Transcript Introduction to Antibacterial Therapy: Clinically Relevant Microbiology and Antibiotic Use Hospital Epidemiologist

Introduction to Antibacterial Therapy: Clinically
Relevant Microbiology and Antibiotic Use
Edward L. Goodman, MD
Hospital Epidemiologist
Core Faculty
July 11, 2013
Outline

Basic Clinical Bacteriology
 Antibiotics
– Categories
– Pharmacology
– Mechanisms of Resistance

Antibiotic Stewardship
– “Pearls”
Scheme for the Four Major Classes
of Bacterial Pathogens in
Hospitalized Patients

Gram Positive Cocci
 Gram Negative Rods
 Fastidious Gram Negative Organisms
 Anaerobes
Gram Positive Cocci

Gram stain: clusters
 Catalase pos = Staph
 Coag pos = S aureus
 Coag neg = variety of
species

Chains and pairs
 Catalase neg =
streptococci
 Classify by hemolysis
 Type by specific CHO
Staphylococcus aureus

>95% produce penicillinase (beta lactamase) =
penicillin resistant
 At PHD ~53% of SA are hetero (methicillin)
resistant = MRSA (less than national average)
 Glycopeptide (vancomycin) intermediate (GISA)
– MIC 8-16
– Eight nationwide

First VRSA reported July 5, 2002 MMWR
– Seven isolates reported (5/7 from Michigan)
– MICs 32 - >128
– No evidence of spread w/in families or hospital
Coagulase Negative Staph
Many species – S. epidermidis most
common
 Mostly methicillin resistant (65-85%)
 Often contaminants or colonizers – use
specific criteria to distinguish

– Major cause of overuse of vancomycin

S. lugdunensis is rarely a contaminant
– Causes destructive endocarditis
Streptococci

Beta hemolysis: Group A,B,C etc.
 Invasive – mimic staph in virulence
 S. pyogenes (Group A)
– Pharyngitis,
– Soft tissue
 Invasive
 TSS
– Non suppurative sequellae: ARF, AGN
Other Beta hemolytic

S. agalactiae (Group B)
– Peripartum/Neonatal
– Diabetic foot
– Bacteremia/endocarditis/metastatic foci

Group C/G Streptococcus
– large colony variants: similar clinical illness as GAS
plus bacteremia, endocarditis, septic arthritis
– Small colony variants = Strept milleri
Viridans group

Anginosus sp.
 Bovis sp.: Group D
 Mutans sp.
 Salivarius sp.
 Mitis sp.
Enterococci

Formerly considered Group D Streptococci
now a separate genus
– Bacteremia without IE does not need cidal/syngergistic
therapy
– Endocarditis does need cidal/syngergistic
– Bacteriuria in elderly, obstructed
– Part of mixed abdominal/pelvic infections

Role in mixed flora intra-abdominal infection trivial- therapy
for 2° peritonitis need not cover it

Intrinsically resistant to cephalosporins
 No bactericidal single agent
– For endocarditis need pen/amp/vanc plus AG
– Daptomycin is cidal in vitro


Little experience in endocarditis
Resistance develops (NEJM Aug 25, 2011)
Gram Negative Rods





Fermentors
Oxidase negative
Facultative anaerobes
Enteric flora
Numerous genera
– Escherischia
– Enterobacter
– Serratia, etc

UTI, IAI, LRTI, 2°B

Non-fermentors
 Pure aerobes
 Pseudomonas (oxidase
+) and Acinetobacter
(oxidase -)
– Nosocomial LRTI,
bacteremia, UTI
– Opportunistic
– Inherently resistant

New mechanisms of
MDR emerging
Fastidious Gram Negatives

Neisseria, Hemophilus, Moraxella, HACEK
 Growth requirements
– CO² and enrichment

Culture for Neisseria must be plated at bedside
– Chocolate agar with CO2
– Ligase chain reaction (like PCR) has reduced number
of GU cultures for N. gonorrhea


Can’t do MIC without culture (at reference lab only)
FQ resistance 13% in 2011
– FQ not recommended for empiric Rx since 2007
Anaerobes



Gram negative rods
– Bacteroides (gut/gu flora)
– Fusobacteria (oral and gut)
– Prevotella (mostly oral)
Gram positive rods
– Clostridia (gut)
– Proprionobacteria (skin)
Gram positive cocci
– Peptostreptococci and peptococci (oral, gut, gu)
Anaerobic Gram Negative
Rods

Fastidious
 Produce beta lactamase
 Endogenous flora
 When to consider
– Part of mixed infections
– Confer foul odor
– Heterogeneous morphology
– Gram stain shows GNR but routine cults
negative
(My) Antibiotic Classification

Narrow Spectrum
– Active against only one of the four classes of
bacteria

Broad Spectrum
– Active against more than one of the classes
Narrow Spectrum

Active mostly against only one of the
classes of bacteria
– gram positive: glycopeptides, linezolid,
daptomycin, telavancin
– aerobic gram negative: aminoglycosides,
aztreonam
– anaerobes: metronidazole
Narrow Spectrum
GPC
GNR
Fastid
Anaer
++++
-----
-----
Linezolid ++++
-----
-----
Dapto/Te ++++
lavancin
AG
-----
-----
-----
only
clostridia
Only
gram pos
-----
++++
++
-----
Aztreon
-----
+++
+
-----
Metro
-----
-----
-----
++++
Vanc
BROAD SPECTRUM
Penicillins/Carbapenems
Strep
OSSA
GNR
Fastid
Anaer
Pen
++++
--
+/--
--
+/--
Amp/
amox
Ticar
++++
--
+
+/--
+/--
++
--
++
+/--
+
Pip
+++
--
+++
+++
++
++++
+++
+++
++++
++++
++++
++++
++++
Pip/BL ++++
I
Carba ++++
Cephalosporins
FASTID ANAER
Ceph 1
GPC non GNR
-MRSA
++++
+
--
--
Ceph 2
++
++
+
--
cefoxitin ++
cefotetan
Ceph 3
+++
++
+
+++
+++
+++
--
Ceph 4
++++
+++
--
+++
Pharmacodynamics

MIC=lowest concentration to inhibit growth
 MBC=the lowest concentration to kill
 Peak=highest serum level after a dose
 AUC=area under the concentration time
curve
 PAE=persistent suppression of growth
following exposure to antimicrobial
Pharmocodynamics: Dosing for
Efficacy
Peak
MIC
Trough
Time
Parameters of antibacterial
efficacy

Time above MIC (non concentration killing) - beta
lactams, macrolides, clindamycin, glycopeptides
 24 hour AUC/MIC - aminoglycosides,
fluoroquinolones, azalides, tetracyclines,
glycopeptides, quinupristin/dalfopristin
 Peak/MIC (concentration dependent killing) aminoglycosides, fluoroquinolones, daptomycin,




Time 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
associated 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 = 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
Antimicrobial Resistance
ESKAPE Organisms (mechanism)
Enterococcus faecium VRE (Van A)
 Staphylococcus aureus MRSA (MEC A)
 Klebsiella pneumoniae (ESBL – KPC)
 Acinetobacter baumanii (KPC – NDM1)
 Pseudomonas aeruginosa(AmpC, KPC,
NDM-1)
 Enterobacter species (AmpC)

Mechanisms of Antimicrobial Resistance in
Bacteria
FC Tenover Amer J Med 2006;119: S3-10
DNA gyrase
Quinolones
Cell wall synthesis
DNA-directed RNA
polymerase
Rifampin
ß-lactams &
Glycopeptides
(Vancomycin)
DNA
THFA
Trimethoprim
mRNA
Ribosomes
Folic acid
synthesis
DHFA
50
30
50
30
50
30
Protein
synthesis
inhibition
Macrolides &
Lincomycins
Sulfonamides
PABA
Protein synthesis
mistranslation
Aminoglycosides
Cohen. Science 1992; 257:1064
Protein synthesis
inhibition
Tetracyclines
Mechanisms of Antibiotic Resistance
PM Hawkey, The origins and molecular basis of antibiotic resistance. Brit Med J
1998;317: 657-660
Interplay of β lactam antibiotics and bacteria
PM Hawkey, The origins and molecular basis of antibiotic resistance. Brit Med J
1998;317: 657-660
Bad Beta Lactamases (for
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
Really 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 Resistance

Strong epidemiological evidence that
antibiotic use in humans and animals
associated with increasing resistance
 Subtherapeutic dosing encourages resistant
mutants to emerge; conversely, rapid
bactericidal activity discourages
 Hospital antibiotic control programs have
been demonstrated to reduce resistance
Antibiotic Armageddon
“There is only a thin red line of ID
practitioners who have dedicated
themselves to rational therapy and control
of hospital infections”
Kunin CID 1997;25:240
When to Cover for MRSA

Severe purulent SSTI
 Necrotizing pneumonia/empyema
 Central line associated
 (Known MRSA carriers?)

Go To Drug = Vancomycin
Is Vancomycin Needed for every
patient with SSTI?
CID 2011:1-38
When to Cover for Pseudomonas

Severe COBPD/bronchiectasis
– Frequent ABX
– Steroid dependent
– Known airway colonization

Neutropenic septic leukemic
 (Burn patients)
Is Pseudomonas Coverage Needed
for Every Diabetic Foot Infection?
CID 2012; 54 (12):132-173
Historic overview on treatment of
infections

2000 BC: Eat this root
 1000 AD: Say this prayer
 1800’s: Take this potion
 1940’s: Take penicillin, it is a miracle drug
 1980’s – 2000’s: Take this new antibiotic, it
is a bigger miracle!
 ?2014: Eat this root!
Thanks 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