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 Torontonorman.dewhurst@utoronto.ca

May 7th, 2014Evolutions Critical Care Conference

Knowledge is Power: An Antibiotic Overview to Maximize

Outcomes in the Critically Ill

1

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

2

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

3

4

Outline

I. Microbiology Review

II. General Considerations

III. Antibiotic Options

IV. Clinical Applications

V. Allergies

VI. Dosing & Monitoring

5

“How do microbiology reports help me treat a patient?”

I. Microbiology Review6

Microbiology Review

7

•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

Gram Staining

8

Gram Stain

Gram Positives Gram Negatives

Gram Positives (+)

9

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 ? ? ?

Gram Negatives (-)

10

Gram Negative

Bacilli(GNB)

Coccobacilli Diplococci

HaemophilusPasteurella

EnterobacteriaceaePseudomonas

NeisseriaMoraxella

Acinetobacter

FermenterEnterobacteriaceae

COLIFORM

FermenterEnterobacteriaceae

COLIFORM

Non-fermenterPseudomonas

StenotrophomonasGNB

Non-fermenterPseudomonas

StenotrophomonasGNB

10

Spectrum Staph.(MSSA)

Strep. Enter.faecalis

GNB ExpandedGNB

Pseudo-monas

Gut Anaerobes

Drug ? ? ?

“What do I need to consider before treatment?”

II. General Considerations11

12

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

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.

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.

16

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

17

18

Cultures before

treatment

ICU Treatment Principles

• Bactericidal

• High doses

• IntravenousSerious infection

• Non-toxic

Other Considerations

• Allergies

• Local antibiogram

• Is oral route feasible?

• IV to PO stepdown?

“What are my antibiotic options?”

III. Antibiotic Options21

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

Therapeutic Options

23

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

24

Therapeutic Options

25

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

Therapeutic Options

26

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

“How do I treat this?”

IV. Clinical Applications27

Staphylococcus aureus

• Gram positive

• Skin & soft tissue infections

• VAP

• Line infections

28

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

30

Staphylococcus aureus

Methicillin Sensitive S. aureus(MSSA)

Methicillin Resistant S. aureus(MRSA)

CloxacillinCefazolin

Vancomycin

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 + + - - - - -

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 - - - + + + -

-LactamsSide Effects • Hypersensitivity reactions

• Seizures• Antibiotic Associated Diarrhea

• Thrombocytopenia• C. difficile

Cautions/ Contraindications

• Allergy / anaphylaxis

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

35

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

Community Acquired Pneumonia

• S. pneumoniae

• S. aureus• Gram-negative bacilli• H. influenzae• Legionella species

37

Ceftriaxone

Azithromycin

Levofloxacin

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 + - - -

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 + + - + + - +

HAP/VAP

• S. pneumoniae

• S. aureus• Gram-negative bacilli• H. influenzae• Legionella species

• ? MRSA• ? Pseudomonas

40

Ceftriaxone

Azithromycin

Levofloxacin

Vancomycin

Anti-pseudomonal

HAP/VAP

< 5 days > 5 days

Pseudomonas coverage

Ceftriaxone

Levofloxacin

Vancomycin

? MRSA

Anti-Pseudmonal

42

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

Anti-Pseudomonal

43

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

Anti-Pseudomonal

44

Penicillins

Piperacillin

β-Lactamase Inhibitor

Tazobactam

Cephalosporins

Ceftazidime (3rd)

Carbapenems

Imipenem

Meropenem

Aminoglycosides

Tobramycin

Fluoroquinolones

CiprofloxacinHigh Resistance

NephrotoxicityOtotoxicity

Not empiric

Reserve Use

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 + + + + + + +

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 - - - + + ++ -

HAP/VAP

< 5 days > 5 days

Pseudomonas coverage

Ceftriaxone

Levofloxacin

Pip/Tazo

Ceftazidime

Vancomycin

? MRSA

Tobramycin

48

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

MDRs / “Super bugs”• MRSA

– Methicillin Resistant Staphylococcus aureus

• VRE– Vancomycin Resistant Enterococcus

• ESBL– Extended spectrum beta-lactamases

• CRE / CRP– Carbapenemase Resistant Enterobacteriaceae

50

51

WHO

IDSA

Resistance Alarms

The Antimicrobial Pipeline

www.antibiotic-action.com

54

ESBL Infections

Therapeutic Options

56

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

Therapeutic Options

57

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

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

MDRs / “Super bugs”• MRSA

– Methicillin Resistant Staphylococcus aureus

• VRE– Vancomycin Resistant Enterococcus

• ESBL– Extended spectrum beta-lactamases

• CRE [ CRP / KPC / NDM ]– Carbapenemase Resistant Enterobacteriaceae

59

CRE Infections

Therapeutic Options

61

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

62

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)- - + + - -

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

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!

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 +)

“What about allergies?”

V. Allergies67

“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

-Lactam Allergy

Penicillins Cephalosporins Carbapenems

Cloxacillin Cefazolin Meropenem

Ampicillin / Amoxicillin Ceftriaxone Imipenem

Piperacillin-tazobactam Ceftazidime Ertapenem

69

•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%

“Is the dose correct?”

“When do I do a drug level?”

VI. Dosing & Monitoring70

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

Mistakes happen

Therapeutic Drug Monitoring

• Guide and monitor dosing changes

• Evaluate efficacy and toxicity

• To assess penetration into body fluids (sites of infection)

73

• Levels are typically done after 3 doses, with the 4th dose• Will be at steady-state equilibrium

Drug Levels

75

76

Drug Levels

Stable PatientUnstable Patient

Renal Failure

Wait until steady state(With the 4th dose)

Check levels earlierCheck more frequently

Talk to Pharmacist

First

Outline

I. Microbiology Review

II. General Considerations

III. Antibiotic Options

IV. Clinical Applications

V. Allergies

VI. Dosing & Monitoring

77

Thank you!

Questions?

78

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