Pharmacology of Antibacterial

and Antifungal Agents

Part I
Dana Whitney, Pharm.D., BCPS
Clinical Pharmacy Specialist Infectious Diseases
Boston Medical Center
dana.whitney@bmc.org

Learning Objectives
Recall the mechanisms of action, pharmacodynamic
and pharmacokinetic properties of the major classes
of antibiotics
Identify the representative spectrum for antibiotic
prototypes
Identify the adverse effects for the major antibiotic
classes
Describe common mechanisms of resistance to
antibiotics

Antibiotic prescriptions by dentists

represent what percentage of the total
volume of outpatient antibiotic
prescriptions?
A.
B.
C.
D.

50%
25%
10%
1%

Structure
Lecture I

Introduction
Cell wall synthesis inhibitors

Lecture II

Vancomycin
Protein synthesis inhibitors
Nucleic acid structure inhibitors

Lecture III

Antifolates
Antimycobacterials
Antifungal agents

Principles of Antibiotic Therapy

Treatment of infection

Empiric
based on most likely
microbes and their
probable susceptibility
Documented/definitive
by culture of microbes and
determination of
susceptibility to drugs

Prophylactic therapy to
prevent infection

Use the most narrow, least

toxic, most cost-effective
agent
Antibiotics aid the bodys
defenses in clearing the
infection

Eliminate the organism by

physical means (i.e. incision
and debridement)

Antibiotic Selection
Pathogen
Likely organisms
Susceptibility

Antibiotic
Factors
Spectrum
PK/PD
Adverse effects
Drug interactions
Cost

Host Factors
Age
Immune status
Renal and Hepatic function
Recent antibiotic exposure
Allergy/Intolerance
Disease severity
Pregnancy and Lactation

Pharmacokinetics (PK) of Antibiotics

PK describes what the

body does to the drug

A Absorption
D Distribution
Vd (__L/kg)

Lung Tissue

Hydrophobic v. hydrophilic
Molecular size
Polarity
Protein binding

M Metabolism
E Elimination
Half life (t )

CNS

Serum
Fat

Urine
Muscle
Bone/Joints

Pharmacodynamics (PD) of Antibiotics

PD

describes what the drug does to the body [or

microorganism]

Describes antimicrobial effect

Bactericidal
Bacteriostatic
Post antibiotic effect (PAE)
PD parameters:
Time dependent activity (T>MIC, AUC:MIC)
Concentration dependent activity (Cmax:MIC, AUC:MIC)

Bactericidal vs. Bacteriostatic

Log
Immune Assistance

Log
Bacteria

Static

Cidal
Time
Antibiotic

Cell wall
synthesis
inhibitors

Pharmacodynamics

Rybak M. Am J Med 2006;119:S37-44.

70 y/o woman with estimated

CrCl 30 ml/min, being treated for
peridontal abscess
Drug

A (concentration dependent) 250mg q12h

Drug A (concentration dependent) 500mg q24h
Drug

B (time dependent) 1g q4h

Drug B (time dependent) 2g q8h

Bactericidal

A.

Bacteriostatic

B.

Cmax:MIC

T>MIC

C.

D.

Concentration dependent
activity
Requires immune
assistance to clear
infection
Cell wall synthesis
inhibitors
Time dependent activity

Cell Wall Synthesis Inhibitors

Penicillins

Beta lactamase inhibitor combinations

Cephalosporins
Carbapenems

Vancomycin

Beta lactams

Mechanism of Action

Inhibits PBPs

Involved in the cross linkage of peptide chains

Prevents the development of normal peptidoglycan structure

Cell lysis

Osmotic pressure or activation of endogenous autolysins

Basic beta-lactam structure

Manipulations of side chain alter spectrum, susceptibility and

pharmacokinetic properties
Goal:
Rapidly bactericidal, nontoxic, bioavailable, resistant to degradation,
high affinity for PBPs

Penicillins

Cephalosporins

Carbapenems

Penicillins (spectrum)
Narrow spectrum

MSSA

Natural PCNs:
penicillin VK
Penicillinase
resistant PCNs

Aminopenicillins:
amoxicillin
Amoxicillin/
clavulanic acid
CarboxyPCNs,
ureidoPCNs
Broader Spectrum

streptococci

S. pneumoniae
H. influenzae

Enteric Gram
neg. (E.coli,
Klebsiella,
Proteus)

anaerobes
G+ only

G+ only

G+ only

G+ only

Average MIC

Penicillin and amoxicillin: PK

Absorption

Good penetration into most tissues, except prostate, eye,

and uninflamed CSF
Primarily excreted by kidneys

Adjust with moderate-severe renal impairment

In general, shorter half-life than most antimicrobials

Difficult to achieve high serum concentrations with PO formulations

Amoxicillin > penicillin

Amoxicillin > penicillin

Probenecid blocks renal excretion and causes increased

serum levels of penicillin

PK
F%

Protein Time to Peak

Time to
binding Peak
(mcg/mL) Trough
%
(hr)
(hr)

Pencillin G IV

--

50

0.5-1

25-50

4-6

Penicillin VK

60

80

2.5-5

Penicillin G procaine

--

50

2-4

10

12

Penicillin G benzathine --

50

24-48

0.2

3-4 wks

Ampicillin IV

--

20

0.5-1

25-50

Amoxicillin

75-90 20

7-10

6-8

Penicillins (Adverse effects)

Hypersensitivity

(1-10%)

Anaphylaxis (0.004 to 0.015%)

Cross-reactivity with cephalosporins: 5-10%

Phlebitis

(1-10%)
GI disturbances (1-10%)
Hematologic (<1%)
Electrolyte disturbances (<1%)
Neurologic (<1%)
Renal (interstitial nephritis) (<1%)

Case AB
45

y/o male with recent aortic valve replacement.

Cardiologist instructs him to call you prior to his
next dental appointment for a prescription for
antibiotics.

What type of therapy is this?

American Heart Association Guidelines for

the Prevention of Infective Endocarditis (IE)

Prophylaxis is recommended for dental procedures that

involve:
Manipulation of gingival tissues or periapical region of
teeth
Perforation of oral mucosa
Prophylaxis is only for patients with:
Underlying cardiac conditions associated with the
highest risk of adverse outcome from IE

Circulation. 2007;115

Underlying cardiac conditions

associated with the highest risk
Prosthetic cardiac valve
Prior history of infective endocarditis
Congenital heart disease (CHD)

Unrepaired cyanotic CHD

Completely repaired, during the first 6 months after the
procedure
Repaired CHD with residual defects

Cardiac transplantation recipients who develop cardiac

valvulopathy

Circulation. 2007;115

Recommended Regimens

Coverage of Streptococcus viridans

Oral regimens: 1 hour prior to procedure
IV regimens: 30 min prior to procedure

Standard general prophylaxis

Amoxicillin 2gm PO

Unable to take oral medications

Ampicillin 2gm IM or IV

Allergic to penicillin

Clindamycin 600mg PO
Cephalexin 2gm PO*
Azithromycin 500mg PO
Clarithromycin 500mg PO

Allergic to penicillin and unable to take oral

medications

Clindamycin 600mg IV
Cefazolin 1gm IV*
Ceftriaxone 1gm IV*

* should not be used in individuals with immediate-type hypersensitivity reaction (urticaria,

angioedema, or anaphylaxis) to penicillins
Circulation. 2007;115

Case AB
45

y/o male with recent aortic valve replacement.

Which prophylactic antibiotic should be given?

What should be considered prior to writing the

prescription?

Amoxicillin 2 g PO x 1 (take 1 hour prior to procedure)

Allergies if allergic to PCN, assess allergy and consider

alternatives

Which adverse effects should he be made aware of?

Antimicrobial Resistance

Intrinsic characteristics of the drug prevent reaching the

target site or the drug is inactivated

Acquired resistance which develops (horizontally or

vertically)

Mechanisms

Drug cannot reach the target site

Drug is inactivated
Target site is altered

Resistance to beta-lactam Antibiotics

Drug

is inactivated - beta-lactamases

Beta Lactamase Inhibitors

Clavulanic acid

Compounded with some

penicillins
Binds to beta lactamase,
prevents the destruction of
the parent drug
Enhances the spectrum of
the parent drug if the
decreased activity is a result
of beta-lactamases

*Augmentin = amoxicillin + clavulanic acid

Penicillins

Cephalosporins

Cephalosporins (spectrum)
Narrow spectrum

S. pneumoniae
H. influenzae

Enteric Gram
neg. (E.coli,
Klebsiella,
Proteus)

MSSA

streptococci

1st generation:
cephalexin

2nd generation

2nd generation:
cephamycins

3rd generation:
cefpodoxime

4th generation

Broader Spectrum

anaerobes

Cephalosporins

Pharmacokinetics

Absorption
IV for severe infections
PO for mild/moderate
infections
Distribution
Similar to penicillins
Metabolism
Excretion
renal

Adverse Effects

Generally well tolerated

GI disturbances (1-10%)
Phlebitis (1-10%)
Hypersensitivity (< 1%)
Hematologic (< 1%)
Renal (< 1%)
Neurotoxicity (< 1%)

Resistance to beta-lactam Antibiotics

Drug

is inactivated - beta-lactamases

Penicillinases
Cephalosporinases
Extended spectrum beta lactamases (ESBLs)

Drug

cannot reach the target site - alterations in

membrane permeability or efflux
Target site is altered - alterations in PBP

Penicillin resistant S. pneumoniae (PRSP)

Methicillin resistant S. aureus (MRSA)

Carbapenems

Mechanism of action: similar to PCNs

Broad spectrum agent - reserved as last line for
resistant organisms

Pharmacokinetics

Gram positive, gram negative, anaerobes

IV only
Good distribution
Renally excreted - requires dose adjustment in patients with
renal dysfunction

Adverse effects

Hypersensitivity, seizures (caution in patients with seizure

history or renal disease)

Which of the following is true of

beta lactam agents?
a)
b)

c)
d)

e)

Primarily bacteriostatic
Common mechanisms of resistance include enzymatic
inactivation, altered target sites
Intravenous and oral formulations are equally bioavailable
Responsible for many drug drug interactions due to
inhibition of CYP 450, isoenzyme 3A4
Antibacterial activity is concentration dependent (higher
peaks have greater antibacterial activity

Summary
cell wall synthesis inhibitors
beta lactams
Penicillins

(penicillin, amoxicillin)
Cephalosporins

cephalexin
cefpodoxime

Carbapenems