  20. 20. Colonisation versus Infection  Colonisation - Pseudomonas present in clinical sample but it is not causing an infection - eg present on normal skin present in airways with no signs of ongoing infection - Patients colonised with Pseudomonas can later develop infection  Infection with Pseudomonas - Clinical evidence of infection and sample taken from site of infection grows Pseudomonas
  21. 21. Pseudomonas aeruginosa infections  Usually causes infections in individuals with either chronic chest problems or individuals with poor immune function  Can cause a variety of infections including - Skin infections - Surgical wound infections - Chest infections - Ear and sinus infections - Urinary tract infections - Bloodstream infections  Pseudomonas aeruginosa accounts for about 10% of hospital acquired infections (often urinary and chest infections)
  22. 22. Skin and nail infections  Green nail syndrome - If hands immersed in water for prolonged periods of time  Skin - Infected skin lesions – eg eczema, burns - Blue-green discharge - Swimming pool folliculitis
  23. 23. Urinary and Bloodstream infections  Urinary infections - Occur in patients who have had surgery or a catheter  Blood stream infections: - Rare - Pseudomonas - Stenotrophomonas 2012 3,743 cases in E&W&NI in 2012 Commoner at the extremes of age 453 cases in E&W&NI in Commoner is patients > 64 years old
  24. 24. Pseudomonas aeruginosa in the lungs  Colonisation - Tends to occur in individuals with chronic lung problems - Eg Bronchiectasis Cystic Fibrosis (about 80% of patients are colonised)  Chest infection symptoms - productive cough – sweet / fruity odour - more breathless / wheezing - chest pain - fevers - loss of apetite - weight loss
  25. 25. Investigations to determine colonisation versus infection  Bloods:  Sputum culture: confirm the presence of pseudomonas and once grown can test for antibiotic sensitivities to look for evidence of ongoing infection some patients have more than 1 strain of pseudomonas in their sputum and Non mucoid mucoid strains
  26. 26. Investigations to determine colonisation versus infection  Chest X ray: to look for signs of pneumonia  Blood culture: to exclude infection in the blood in very unwell patients
  27. 27. How do we treat Pseudomonas aeruginosa in the lungs ?        Once Pseudomonas present it is very difficult to eradicate it Best chance of eradicating Pseudomonas is early treatment after initial detection in sputum Only 1 oral antibiotic treats Pseudomonas – Ciprofloxacin All the other antibiotics need to be given intravenously Eradication treatment options Control of Pseudomonas colonisation Treatment of Pseudomonas infections
  28. 28. How do we treat Pseudomonas aeruginosa in the lungs ?  Early eradication treatment options - Oral ciprofloxacin and antibiotic nebulisers (Tobramycin, Gentamycin, Colomycin) - Intravenous antibiotics - Treatment can be associated with improvements in lung function tests  Colonised with Pseudomonas - Antibiotic nebulisers used to keep down Pseudomonas levels in sputum
  29. 29. How do we treat Pseudomonas aeruginosa in the lungs ?  Treatment of Pseudomonas infection - Oral ciprofloxacin (if Pseudomonas is sensitive to this) - Combination of 2 intravenous antibiotics initially, then consider reducing to 1 antibiotic once sensitivities of Pseudomonas known
  30. 30. Stenotrophomonas  Tends to be found in watery environments  Usually results in colonisation rather than infection - no treatment needed  Immunocompromised patients more likely to develop infections  Can cause the following infections - Chest infections - Urinary infections - Long-term line infections  Treatment: Usually co-trimoxazole as a single agent
  31. 31. Regular cleaning of Nebulisers   Both Pseudomonas and Stenotrophomonas like watery environments Need to regularly clean home nebulisers to prevent bacterial contamination
  32. 32. Summary    Pseudomonas related bacteria – concentrated on Pseudomonas aeruginosa - Different clinical infections that may occur - Colonisation versus infection - Treatment of colonisation and infections Stenotrophomonas Importance of keeping any home nebulisers regularly clean to prevent contamination with these bacteria
  33. 33. Suggest a subject Can be on any relevant subject you would like to hear our opinion or get our help with Send suggestions to Pass notes to me at clinic or at the meeting Phone them in (24 hrs) at 0161 291 5866
  34. 34. Other advances Stem cells proving to have the ability to help cure Tb! (this was a surprise result – the experiment was only intended to test for safety)  A group found that when they gave patients back their own stem cells (patients who had infections that were resistant to multiple drugs), three times as many as controls were cured after 6 months! Itraconazole may be useful to treat prostatic cancers!
  35. 35. Other news Periodical for clinic is in development An ‘expanded newsletter’ with news, information, art, poetry. Probably do 4 editions. Ideas welcome!
  36. 36. Thank You “The best chance we have of beating this illness is to work together” Living with it, Working with it, Treating it Fungal Infection Trust