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Bugs and Drugs

Bugs and Drugs. Stéphane Paulus Consultant in Paediatric Infectious Diseases, Alder Hey Children’s NHS Foundation Trust, Liverpool Honorary Senior Lecturer, Institute of Infection & Global Health, University of Liverpool.

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Bugs and Drugs

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  1. Bugs and Drugs Stéphane Paulus Consultant in Paediatric Infectious Diseases, Alder Hey Children’s NHS Foundation Trust, Liverpool Honorary Senior Lecturer, Institute of Infection & Global Health, University of Liverpool

  2. “It is said that if you know your Enemies and know Yourself, you will not be imperiled in a Hundred Battles…” SunTzu 孫子 “The Art of War”, 6th century BC

  3. Bugs “It is said that if you know your Enemies and know Yourself, you will not be imperiled in a Hundred Battles…” Drugs SunTzu 孫子 “The Art of War”, 6th century BC

  4. Programme • The Bugs • The Drugs • ‘La Resistance’ • Clinical Scenarios from the Children’s Hospital • The Bad • The Good • The Ugly

  5. Bacteria – The ‘Bad’? • Earliest bacterial fossil is 3.5 billion years old • Cyanobacteria from Archean rock (W. Australia) • Small, unicellular • Aquatic & photosynthetic (chloroplast in plants) www.ucmp.berkeley.edu/bacteria/cyanofr.html

  6. A large bloom of cyanobacteria in lake Atitlan, Guatemala wikipedia.org/wiki/File:Harmful_Bloom_in_Lake_Atitlán,_Guatemala.jpg

  7. Survival in Extreme Environments Acid Hot Springs, Yellowstone National Park, US (Thermophiles) Canadian Journal of Microbiology, 1973, 19:183-188, 10.1139/m73-028 Deep sea hydrothermal vents 2,500m below sea level, East pacific Rise (Nautilia profundicola) Int J SystEvolMicrobiol. 2008 Jul;58(Pt 7):1598-602.

  8. Survival in Extreme Environments 3 new UV-resistant Bacteria found living in Stratosphere (Janibacter hoylei, Bacillus isronensis and Bacillus aryabhata)* A reservoir of briny liquid buried deep beneath an Antarctic glacier supports hardy microbes that have lived in isolation for millions of years** *International Journal of Systematic and Evolutionary Microbiology 2009;59:2977 and **Science 2009, 324 (5925)

  9. More friend than Foe • 10 times as many bacteria as human cells in the body (~1014 versus 1013) • 500 to 1000 species of bacteria live in the human gut and a similar number on the skin • On the whole, symbiotic relationship between bacteria and host

  10. The Secret of Success • Simple, efficient and highly adaptable • Free floating DNA (nucloid) with plasmids www.ucmp.berkeley.edu/bacteria

  11. Cell Wall Structure

  12. Dr Gram

  13. GramStain

  14. Organisms on Culture path.cam.ac.uk

  15. ID & Sensitivities

  16. Antimicrobials

  17. The Drugs - “The Good” Gram + β-lactams Penicillin, Amoxicillin O/IV Flucloxacillin (O)/IV Piperacillin/tazobactam IV Amoxicillin/clavulanate O/IV Meropenem IV Cefalexin – 1st O Cefuroxime – 2nd (O)/IV Ceftriaxone/Cefotaxime – 3rd IV Ceftazidime – (3rd) IV (Cefipime 4th IV) Anae Gram -

  18. Drugs Spectrum of Activity Gram - Aminoglycosides IV • Gentamycin • Tobramycin • Amikacin Glycopeptides IV • Vancomycin • Teicoplanin Metronidazole O/IV Clindamycin (O)/IV Linezolid O/IV Daptomycin IV Septrin O/IV Macrolides O/IV Fluoroquinolones O/IV Anae MRSA Gram + Intra Gram - Gram + *2012 Sanford Antimicrobial Guide

  19. Bacteriostatic vs. Bacteriocidal Antibiotics • Bacteriostatic Antibiotics • Inhibit bacterial cell growth • Need intact immune system to fight infection • Clindamycin, Linezolid, Macrolides • Bacteriocidal Antibiotics • Kill bacteria directly • Do not rely on immune system of patient • β-lactams, Aminoglycosides, Quinolones, Vancomycin

  20. Advantages of some bacteriostatic drugs • Clindamycin • Binds to 50s ribosomal subunit of the bacteria • Inhibits protein synthesis • Changes in the cell wall surface which decreases adherence of bacteria to host cells and increases intracellular killing of organisms • Reduction in toxin production in • Staphylococcus aureusand Group A Streptococcus TSS • Exerts an extended postantibiotic effect against some strains of bacteria (attributed to persistence of the drug at the ribosomal binding site)

  21. Pharmacokinetic/Pharmacodynamic Parameters • Peak:MIC • Aminoglycosides • AUC:MIC • Fluoroquinolones, Clindamycin Concentration • Time > MIC • -lactams • Macrolides MIC 0 Time (hours) Craig WA: Clin Infect Dis 26: 1-12, 1998. Ambrose PG, Owens RC, Grasela D: Med Clin North America. 84(6)1431-46, 2000.

  22. PK - Bioavailability • High (>90%) • Cefalexin • Clindamycin • Rifampicin • Fusidic acid • Levofloxacin (99%) • Metronidazole • Linezolid (100%) • Low (<60%) • Cefuroxime • Cefixime • Flucloxacillin • Macrolides *2010 Sanford Antimicrobial Guide

  23. Be aware of bad taste! • Do not use flucloxacillin (clindamycin) suspensions!! • flucloxacillin cefalexin

  24. Penetration in Tissues - CSF • Penetration of various drugs in CSF • Increases with inflammation, lipid solubility • Decreases with molecular weight, protein binding

  25. CSF Penetration Good Cefotaxime Ceftriaxone Meropenem Metronidazole Ciprofloxacin Vancomycin* Bad Penicillin Pip/Tazo Cefuroxime Clindamycin Macrolides Aminoglycosides

  26. Bone Penetration • Flucloxacillin/Cefalexin • Clindamycin/Fluoroquinolones • + Rifampicin/Fusidic acid • [3rd generation cephalosporins]

  27. Beneficial Antibiotic Combinations • Ampicillin + Gentamicin for Enterococcus spp. • Flucloxacillin + Gentamcin for MSSA endocarditis • Double Gram -ve for Pseudomonasspp. ?? • Add Clindamycin in SA/GAS TSS • Add Rifampicin when foreign material present

  28. Choice of optimal Drug • Spectrum of activity/Sensitivities • Oral/IV forms • Static/Cidal • PK/PD parameters • Bioavailability/palatability • Achievable plasma levels/tissue penetration • Renal/Hepatic dysfunction

  29. Resistance!?

  30. Resistant Organisms - “The Ugly”

  31. Physical Mechanisms of Resistance • Decreased Permeability • Porin mutations, efflux system • Enzymatic Drug Modification • Β-Lactamase (ESBL), carbapenemase production • Altered Drug Target • PBP2’MRSA, DNA Gyrase mutation • Metabolic Bypass • Sulfonamides • Tolerance • Inhibition/killing discrepancy

  32. Spread of CRE across the Globe: KPC EID, Volume 17, Number 10—October 2011

  33. Spread of CRE across the Globe: NDM-1 EID, Volume 17, Number 10—October 2011

  34. Disk diffusion antibacterial drug susceptibility testing of A)Klebsiella pneumoniae carbapenemase-2 (KPC-2) , B) New Delhi metallo-β-lactamase-1 (NDM-1)–, and C) oxacillinase-48 (OXA-48)–producing K. pneumoniae clinical isolates

  35. Few New Antibiotics in Pipeline!

  36. Clinical Vignettes

  37. Case 1 • 8yo boy in A&E with 5cm boil on buttocks • On Flucloxacillin for 3 days – not improving • History of recurrent boils / cellulitis in last year • Obs stable, clinically well

  38. Clue – Previous Sample

  39. Options • I&D • Co-amoxiclav • I&D + co-amoxiclav • Septrin • I&D + Septrin

  40. Options • I&D • Co-amoxiclav • I&D + co-amoxiclav • Septrin • I&D + Septrin

  41. CA-MRSA • Swap and swab! • I&D is key (sometimes enough) • What abx are effective for MRSA? • TMP/SMX, Erythomycin, Clindamycin (variable, D-test) • Rifampicin, Fusidic acid (never alone) • Vancomycin, Teicoplanin • Daptomycin, Linezolid • What is not effective: ANY β-lactam (PBP2’ mutation)

  42. Case 2 • 8 years male, short bowel, TPN dependent • Previous central line (Broviac) infections • Frequent hospitalisation • Febrile 39.5c in A&E, Hypotensive • Needing fluid bolus

  43. Empiric Therapy Choices • Ceftriaxone • Vancomycin + Ceftriaxone • Piperacillin/Tazobactam • Ciprofloxacin • Vancomycin + Ciprofloxacin • Meropenem

  44. Empiric Therapy Choices • Ceftriaxone • Vancomycin + Ceftriaxone • Piperacillin/Tazobactam • Ciprofloxacin • Vancomycin + Ciprofloxacin • Meropenem

  45. A couple of days later…

  46. Resistant Gram Negative Infections • At risk for hospital acquired MDR infections: • ESBL – plasmid mediated • Klebsiella, E.coli, Enterobacter spp. • AmpC – chromosomally induced • Serretia, Acinetobacter, Citrobacter, Enterobacter spp. • CRE –carbapenem resistant Enterobacteriaceae • No Cephalosporins • Ciprofloxacin/mero (+/- Glycopeptide/AG if CVL) if septic

  47. Case 3 • 3 yo old female • Unwell for 3 days with coryza/headaches (January) • Now in A&E, T 40c, Fluid bolusesx3 • Respiratory Distress Rapid sequence intubation • Diffuse erythrodermic rash, rapidly spreading

  48. Case 3

  49. Treatment Options • Oseltamivir + Cefuroxime • Cefuroxime + Clarythromycin • Cefuroxime + Clindamycin • Oseltamivir + Cefuroxime + Clindamycin • Oseltamivir + Vancomycin + Meropenem

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