Antimicrobial Drugs II

Dental Pharmacology (PHCL 5-103)

April 8, 2008

Hiroshi Hiasa, Ph.D.

Office: 3-117 NHH
Tel. 626-3101
hiasa001@umn.edu

3. Antimicrobial agents used today

Category a. Inhibition of cell wall synthesis
penicillins, cephalosporins, vancomycin

Penicillins
cephalosporins

vancomycin

A. Penicillins and penicillinase inhibitors

First antibiotic to be identified and used in
clinics
(1) Chemical structure - All penicillins are -lactams
(2) Mechanism and spectrum of action
a. Bactericidal agent
Interferes with cell wall
synthesis by inhibiting
transpeptidase
b. Spectrum
Differs with types

(3) Drug resistance

a. -lactamase (penicillinase) inactivates drugs
Carried on plasmids
b. A major problem
>95% of hospital Staphylococci are
resistant to Penicillin G

(4) Adverse reactions

a. Allergy
Rash accounts for most of the reactions
Anaphylactic shock
100-300 deaths per year
b. Toxicity
Essentially non-toxic at most dosages
c. GI effect
Nausea, vomiting, and diarrhea

(5) Types and features

a. Penicillin G
Effective against Gram-positive bacteria
Ineffective against Gram-negative bacteria
b. Penicillin V
Not suitable for serious infections
c. Penicillins resistant to -lactamase
(i) Methicillin, Nafcillin, Oxacillin
(ii) For use against penicillinase producing
Staphylococci
(iii) In general, less effective against non-penicillinase
producers
(iv) Produce more side effects
(v) Emerging problem
Methicillin-resistant Staphylococcus aureus (MRSA)

d. Extended spectrum penicillins

(i) Ampicillin-like
Ampicillin, Amoxicillin, Cyclacillin, Bacampicillin
Effective against Gram-negatives and bacilli
E. coli, H. influenzae, Salmonella, Shigella
(ii) Carbenicillin-like
Carbenicillin, Ticarcillin, Piperacillin, Azocillin
Not penicillinase resistant
Reserved for serious infections - Pseudomonas
e. -lactamse inhibitor
Clavulanic acid, sulbactam, tazobactam
Synergistic when used with Amoxicillin

B. Cephalosporins
(1) Mechanism and spectrum of action
a. Inhibitors of cell wall synthesis
b. Active against most Gram-positive cocci and
penicillinase producing Staph
c. Effective against some Gram-negatives
such as, E.coli, Klebsiella, H. Influenzae, and
Salmonella
(2) Bacterial resistance
Cephalosporinase inactivates
(3) Types
a. Cefazolin, Cephalexin, Cephalothin, Cephradine
b. Cefaclor, Cefamandole, Cefonacid
c. Cefoperazone, Cefotaxime, Cefazidime

C. Vancomycin
(1) Pharmacology and chemistry
Glycopeptide isolated from Streptomyces orientalis
(2) Mechanism and spectrum of action
a. Inhibits cell wall synthesis
Interferes with peptidoglycan synthesis
b. Bactericidal with narrow spectrum
Gram-positive cocci (Staph and Strep)
c. Resistance was rare, but emerging
BIG PROBLEM TODAY
(3) Adverse reactions are infrequent
(4) Clinical uses
Reserved for serious, life threatening infections in
hospital setting

Category c. Inhibition of protein synthesis (ribosome)

aminoglycosides, macrolides, tetracyclines,
clindamycin, chloramphenicol

D. Aminoglycosides
Streptomycin, Amikacin, Neomycin, Kanamycin,
Gentamicin
(1) Pharmacology and chemistry
Bactericidal drugs
(2) Mechanism and spectrum of action
a. Interfere with bacterial protein synthesis
Bind to 30S subunit
b. Most useful against aerobic Gram-negative
infections which dont respond to other agents
(3) Clinical uses
Usually reserved for serious Gram-negatives in
hospital setting

E. Macrolides
Erythromycin, Clarithromycin
(1) Mechanism and spectrum of action
a. Generally bacteriostatic, can be bactericidal
b. Protein synthesis inhibitor
Binds to bacterial the P site of the 50S subunit
Other antimicrobials, such as chloramphenicol
and clindamycin,bind to same site
antagonism and cross-resistance
c. Spectrum
Many Gram-positives and some Gram-negatives
(2) Bacterial resistance
Modification of adenine residue within ribosome
(3) Clinical uses
To replace penicillin in sensitive patients

F. Tetracyclines
(1) Mechanism and spectrum of action
Bacteriostatic
Interferes with protein synthesis
Prevent tRNA from associating with ribosome
Broad spectrum
Against both Gram-negatives and Gram-positives
(2) Bacterial resistance
Develops slowly - reduced uptake
(3) Adverse reactions
a. GI effects not uncommon
Pseudomembranous colitis
b. Teeth and bones
Is incorporated into calcifying structures
Avoid use in children

G. Clindamycin
(1) Mechanism and spectrum of action
a. Bacteriostatic (may be bactericidal at high dose)
b. Inhibits protein synthesis
Binds to 50S subunit
c. Spectrum
Many Gram-positives and some Gram-negatives
Similar to erythromycin
(2) Bacterial resistance
Altered bacterial ribosomal structures
(3) Clinical uses
Best reserved for treatment of anaerobes when
penicillin is contraindicated

H. Chloramphenicol
(1) Spectrum and action
a. Bacteriostatic
b. Inhibits protein synthesis
Binds to 50S subunit
c. Broad spectrum
Gram-positives and Gram-negatives including
Salmonella
(2) Bacterial resistance
Altered bacterial ribosomal structures
(3) Adverse reactions
Can cause bone marrow suppression
(4) Clinical uses
Reserved for dangerous infections when other
antimicrobials are ineffective

Category d. Inhibition of nucleic acids synthesis

(i) Inhibition of DNA replication
(bacterial topoisomerases =
DNA gyrase & topoisomerase IV)
ciprofloxacin

I. Fluoroquinolones (Quinolones)
Ciprofloxacin, Norfloxacin
(1) Mechanism and spectrum of action
a. Target DNA gyrase and topoisomerase IV
Cause the Inhibition of DNA replication and
the generation of DNA breaks
b. Broad spectrum
Both Gram-positive and Gram-negative bacteria including
Pseudomonas
(2) Bacterial resistance
Rapid appearance of drug-resistant mutations
Genomic mutations in topoisomerase genes
(3) Adverse reactions
a. CNS
Headache, dizziness, tinnitus, insomnia, shakiness
b. Cartilage
Avoid use in children

Category d. Inhibition of nucleic acids synthesis

(ii) Transcription (RNA polymerase)
rifampicin

J. Rifampicin
(1) Mechanism of action
Inhibits bacterial RNA polymerase (transcription)
(2) Resistance
One-step resistance develops spontaneously
(3) Clinical uses
One of four drugs used for the treatment of tuberculosis
Essentially not useful in monotherapy.
Tuberculosis (TB)
1. About one-third of the
world's population are infected.
2. Each year about 2 million die.
3. Increased in the West including
US.
4. Deadly synergy with HIV.
5. Multidrug resistant strains.
[TB will not be in the exams]

Category e. Inhibition of folic acid metabolism

sulfonamides, trimethoprim
Human

Bacteria

Folate

PABA

Dietary
Intake

Dihydrofolic
Acid
Dihydrofolic Acid
Reductase

Folic Acid (THFA)

Dihydropteroate
Synthetase

Sulfonamides

Dihydrofolic
Acid
Dihydrofolic Acid
Reductase

Trimethoprim

Folic Acid (THFA)

K. Sulfonamides
(1) Mechanism of Action
a. Sulfonamides are structural analogs (competitive
inhibitors) of para-aminobenzoic acid (PABA), a
precursor in synthesis of folic acid.
b. Bacteriostatic
(2) Clinical uses
a. Urinary Tract Infections
b. Often used in combination therapy
First successful combination therapy

L. Trimethoprim
(1) Mechanism of action
a. A highly specific inhibitor of bacterial dihydrofolate
reductase
b. Usually bacteriostatic, but may be bactericidal
(2) Clinical uses
a. Urinary Tract Infections
b. Since this reaction is part of folate biosynthetic
pathway drug synergizes with sulfanilamides