Introduction to Antibacterial Introduction to Antibacterial Therapy: Clinically Relevant Therapy: Clinically Relevant Microbiology and Antibiotic Use Microbiology and Antibiotic Use Edward L. Goodman, MD Hospital Epidemiologist Core Faculty July 11, 2013
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Introduction to Antibacterial Therapy: Clinically Relevant Microbiology and Antibiotic Use
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Introduction to Antibacterial Therapy: Clinically Introduction to Antibacterial Therapy: Clinically Relevant Microbiology and Antibiotic UseRelevant Microbiology and Antibiotic Use
Edward L. Goodman, MD
Hospital Epidemiologist
Core Faculty
July 11, 2013
OutlineOutline
Basic Clinical BacteriologyAntibiotics
– Categories– Pharmacology – Mechanisms of Resistance
Antibiotic Stewardship – “Pearls”
Scheme for the Four Major Classes Scheme for the Four Major Classes of Bacterial Pathogens in of Bacterial Pathogens in
MIC=lowest concentration to inhibit growth MBC=the lowest concentration to killPeak=highest serum level after a dose AUC=area under the concentration time
curvePAE=persistent suppression of growth
following exposure to antimicrobial
Pharmocodynamics: Dosing Pharmocodynamics: Dosing for Efficacyfor Efficacy
Blo
od L
evel
Time
Peak
MIC
Trough
Parameters of antibacterial Parameters of antibacterial efficacyefficacy
Time above MIC (non concentration killing) - beta lactams, macrolides, clindamycin, glycopeptides
Time over MICTime over MIC For beta lactams, should exceed MIC > 50% of
dose interval Higher doses may allow adequate time over MIC For most beta lactams, optimal time over MIC can
be achieved by continuous infusion (except temperature labile drugs such as imipenem, ampicillin)
For Vancomycin, evolving consensus that troughs should be >15 for most serious MRSA infections, especially pneumonia and bacteremia– If MRSA MIC >= 2 and patient responding slowly or
poorly, should change vancomycin to daptomycin, linezolid or tigecycline
– Few THD MRSA have MIC >1
Higher Serum/tissue levels are Higher Serum/tissue levels are
associated with faster killingassociated with faster killing Aminoglycosides
– Peak/MIC ratio of >10-12 optimal – Achieved by “Once Daily Dosing”– PAE helps
Fluoroquinolones – 10-12 ratio achieved for enteric GNR
PAE helps– not achieved for Pseudomonas – Not always achieved for Streptococcus pneumoniae
Daptomycin– Dose on actual body weight
FQ AUC/MIC = AUICFQ AUC/MIC = AUIC
For Streptococcus pneumoniae, FQ should have AUIC >= 30
For gram negative rods where Peak/MIC ratio of 10-12 not possible, then FQ AUIC should >= 125
For MRSA, vancomycin AUIC needs to be >=400. Not easily achieved when MIC >=2.
A Brief Overview of A Brief Overview of Antimicrobial ResistanceAntimicrobial Resistance
Mechanisms of Antimicrobial Resistance in Mechanisms of Antimicrobial Resistance in BacteriaBacteria
FC Tenover Amer J Med 2006;119: S3-10FC Tenover Amer J Med 2006;119: S3-10
Folic acid synthesis
ß-lactams & Glycopeptides (Vancomycin)
50 50 5030 30 30
DNA
mRNA
Ribosomes
PABA
DHFA
THFA
Cell wall synthesis
DNA gyrase
Quinolones
Protein synthesis inhibition
Protein synthesis inhibitionTetracyclines
Protein synthesis mistranslation
Macrolides & Lincomycins
Cohen. Science 1992; 257:1064
DNA-directed RNA polymerase
Rifampin
Aminoglycosides
Sulfonamides
Trimethoprim
Mechanisms of Antibiotic ResistanceMechanisms of Antibiotic ResistancePM Hawkey, The origins and molecular basis of antibiotic resistance. Brit Med J PM Hawkey, The origins and molecular basis of antibiotic resistance. Brit Med J
1998;317: 657-6601998;317: 657-660
Interplay of Interplay of ββ lactam antibiotics and bacteria lactam antibiotics and bacteriaPM Hawkey, The origins and molecular basis of antibiotic resistance. Brit Med J PM Hawkey, The origins and molecular basis of antibiotic resistance. Brit Med J
1998;317: 657-6601998;317: 657-660
Bad Beta Lactamases (for Bad Beta Lactamases (for dummies like me)dummies like me)
ESBL– Klebsiella and E coli– Require carbapenems although for UTI Pip/tazo might
work– Not clear how transmissible but use Contact Isolation
AMP C– SPICE organisms
Inducible/derepressed chromosomal beta lactamases– Requires carbapenems when AMP C expressed– Do not require Contact Isolation unless associated
plasmid transmits MDR
ReallyReally Bad Beta Lactamases Bad Beta Lactamases
Carbapenem Resistant Enterobacteraciae (CRE)– Resistant to everything but colistin and sometimes
tigecycline
New Delhi Metalloproteinases (NDM)– Pseudomonas and enterobacteraciae– Resistant to all but colistin
These patients require Contact Isolation and Cohorting
Antibiotic Use and ResistanceAntibiotic Use and Resistance
Strong epidemiological evidence that antibiotic use in humans and animals associated with increasing resistance
Historic overview on treatment of Historic overview on treatment of infectionsinfections
2000 BC: Eat this root1000 AD: Say this prayer1800’s: Take this potion1940’s: Take penicillin, it is a miracle drug1980’s – 2000’s: Take this new antibiotic, it
is a bigger miracle!?2014: Eat this root!
Thanks toThanks to
Shahbaz Hasan, MD for allowing me to use slides from his 6/6/07 Clinical Grand Rounds on Streptococci
Eliane S Haron, MD for allowing me to use the “Eat this root” slide
Terri Smith, PharmD for collecting data from the Antibiotic Stewardship Program