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Norman Dewhurst, BScPhm, ACPR, PharmD, RPhClinical Pharmacy Specialist/Leader, Critical Care
St. Michael’s Hospital, Toronto, ONAssistant Professor (Status)
Leslie Dan Faculty of Pharmacy, University of [email protected]
May 7th, 2014Evolutions Critical Care Conference
Knowledge is Power: An Antibiotic Overview to Maximize
Outcomes in the Critically Ill
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Goal
• To review antibiotics & rationalize why we choose the drugs we do for various diseases / infection issues which comes up in the critical care environment
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Learning ObjectivesBy the end of this session, attendees should be able to:
1. Review basic microbiologic principles2. Provide an overview of commonly used ICU
antimicrobials3. Explore clinical syndromes from an antibiotic
perspective4. Highlight the importance of antimicrobial
stewardship
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Outline
I. Microbiology Review
II. General Considerations
III. Antibiotic Options
IV. Clinical Applications
V. Allergies
VI. Dosing & Monitoring
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“How do microbiology reports help me treat a patient?”
I. Microbiology Review6
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Microbiology Review
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•Gram Stain• Blue / Purple = Gram positives• Red / Pink = Gram negatives
•Bacterial Shape• Bacilli = rods = long, thin• Cocci = round, oval
•Ability to grow in presence/absence of oxygen• Aerobes = ability to grow in the presence of
oxygen• Anaerobes = ability to grow in the absence
of oxygen
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Gram Staining
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Gram Stain
Gram Positives Gram Negatives
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Gram Positives (+)
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Gram Positive
Cocci Bacilli
Clusters/Clumps
Pairs/Chains
Staphylococcus(MSSA, MRSA
Coagulase negative)
ListeriaBacillus spp.
CorynebacteriumLactobacillusClostridium
Streptococcus
Enterococcus(E. faecalis)(E. faecium)
Pairs
Spectrum Staph.(MSSA)
Strep. Enter.faecalis
GNB ExpandedGNB
Pseudo-monas
Gut Anaerobes
Drug ? ? ?
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Gram Negatives (-)
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Gram Negative
Bacilli(GNB)
Coccobacilli Diplococci
HaemophilusPasteurella
EnterobacteriaceaePseudomonas
NeisseriaMoraxella
Acinetobacter
FermenterEnterobacteriaceae
COLIFORM
FermenterEnterobacteriaceae
COLIFORM
Non-fermenterPseudomonas
StenotrophomonasGNB
Non-fermenterPseudomonas
StenotrophomonasGNB
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Spectrum Staph.(MSSA)
Strep. Enter.faecalis
GNB ExpandedGNB
Pseudo-monas
Gut Anaerobes
Drug ? ? ?
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“What do I need to consider before treatment?”
II. General Considerations11
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Primary Site of Infection
Image: http://en.wikipedia.org/wiki/Commons:File:Human_body_features.svg
Respiratory tract infection
Intra-abdominal
Urinary Tract
Skin & Soft Tissue Infection
Other
Unknown Origin
CVC / Line infection
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Management Decisions• Do the bacteria represent infection or colonisation?
• Can the condition be treated without antibiotics?
• Can this infection be treated with antibiotics alone?
• What is the most appropriate antibiotic(s)?
– Pharmacotherapeutic considerations?
– Alternatives in case of allergy?
• Side effects, contraindications?
• OPAT?
• Is it hospital acquired or community acquired?
• How to screen patients for MDR organisms?
• How to prevent the spread of MDR in wards?
• Which antibiotics to avoid in MDR positive patients?
Bhattacharya S. J Med Microbiol. 2006 Jan;24(1):20-4.
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Infection versus Colonisation?
• a) Specimen type?• Physiologically sterile sites• Non-sterile sites • Catheterised specimens
• b) Inflammatory parameters of the patient• WBC, CRP, ESR
• c) General condition of the patient• Temperature• Blood pressure, pulse rate• Arterial oxygen saturation, inotrope requirement,
organ support requirement
Bhattacharya S. J Med Microbiol. 2006 Jan;24(1):20-4.
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Therapeutic Thought Process
Safety
Cost
Efficacy / Spectrum
Convenience
Indication Know the infection you’re treating
Assess alternatives, drug of choice?
Maximize dosing, monitor, minimize toxicity
Address above before considering cost
Considerations for discharge
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Cultures before
treatment
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ICU Treatment Principles
• Bactericidal
• High doses
• IntravenousSerious infection
• Non-toxic
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Other Considerations
• Allergies
• Local antibiogram
• Is oral route feasible?
• IV to PO stepdown?
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“What are my antibiotic options?”
III. Antibiotic Options21
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Mechanism of ActionCell Wall Synthesis
PenicillinsCephalosporinsCarbapenemsVancomycin
Cell Wall IntegrityBeta-lactamases DNA Synthesis
MetronidazoleDNA Gyrase
Fluoroquinolones
RNA PolymeraseRifampin
Phospholipid membranesPolymyxins
Protein (30S) Synthesis
TetracyclinesStreptomycin
SpectinomycinKanamycin
Protein (50S) SynthesisMacrolides
ChloramphenicolClindamycinLincomycin
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Therapeutic Options
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Penicillins
Penicillin
Cloxacillin
Amoxicillin/Ampicillin
Piperacillin
Ticarcillin
β-Lactamase Inhibitor
Clavulanate
Tazobactam
Cephalosporins
Cefazolin (1st)
Ceftriaxone (3rd)
Ceftazidime (3rd)
Cefipime (4th)
Ceftaroline (5th)
Carbapenems
Imipenem
Meropenem
Doripenem
Ertapenem
Trimethoprim/ Sulfamethoxazole
Nitrofurantoin
Fosfomycin
Metronidazole
Clindamycin
Aminoglycosides
Gentamicin
Tobramycin
Amikacin
Fluoroquinolones
Ciprofloxacin
Levofloxacin
Moxifloxacin
Vancomycin
Tigecycline
Colistin
Macrolides
Erythromycin
Clarithromycin
Azithromycin
Daptomycin
Linezolid
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Therapeutic Options
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Penicillins
Penicillin
Cloxacillin
Amoxicillin/Ampicillin
Piperacillin
Ticarcillin
β-Lactamase Inhibitor
Clavulanate
Tazobactam
Cephalosporins
Cefazolin (1st)
Ceftriaxone (3rd)
Ceftazidime (3rd)
Cefipime (4th)
Ceftaroline (5th)
Carbapenems
Imipenem
Meropenem
Doripenem
Ertapenem
Trimethoprim/ Sulfamethoxazole
Nitrofurantoin
Fosfomycin
Metronidazole
Clindamycin
Aminoglycosides
Gentamicin
Tobramycin
Amikacin
Fluoroquinolones
Ciprofloxacin
Levofloxacin
Moxifloxacin
Vancomycin
Tigecycline
Colistin
Macrolides
Erythromycin
Clarithromycin
Azithromycin
Daptomycin
Linezolid
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Therapeutic Options
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Penicillins
Cloxacillin
Piperacillin
β-Lactamase Inhibitor
Tazobactam
Cephalosporins
Cefazolin (1st)
Ceftriaxone (3rd)
Ceftazidime (3rd)
Carbapenems
Imipenem
Meropenem
Ertapenem
Trimethoprim/ Sulfamethoxazole
Metronidazole
Aminoglycosides
Gentamicin
Tobramycin
Fluoroquinolones
Ciprofloxacin
Levofloxacin
Moxifloxacin
VancomycinMacrolides
Azithromycin
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“How do I treat this?”
IV. Clinical Applications27
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Staphylococcus aureus
• Gram positive
• Skin & soft tissue infections
• VAP
• Line infections
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Primary Site of Infection
Image: http://en.wikipedia.org/wiki/Commons:File:Human_body_features.svg
Respiratory tract infection
Intra-abdominal
Urinary Tract
Skin & Soft Tissue Infection
Other
Unknown Origin
CVC / Line infection
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Staphylococcus aureus
Methicillin Sensitive S. aureus(MSSA)
Methicillin Resistant S. aureus(MRSA)
CloxacillinCefazolin
Vancomycin
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CLOXACILLIN
Mechanism of Action
• Cell wall synthesis inhibitor
Uses • MSSA VAP, Cellulitis• Endocarditis
Standard Dosing
• 1-2 g IV q6h• Endocarditis: 2 g IV q4h
• No need to adjust in renal dysfunction
Side Effects • Hypersensitivity reactions• Seizures
• Antibiotic Associated Diarrhea
Cautions/ Contra-indications
• Allergy / anaphylaxis
Spectrum Staph.(MSSA)
Strep. Enter.faecalis
GNB ExpandedGNB
Pseudo-monas
Gut Anaerobes
Cloxacillin + + - - - - -
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CEPHALOSPORINS
Mechanism of Action
Cell-wall synthesis inhibitors
Uses • Cefazolin: surgical prophylaxis• Ceftriaxone: CAP/HAP/VAP
• Ceftazidime: VAP
Standard Dosing
• Cefazolin 1-2 g IV q8h• Ceftriaxone 1-2 g IV q24h• Ceftazidime 1-2 g IV q8h
Common Side Effects
• Hypersensitivity reactions• Seizures
• Thrombocytopenia• Clostridium difficile
Cautions/ Contra-indications
• Allergy / anaphylaxis
Spectrum Staph.(MSSA)
Strep. Enter.faecalis
GNB ExpandedGNB
Pseudo-monas
Gut Anaerobes
Cefazolin + + - + - - -
Ceftriaxone + + - + + - -
Ceftazidime - - - + + + -
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-LactamsSide Effects • Hypersensitivity reactions
• Seizures• Antibiotic Associated Diarrhea
• Thrombocytopenia• C. difficile
Cautions/ Contraindications
• Allergy / anaphylaxis
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VANCOMYCIN
Mechanism of Action
• Cell wall synthesis inhibitor
Uses • MRSA infection• Meningitis (Until resistance R/O)
• C. difficile (oral only)
Standard Dosing
• IV Load: 15-25 mg/kg (up to 2 g)• IV Maintenance: 1 g IV q8-12h• Level just prior to 4th dose• Random level anytime
• PO (C.diff): 125 mg PO q6h
Side Effects • Nephrotoxicity• Red Man’s syndrome (facial and torso flushing, hypotension)
Cautions/ CIs
• Dosing in renal failure
Spectrum Staph.(MSSA)
Strep. Enter.faecalis
GNB ExpandedGNB
Pseudo-monas
Gut Anaerobes
IV+
(+ MRSA)
+ +(+ E. faecium)
- - - -
Oral - - - - - - C. diff +
On combo: Caution when d/c’ing IV or
PO
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Primary Site of Infection
Image: http://en.wikipedia.org/wiki/Commons:File:Human_body_features.svg
Respiratory tract infection
Intra-abdominal
Urinary Tract
Skin & Soft Tissue Infection
Other
Unknown Origin
CVC / Line infection
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Community Acquired Pneumonia
• S. pneumoniae
• S. aureus• Gram-negative bacilli• H. influenzae• Legionella species
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Ceftriaxone
Azithromycin
Levofloxacin
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MACROLIDES
Mechanism of Action
Protein Synthesis Inhibitor (50S ribosome)
Uses • CAP (atypical coverage) + beta-lactam
Standard Dosing
• Azithromycin 500 mg IV/po X 1, then 250 mg IV/po daily (X 4 days)• Azithromycin 500 mg IV/po q24h (X 5 days)
Common Side Effects
• QTc prolongation• LFT elevation
• Diarrhea• Ototoxicity
Cautions/ Contra-indications
• Prolonged QTc
Spectrum Staph.(MSSA)
Strep. Enter.faecalis
GNB ExpandedGNB
Pseudo-monas
Gut Anaerobes
Erythromycin +/- Atypicals +
Clarithromycin + Atypicals +
Azithromycin - + - Atypicals + - - -
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FLUOROQUINOLONES
Mechanism of Action
DNA Synthesis Inhibitor
Uses • Cipro: gram negative infections
• Levofloxacin: CAP/HAP/VAP• Moxifloxacin: Intra-abdominal
Standard Dosing
• Ciprofloxacin 400 mg IV q8-12h• Levofloxacin 750 mg IV q24h• Moxifloxacin 400 mg IV q24h
Common Side Effects
• QTc prolongation• Seizure
• Tendon rupture• LFT elevation
Cautions/ Contra-indications
• QTc prolongation• Use within previous 3 months (resistance)
Spectrum Staph.(MSSA)
Strep. Enter.faecalis
GNB ExpandedGNB
Pseudo-monas
Gut Anaerobes
Ciprofloxacin - - - + + + -
Levofloxacin + + - + + - -
Moxifloxacin + + - + + - +
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HAP/VAP
• S. pneumoniae
• S. aureus• Gram-negative bacilli• H. influenzae• Legionella species
• ? MRSA• ? Pseudomonas
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Ceftriaxone
Azithromycin
Levofloxacin
Vancomycin
Anti-pseudomonal
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HAP/VAP
< 5 days > 5 days
Pseudomonas coverage
Ceftriaxone
Levofloxacin
Vancomycin
? MRSA
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Anti-Pseudmonal
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Penicillins
Penicillin
Cloxacillin
Amoxicillin/Ampicillin
Piperacillin
Ticarcillin
β-Lactamase Inhibitor
Clavulanate
Tazobactam
Cephalosporins
Cefazolin (1st)
Ceftriaxone (3rd)
Ceftazidime (3rd)
Cefipime (4th)
Ceftaroline (5th)
Carbapenems
Imipenem
Meropenem
Doripenem
Ertapenem
Trimethoprim/ Sulfamethoxazole
Nitrofurantoin
Fosfomycin
Metronidazole
Clindamycin
Aminoglycosides
Gentamicin
Tobramycin
Amikacin
Fluoroquinolones
Ciprofloxacin
Levofloxacin
Moxifloxacin
Vancomycin
Tigecycline
Colistin
Macrolides
Erythromycin
Clarithromycin
Azithromycin
Daptomycin
Linezolid
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Anti-Pseudomonal
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Penicillins
Cloxacillin
Piperacillin
β-Lactamase Inhibitor
Tazobactam
Cephalosporins
Cefazolin (1st)
Ceftriaxone (3rd)
Ceftazidime (3rd)
Carbapenems
Imipenem
Meropenem
Ertapenem
Trimethoprim/ Sulfamethoxazole
Metronidazole
Clindamycin
Aminoglycosides
Gentamicin
Tobramycin
Fluoroquinolones
Ciprofloxacin
Levofloxacin
Moxifloxacin
VancomycinMacrolides
Azithromycin
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Anti-Pseudomonal
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Penicillins
Piperacillin
β-Lactamase Inhibitor
Tazobactam
Cephalosporins
Ceftazidime (3rd)
Carbapenems
Imipenem
Meropenem
Aminoglycosides
Tobramycin
Fluoroquinolones
CiprofloxacinHigh Resistance
NephrotoxicityOtotoxicity
Not empiric
Reserve Use
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PIPERACILLIN/TAZOBACTAM
Mechanism of Action
• Cell wall synthesis inhibitor + beta-lactamase inhibitor
Uses • Broad spectrum / poly-microbial infections• Severe intra-abdominal infections• Pip/tazo: HAP/VAP (requiring pseudomonas coverage)
Standard Dosing
• Pip/tazo: 4.5 g IV q6h
Side Effects • Hypersensitivity reactions• Seizures
• Antibiotic Associated Diarrhea
Cautions/ Contra-indications
• Allergy / anaphylaxis
Spectrum Staph.(MSSA)
Strep. Enter.faecalis
GNB ExpandedGNB
Pseudo-monas
Gut Anaerobes
Pip/tazo + + + + + + +
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AMINOGLYCOSIDES
Mechanism of Action
Protein Synthesis Inhibitor (30S ribosome)
Uses • Gram negative infections
Standard Dosing
• 1-2 mg/kg IV q8h• 5-7 mg/kg IV q24h
Traditional drug monitoring:•Peak – 30 min post infusion•Trough – just prior to dose
Common Side Effects
• Nephrotoxicity• Ototoxicity
Once daily:• 8 hour random only
Cautions/ Contra-indications
• Renal failure
Spectrum Staph.(MSSA)
Strep. Enter.faecalis
GNB ExpandedGNB
Pseudo-monas
Gut Anaerobes
Gentamicin - - - + + + -
Tobramycin - - - + + ++ -
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HAP/VAP
< 5 days > 5 days
Pseudomonas coverage
Ceftriaxone
Levofloxacin
Pip/Tazo
Ceftazidime
Vancomycin
? MRSA
Tobramycin
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Primary Site of Infection
Image: http://en.wikipedia.org/wiki/Commons:File:Human_body_features.svg
Respiratory tract infection
Intra-abdominal
Urinary Tract
Skin & Soft Tissue Infection
Other
Unknown Origin
CVC / Line infection
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MDRs / “Super bugs”• MRSA
– Methicillin Resistant Staphylococcus aureus
• VRE– Vancomycin Resistant Enterococcus
• ESBL– Extended spectrum beta-lactamases
• CRE / CRP– Carbapenemase Resistant Enterobacteriaceae
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WHO
IDSA
Resistance Alarms
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The Antimicrobial Pipeline
www.antibiotic-action.com
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Therapeutic Options
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Penicillins
Penicillin
Cloxacillin
Amoxicillin/Ampicillin
Piperacillin
Ticarcillin
β-Lactamase Inhibitor
Clavulanate
Tazobactam
Cephalosporins
Cefazolin (1st)
Ceftriaxone (3rd)
Ceftazidime (3rd)
Cefipime (4th)
Ceftaroline (5th)
Carbapenems
Imipenem
Meropenem
Doripenem
Ertapenem
Trimethoprim/ Sulfamethoxazole
Nitrofurantoin
Fosfomycin
Metronidazole
Clindamycin
Aminoglycosides
Gentamicin
Tobramycin
Amikacin
Fluoroquinolones
Ciprofloxacin
Levofloxacin
Moxifloxacin
Vancomycin
Tigecycline
Colistin
Macrolides
Erythromycin
Clarithromycin
Azithromycin
Daptomycin
Linezolid
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Therapeutic Options
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Penicillins
Penicillin
Cloxacillin
Amoxicillin/Ampicillin
Piperacillin
Ticarcillin
β-Lactamase Inhibitor
Clavulanate
Tazobactam
Cephalosporins
Cefazolin (1st)
Ceftriaxone (3rd)
Ceftazidime (3rd)
Cefipime (4th)
Ceftaroline (5th)
Carbapenems
Imipenem
Meropenem
Doripenem
Ertapenem
Trimethoprim/ Sulfamethoxazole
Nitrofurantoin
Fosfomycin
Metronidazole
Clindamycin
Aminoglycosides
Gentamicin
Tobramycin
Amikacin
Fluoroquinolones
Ciprofloxacin
Levofloxacin
Moxifloxacin
Vancomycin
Tigecycline
Colistin
Macrolides
Erythromycin
Clarithromycin
Azithromycin
Daptomycin
Linezolid
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CARBAPENEMS
Mechanism of Action
Cell wall synthesis inhibitors
Uses • ESBL infections• Beta-lactam allergy
• Polymicrobial infection
Standard Dosing
• Imipenem 500 mg IV q6h• Ertapenem 1 g IV q24h
Common Side Effects
• Hypersensitivity reactions• Seizures
• Thrombocytopenia• Eosinophilia
Cautions/ Contra-indications
• Allergy / anaphylaxis
Spectrum Staph.(MSSA)
Strep. Enter.faecalis
GNB ExpandedGNB
Pseudo-monas
Gut Anaerobes
Imipenem + + + + + + +
Meropenem + + +(?) + + + +
Ertapenem + + - + + - +
BROAD SPECTRUM
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MDRs / “Super bugs”• MRSA
– Methicillin Resistant Staphylococcus aureus
• VRE– Vancomycin Resistant Enterococcus
• ESBL– Extended spectrum beta-lactamases
• CRE [ CRP / KPC / NDM ]– Carbapenemase Resistant Enterobacteriaceae
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Therapeutic Options
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Penicillins
Penicillin
Cloxacillin
Amoxicillin/Ampicillin
Piperacillin
Ticarcillin
β-Lactamase Inhibitor
Clavulanate
Tazobactam
Cephalosporins
Cefazolin (1st)
Ceftriaxone (3rd)
Ceftazidime (3rd)
Cefipime (4th)
Ceftaroline (5th)
Carbapenems
Imipenem
Meropenem
Doripenem
Ertapenem
Trimethoprim/ Sulfamethoxazole
Nitrofurantoin
Fosfomycin
Metronidazole
Clindamycin
Aminoglycosides
Gentamicin
Tobramycin
Amikacin
Fluoroquinolones
Ciprofloxacin
Levofloxacin
Moxifloxacin
Vancomycin
Tigecycline
Colistin
Macrolides
Erythromycin
Clarithromycin
Azithromycin
Daptomycin
Linezolid
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SEPTRA (Trimethoprim & Sulfamethoxazole)
Mechanism of Action
Protein Synthesis Inhibitors (dihydrofolate reductase & dihydropteroate synthetase inhibitors)
Uses • Urinary tract infections• MRSA infections• Skin and soft tissue infections
Standard Dosing
• 15 mg/kg of TMP component / 24 hours (divided q6-q8h)• 2 DS tabs po q8h (~for 60 kg patient, 6 DS tabs per day)
Common Side Effects
• Hyperkalemia• Hypoglycemia
• Skin reactions• Cystalluria
• Bone marrow suppression• Hepatotoxicity
Cautions/ Contra-indications
• Renal failure
Spectrum Staph.(MSSA)
Strep. Enter.faecalis
GNB ExpandedGNB
Pseudo-monas
Gut Anaerobes
Septra+
(+ MRSA)- - + + - -
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Primary Site of Infection
Image: http://en.wikipedia.org/wiki/Commons:File:Human_body_features.svg
Respiratory tract infection
Intra-abdominal
Urinary Tract
Skin & Soft Tissue Infection
Other
Unknown Origin
CVC / Line infection
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Clostridium difficile infection
Mild-moderate
Severe• Cr 1.5 times• WBC ≥ 15
Severe, uncomplicated
Severe, complicated• Ileus,
megacolon• Hypotension/ shock
Metronidazole PO Vancomycin PO
(+ consider rectal vancomycin if ileus)
(+ consider rectal vancomycin if ileus)
Vancomycin PO
+ Metronidazole IVSTOP unnecessary
antibiotics!
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METRONIDAZOLE
Mechanism of Action
Deactivation of cysteine bearing enzymes, binds to proteins and DNA
Uses • Intra-abdominal Infections• C. difficile infections
Standard Dosing
• 500 mg IV/po q12h • C. difficile: 500 mg IV/po q8h
Common Side Effects
• Peripheral neuropathy• Disulfiram like-reaction
Cautions/ Contra-indications
• Long-term use (> 1 month)
Spectrum Staph.(MSSA)
Strep. Enter.faecalis
GNB ExpandedGNB
Pseudo-monas
Gut Anaerobes
Metronidazole - - - - - - + (C.diff +)
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“What about allergies?”
V. Allergies67
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“Allergies”
I’m allergic to…
Side Effect Intolerance Drug Allergy
NauseaVomitingDiarrhea
HyperkalemiaBradycardia
Rash / HivesSOB
Anaphylaxis
Consider: Who is reporting the reaction
Timeframe (child vs. adult)Nature of reaction
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-Lactam Allergy
Penicillins Cephalosporins Carbapenems
Cloxacillin Cefazolin Meropenem
Ampicillin / Amoxicillin Ceftriaxone Imipenem
Piperacillin-tazobactam Ceftazidime Ertapenem
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•Non-pruritic morbilliform & macupaular rash (amoxicillin)
• Idiopathic, not a contraindication to repeat•Penicillins & Cephalosporins: 8-10% (1970’s) – Flawed studies
• Depends on side chains• Cefazolin not expected to cross react
with any penicillin or cephalosporin• Penicillins & Carbapenems ~1%
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“Is the dose correct?”
“When do I do a drug level?”
VI. Dosing & Monitoring70
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Drug Dosing
Consider
Age
Renal Dysfunction
Drug LevelsAdverse Effects
Indication / Severity
Drug Interactions
Liver Dysfunction
Weight
Serum creatinine, BUN, urine output, dehydration, acute versus chronic, dialysis modality
Cannot always use a cookie
cutter approach
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Therapeutic Drug Monitoring
• Guide and monitor dosing changes
• Evaluate efficacy and toxicity
• To assess penetration into body fluids (sites of infection)
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• Levels are typically done after 3 doses, with the 4th dose• Will be at steady-state equilibrium
Drug Levels
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Drug Levels
Stable PatientUnstable Patient
Renal Failure
Wait until steady state(With the 4th dose)
Check levels earlierCheck more frequently
Talk to Pharmacist
First
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Outline
I. Microbiology Review
II. General Considerations
III. Antibiotic Options
IV. Clinical Applications
V. Allergies
VI. Dosing & Monitoring
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Thank you!
Questions?
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