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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 “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 Bugs “It is said that if you know your Enemies and Drugs know Yourself, you will not be imperiled in a Hundred Battles…” SunTzu 孫子 “The Art of War”, 6th century BC Programme • The Bugs • The Bad • The Drugs • The Good • ‘La Resistance’ • The Ugly • Clinical Scenarios from the Children’s Hospital 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 A large bloom of cyanobacteria in lake Atitlan, Guatemala wikipedia.org/wiki/File:Harmful_Bloom_in_Lake_Atitlán,_Guatemala.jpg 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 Syst Evol Microbiol. 2008 Jul;58(Pt 7):1598-602. 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) 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 The Secret of Success • Simple, efficient and highly adaptable • Free floating DNA (nucloid) with plasmids www.ucmp.berkeley.edu/bacteria Cell Wall Structure Dr Gram Gram Stain Organisms on Culture path.cam.ac.uk ID & Sensitivities Antimicrobials The Drugs - “The Good” β-lactams Penicillin, Amoxicillin O/IV Flucloxacillin (O)/IV Piperacillin/tazobactam IV Amoxicillin/clavulanate O/IV Anae Gram + Cefalexin – 1st O Cefuroxime – 2nd (O)/IV Ceftriaxone/Cefotaxime – 3rd IV Ceftazidime – (3rd) IV (Cefipime 4th IV) Meropenem IV Gram - Drugs Gram - Aminoglycosides IV • Gentamycin • Tobramycin • Amikacin Gram + Glycopeptides IV • Vancomycin • Teicoplanin Spectrum of Activity Metronidazole O/IV Anae Clindamycin (O)/IV Linezolid O/IV Daptomycin IV Septrin O/IV Macrolides O/IV Intra Fluoroquinolones O/IV Gram - *2012 Sanford Antimicrobial Guide MRSA Gram + 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 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 aureus and 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) Pharmacokinetic/Pharmacodynamic Parameters Peak:MIC – Aminoglycosides Concentration AUC:MIC – Fluoroquinolones, Clindamycin 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. PK - Bioavailability • High (>90%) • Cefalexin • Clindamycin • Rifampicin • Fusidic acid • Levofloxacin (99%) • Metronidazole • Linezolid (100%) • Low (<60%) • Cefuroxime • Cefixime • Flucloxacillin • Macrolides *2010 Sanford Antimicrobial Guide Be aware of bad taste! • Do not use flucloxacillin (clindamycin) suspensions!! • flucloxacillin cefalexin Penetration in Tissues - CSF • Penetration of various drugs in CSF • Increases with inflammation, lipid solubility • Decreases with molecular weight, protein binding CSF Penetration Good Bad Cefotaxime Ceftriaxone Meropenem Metronidazole Ciprofloxacin Vancomycin* Penicillin Pip/Tazo Cefuroxime Clindamycin Macrolides Aminoglycosides Bone Penetration • Flucloxacillin/Cefalexin • Clindamycin/Fluoroquinolones • + Rifampicin/Fusidic acid • [3rd generation cephalosporins] Beneficial Antibiotic Combinations • Ampicillin + Gentamicin for Enterococcus spp. • Flucloxacillin + Gentamcin for MSSA endocarditis • Double Gram -ve for Pseudomonas spp. ?? • Add Clindamycin in SA/GAS TSS • Add Rifampicin when foreign material present 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 Resistance!? Resistant Organisms - “The Ugly” Physical Mechanisms of Resistance 1. Decreased Permeability • Porin mutations, efflux system 2. Enzymatic Drug Modification • Β-Lactamase (ESBL), carbapenemase production 3. Altered Drug Target • PBP2’MRSA, DNA Gyrase mutation 4. Metabolic Bypass • Sulfonamides 5. Tolerance • Inhibition/killing discrepancy Spread of CRE across the Globe: KPC EID, Volume 17, Number 10—October 2011 Spread of CRE across the Globe: NDM-1 EID, Volume 17, Number 10—October 2011 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 Few New Antibiotics in Pipeline! CLINICAL VIGNETTES 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 Clue – Previous Sample Options 1. 2. 3. 4. 5. I&D Co-amoxiclav I&D + co-amoxiclav Septrin I&D + Septrin Options 1. 2. 3. 4. 5. I&D Co-amoxiclav I&D + co-amoxiclav Septrin I&D + Septrin 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) 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 Empiric Therapy Choices 1. 2. 3. 4. 5. 6. Ceftriaxone Vancomycin + Ceftriaxone Piperacillin/Tazobactam Ciprofloxacin Vancomycin + Ciprofloxacin Meropenem Empiric Therapy Choices 1. 2. 3. 4. 5. 6. Ceftriaxone Vancomycin + Ceftriaxone Piperacillin/Tazobactam Ciprofloxacin Vancomycin + Ciprofloxacin Meropenem A couple of days later… 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 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 Case 3 Treatment Options • Oseltamivir + Cefuroxime • Cefuroxime + Clarythromycin • Cefuroxime + Clindamycin • Oseltamivir + Cefuroxime + Clindamycin • Oseltamivir + Vancomycin + Meropenem Treatment Options • Oseltamivir + Cefuroxime • Cefuroxime + Clarythromycin • Cefuroxime + Clindamycin • Oseltamivir + Cefuroxime + Clindamycin • Oseltamivir + Vancomycin + Meropenem GAS TSS + Influenza (H1N1) • Viral-Bacterial co-infections, especially with flu • H1N1+GAS, H1N1+SA • Add Clindamycin to Penicillin/Cephalosporin • Inhibition production of TSST-1 by 95%* • Cefuroxime dose – always 50mg/kg! • IVIG *Antimicrob Agents Chemother. 1997 Aug;41(8):1682-5 Case 4 • 2 yo with history of earache and fever • Secondary development of mastoiditis • Transfer to Alder Hey for further management • Bloods Wbc 17.5, N11.6, CRP 150 • CT scan and Drainage in theatre CT Scan Small sudural empyema vs. Transverse Sinus venous thrombosis? Initial Antibiotic Cover • Cefotaxime + Amoxicillin • Amoxicillin + Metronidazole • Cefotaxime + Metronidazole • Vancomycin + Cefotaxime + Metronidazole • Vancomycin + Meropenem Initial Antibiotic Cover • Cefotaxime + Amoxicillin • Amoxicillin + Metronidazole • Cefotaxime + Metronidazole • Vancomycin + Cefotaxime + Metronidazole • Vancomycin + Meropenem Follow up • Microbiology from drainage negative • Patient improving clinically • No fever within 48-72 hours • CRP down to 58 then 6 after 1 week therapy • Surgeons want to send patient home • Still no agreement whether intracranial collection real… Mode and Length of Treatment • Switch to oral co-amoxiclav x 4 wks • Switch to oral cefalexin and metronidazole x 6 wks • Switch to oral septrin and metronidazole x 6 wks • Continue IV ceftriaxone + metronidazole x 6 wks Mode and Length of Treatment • Switch to oral co-amoxiclav x 4 wks • Switch to oral cefalexin and metronidazole x 6 wks • Switch to oral septrin and metronidazole x 6 wks • Continue IV ceftriaxone + metronidazole x 6 wks Step-down therapy in Brain Abscess/SDE • No Consensus on IV to oral switch • IV 6 weeks with cefotaxime + metro standard • Switch at 2-3 weeks to oral agent only if uncomplicated and good response • Oral agent with good CSF penetration • Need for multicenter study Case 5 • 3 month old female • Gastroschisis repair at birth • TPN dependent, Central line in situ • Colonised with CRE • Fever 38.9c, unwell, vomiting • Started on Teicoplanin + Gentamicin IV Case 5 • Staphylococcus epidermidis in Blood culture • Teico MIC=2µ=mg/L, vanco MIC=2mg/L • Both Sensitive • Breakpoint is 2 for vancomycin, 4 for Teicoplanin • No access to Teicoplanin levels What you like to do? 1. Continue with Teicoplanin high dose -10 mg/kg od 2. Add Rifampicin to Teicoplanin 3. Change to Vancomycin and aim levels 15-20mg/L 4. Change to Linezolid 5. Change to Daptomycin What you like to do? 1. Continue with Teicoplanin high dose -10 mg/kg od 2. Add Rifampicin to HD Teicoplanin 3. Change to Vancomycin and aim levels 15-20mg/L 4. Change to Linezolid 5. Change to Daptomycin Continued • Switched to vancomycin 15 mg/kg q8hrs • Blood culture taken when switched is still +ve for same organism • Through level of Vancomycin • Before third dose – 5.6mg/L, dose ↑30 mg/kg • 24 hours later – 6.0mg/L, dose increased to ↑35mg/kg • 24 later – 8.9mg/L • Repeat Blood culture 4 days from initial +ve culture still positive… Now What? 1. Add oral rifampicin 2. Increase dose of vancomycin to 40 mg/kg 3. Switch to linezolid 4. Switch to daptomycin 5. Take line out Now What? 1. Add oral rifampicin 2. Increase dose of vancomycin by 25% 3. Switch to linezolid 4. Switch to daptomycin 5. Take line out End of Story? • Started on linezolid IV • ?Role for loading dose of Vancomycin (30mg/kg) • Repeat blood culture negative • 1 week later, unwell fever, bolus of fluid • Growth of yeast within 24 hours Fungal Sepsis 1. Start Liposomal amphotericin 3mg/kg od 2. Start Fluconazole 12mg/kg od 3. Start Caspofungin 50mg/m2 od 4. Start Micafungin 2mg/kg od 5. ±Take line out Fungal Sepsis 1. Start Liposomal amphotericin 3mg/kg od 2. Start Fluconazole 12mg/kg od 3. Start Caspofungin 50mg/m2 od 4. Start Micafungin 2mg/kg od 5. ±Take line out Resolution • Yeast Identified as Candida albicans • Succesfully treated with • 2 week course linezolid • 2 week course micafungin fluconazole • Still in Hospital, isolated Summary • Know your friends and your enemies • Basic microbiological knowledge paramount • Drug classes and spectrum of activity • Quirks: bioavailability, taste, tissue penetration… • Be Aware of resistance • Hitting hard first then narrow spectrum… • Every clinical case is unique • Understand each antimicrobials individual strengths • Individualised therapy in severe infection Resources • www.bugsanddrugs.ca (www.dobugsneeddrugs.ca) • Sandford antimicrobial guide • Mandell, Sarah Long textbook • Your microbiology lab • Promed • HPA QUESTIONS? [email protected]