“Emerging infections, the re-emergence
of infectious diseases previously
considered to be under control, and
the alarming trend of antibiotic
resistance….require an immediate and
appropriate response.”
Dr. Gail Cassell, Past President,
American Society of Microbiology, May 1994
Mechanisms of Resistance
• Decreased membrane permeability
( Gram negatives only; also need
another mechanism to be significant)
• Enzymatic Inactivation of
Antimicrobial
• Target Site Alteration or Bypass
• Efflux Pumps
Mechanisms Of Resistance
Expressed In Military Terms
•
•
•
•
Armour
Antiballistic Missiles
Diversion & Camouflage
Hand to Hand Combat
Altered Membrane Permeability
Outer
Membrane
Protein
b-Lactam
Antibiotic
Porin
Inner
Membrane
b-LACTAMASE HYDROLYSIS
Penicillins
Cephalosporins
Adapted from Denver LA, Dermody TS. Arch Intern Med. 1991
Action of Aminoglycoside
- Inactivating Enzymes
OH OH OH
I
I
I
-OH HO-P-O-P-O-P-O-adenosine
II
II
II
O O O
OH
I
OH OH
I
I
-O-P-OH  HO-P-O-P-O-adenoside
II
II
II
O
O O
phosphorylation
OH
I
OH OH
I
I
-O-P-O-adenosine  OH-P-O-P-OH
II
II
II
O
O
O
adenylation
-NH  CH -C-S-coenzyme A
2
3 II
O
-NH -C-CH  HS-coenzyme A
3
II
O
acetylation
Target Site Alteration
b-Lactam
Antibiotic
Altered Penicillin
Binding Protein
Porin
Inner
Membrane
Normal Penicillin
Binding Protein
Transmembrane Efflux
Pumps: Antimicrobials
• Tetracyclines
• Fluoroquinolones
• Macrolides
Antibiotic Resistance is a
function of:
Genetic variability and
environmental stimuli
S. pneumoniae Resistance
and Antibiotic Use *
• S. pneumoniae susceptibilities and antibiotic
use were studied in 37 counties in seven US
states
• Antibiotic use: defined as daily doses per
capita from IMS America data
• Counties with greater use of ß - lactams and
macrolides had significantly higher rates of
S. pneumoniae resistance to those agents
* Schwartz et al. ICAAC 1998
Summary of Resistance Development
During Antibiotic Treatment
Antimicrobial No. of
No. of
Development Therapeutic
agent
studies infections of Resistance
failures
Penicillins
6
174
9%
5%
Cephalosporins
9
373
9%
4%
Aminoglycoside
5
149
13 %
11 %
Imipenem
5
278
5%
3%
Ciprofloxacin
7
347
12 %
4%
Number of Organ Transplants,
United States, 1982-1994
20,000
16,000
12,000
8,000
4,000
0
‘82 ‘84 ’86 ‘88 ’90 ‘92 ‘94
YEAR
Penicillin-resistant S. pneumoniae
Canadian isolates 1988-2003
www.microbiology.mtsinai.on.ca.
Clinical Implications: PRSP
• Intermediate R: can overcome with
high doses of usual PO drugs, but
continue to select for higher levels of
resistance
• High Level R: Usual PO drugs fail,
need resp FQ, telithromycin or IV pen
Macrolide-resistant S. pneumoniae
Canadian isolates 1988-2003
www.microbiology.mtsinai.on.ca.
PK/PD Variables in
Selection of Resistance
• Potency: varies with class of
antimicrobial
• Primarily determined within a drug
class by level of free drug in serum
• Low potency favors selection of
resistant isolates
Concentration ( ug/ml )
Effect of Elimination Kinetics
on Bacterial Resistance
10.00
Clarithromycin
Azithromycin
1.00
Selective Window
0.1
MIC
0.01
MAC
0.001
0
1
2
3
4
5
Weeks
Longer half-life antibiotics may create a greater window
of opportunity for the development of resistance
Guggenbichler JP, Kastner H Infect Med 14 Suppl C: 17-25 (1997)
“I
want you to take one of these
with water every four years ”
Handwashing
• The most important method for
preventing the spread of infections
• ~70% of PRSP in US belong to seven
clonal groups
• Antimicrobial handwashing agents
- alcohol based handrinses
• Wash hands before and after:
- all patient contact
- contact with infective material
“….we have too many illusions
that we can… govern… the
microbes that remain our
competitors of last resort for
dominion of the planet.”
Lederberg J. JAMA 1988;260:684-5.
“….Pitted against microbial
genes, we have mainly
our wits.”
Joshua Lederberg, Ph.D. Nobel Laureate
JAMA 1996;276:418