Transcript Bug and Drugs Practical Microbiology

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]