Introduction to Antibacterial Therapy: Clinically Relevant Microbiology and Antibiotic Use

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Introduction to Antibacterial Therapy Clinically
Relevant Microbiology and Antibiotic Use

• Edward L. Goodman, MD
• Hospital Epidemiologist
• Core Faculty
• July 11, 2013

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Outline

• Basic Clinical Bacteriology
• Antibiotics
• Categories
• Pharmacology
• Mechanisms of Resistance
• Antibiotic Stewardship
• Pearls

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Scheme for the Four Major Classes of Bacterial
Pathogens in Hospitalized Patients

• Gram Positive Cocci
• Gram Negative Rods
• Fastidious Gram Negative Organisms
• Anaerobes

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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

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Staphylococcus aureus

• gt95 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 - gt128
• No evidence of spread w/in families or hospital

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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

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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

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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

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Viridans group

• Anginosus sp.
• Bovis sp. Group D
• Mutans sp.
• Salivarius sp.
• Mitis sp.

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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)

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Gram Negative Rods

• Fermentors
• Oxidase negative
• Facultative anaerobes
• Enteric flora
• Numerous genera
• Escherischia
• Enterobacter
• Serratia, etc
• UTI, IAI, LRTI, 2B

• Non-fermentors
• Pure aerobes
• Pseudomonas (oxidase ) and Acinetobacter
  (oxidase -)
• Nosocomial LRTI, bacteremia, UTI
• Opportunistic
• Inherently resistant
• New mechanisms of MDR emerging

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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
• Cant do MIC without culture (at reference lab
  only)
• FQ resistance 13 in 2011
• FQ not recommended for empiric Rx since 2007

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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)

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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

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(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

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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

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Narrow Spectrum
GPC GNR Fastid Anaer
Vanc ----- ----- only clostridia
Linezolid ----- ----- Only gram pos
Dapto/Telavancin ----- ----- -----
AG ----- -----
Aztreon ----- -----
Metro ----- ----- -----






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BROAD SPECTRUMPenicillins/Carbapenems
Strep OSSA GNR Fastid Anaer
Pen -- /-- -- /--
Amp/ amox -- /-- /--
Ticar -- /--
Pip --
Pip/BLI
Carba
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Cephalosporins
GPC non -MRSA GNR FASTID ANAER
Ceph 1 -- --
Ceph 2 --
cefoxitincefotetan
Ceph 3 --
Ceph 4 --
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Boutique Antibiotics

• Just like at NorthPark/Galleria/etc
• Department Stores (NM, Nordstrom, Saks)
• specialty stores (e.g., Mont Blanc store!)
• Examples
• Synercid for VRE faecium, not faecalis, MRSA
• Tigecycline MRSA, VRE, Acinetobacter
• ID consult needed

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Pharmacodynamics

• MIClowest concentration to inhibit growth
• MBCthe lowest concentration to kill
• Peakhighest serum level after a dose
• AUCarea under the concentration time curve
• PAEpersistent suppression of growth following
  exposure to antimicrobial

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Pharmocodynamics Dosing for Efficacy
Peak
Blood Level
MIC
Trough
Time
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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,

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Time over MIC

• For beta lactams, should exceed MIC gt 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 gt15 for most serious MRSA infections,
  especially pneumonia and bacteremia
• If MRSA MIC gt 2 and patient responding slowly or
  poorly, should change vancomycin to daptomycin,
  linezolid or tigecycline
• Few THD MRSA have MIC gt1

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Higher Serum/tissue levels are associated with
faster killing

• Aminoglycosides
• Peak/MIC ratio of gt10-12 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

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FQ AUC/MIC AUIC

• For Streptococcus pneumoniae, FQ should have AUIC
  gt 30
• For gram negative rods where Peak/MIC ratio of
  10-12 not possible, then FQ AUIC should gt 125
• For MRSA, vancomycin AUIC needs to be gt400. Not
  easily achieved when MIC gt2.

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A Brief Overview of Antimicrobial Resistance
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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)

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Mechanisms of Antimicrobial Resistance in
BacteriaFC Tenover Amer J Med 2006119 S3-10
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DNA gyrase
DNA-directed RNA polymerase
Quinolones
Cell wall synthesis
Rifampin

• ß-lactams Glycopeptides (Vancomycin)

DNA
THFA
mRNA
Trimethoprim
Protein synthesis inhibition
Ribosomes
Folic acid synthesis
DHFA
50
50
50
Macrolides Lincomycins
30
30
30
Sulfonamides
PABA
Protein synthesis inhibition
Protein synthesis mistranslation

• Tetracyclines

Aminoglycosides
Cohen. Science 1992 2571064
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Mechanisms of Antibiotic ResistancePM Hawkey,
The origins and molecular basis of antibiotic
resistance. Brit Med J 1998317 657-660
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Interplay of ß lactam antibiotics and
bacteriaPM Hawkey, The origins and molecular
basis of antibiotic resistance. Brit Med J
1998317 657-660
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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

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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

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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

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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 199725240

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When to Cover for MRSA

• Severe purulent SSTI
• Necrotizing pneumonia/empyema
• Central line associated
• (Known MRSA carriers?)
• Go To Drug Vancomycin

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Is Vancomycin Needed for every patient with SSTI?
CID 20111-38
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When to Cover for Pseudomonas

• Severe COBPD/bronchiectasis
• Frequent ABX
• Steroid dependent
• Known airway colonization
• Neutropenic septic leukemic
• (Burn patients)

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Is Pseudomonas Coverage Needed for Every Diabetic
Foot Infection? CID 2012 54 (12)132-173
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Historic overview on treatment of infections

• 2000 BC Eat this root
• 1000 AD Say this prayer
• 1800s Take this potion
• 1940s Take penicillin, it is a miracle drug
• 1980s 2000s Take this new antibiotic, it is
  a bigger miracle!
• ?2014 Eat this root!

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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