““Emerging infections, the re-emergence Emerging infections, the re-emergence of infectious diseases previously of infectious diseases previously

considered to be under control, and considered to be under control, and the alarming trend of antibiotic the alarming trend of antibiotic

resistance….require an immediate and resistance….require an immediate and appropriate response.”appropriate response.”

Dr. Gail Cassell, Past President,

American Society of Microbiology, May 1994

Mechanisms of ResistanceMechanisms 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 Mechanisms Of Resistance Expressed In Military TermsExpressed In Military Terms

• Armour

• Antiballistic Missiles

• Diversion & Camouflage

• Hand to Hand Combat

Altered Membrane Permeability

-LactamAntibiotic Porin

OuterMembrane

Protein

InnerMembrane

Penicillins

Adapted from Denver LA, Dermody TS. Arch Intern Med. 1991

-LACTAMASE HYDROLYSIS

Cephalosporins

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 OH OH I I I

-O-P-OH HO-P-O-P-O-adenoside II II II O O O phosphorylation

OH OH OH I I I

-O-P-O-adenosine OH-P-O-P-OH II II II O O O adenylation

-NH CH -C-S-coenzyme A II O

2 3-NH -C-CH HS-coenzyme A II O acetylation

3

Target Site Alteration

-LactamAntibiotic

InnerMembrane

Porin

Altered PenicillinBinding Protein

Normal PenicillinBinding Protein

Transmembrane Efflux Transmembrane Efflux Pumps: AntimicrobialsPumps: Antimicrobials

• Tetracyclines

• Fluoroquinolones

• Macrolides

Antibiotic Resistance is a Antibiotic Resistance is a function of:function of:

Genetic variability and environmental stimuli

S. pneumoniaeS. pneumoniae Resistance Resistance and Antibiotic Use *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

Antimicrobialagent

Penicillins

Cephalosporins

Aminoglycoside

Imipenem

Ciprofloxacin

No. ofstudies

6

9

5

5

7

No. ofinfections

174

373

149

278

347

Developmentof Resistance

9 %

9 %

13 %

5 %

12 %

Therapeuticfailures

5 %

4 %

11 %

3 %

4 %

Summary of Resistance Development Summary of Resistance Development During Antibiotic TreatmentDuring Antibiotic Treatment

‘82 ‘84 ’86 ‘88 ’90 ‘92 ‘94YEAR

20,000

16,000

12,000

8,000

4,000

0

Number of Organ Transplants,Number of Organ Transplants,United States, 1982-1994 United States, 1982-1994

Penicillin-resistantPenicillin-resistant S. pneumoniae S. pneumoniaeCanadian isolates 1988-2003Canadian isolates 1988-2003

www.microbiology.mtsinai.on.ca.

Clinical Implications: PRSPClinical 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 Macrolide-resistant S. pneumoniaeS. pneumoniae

Canadian isolates 1988-2003Canadian isolates 1988-2003

www.microbiology.mtsinai.on.ca.

PK/PD Variables in PK/PD Variables in Selection of ResistanceSelection 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

ClarithromycinClarithromycin AzithromycinAzithromycin

Selective Window

MAC

MIC

10.00

1.00

0.1

0.01

0.001

Co

nce

ntr

atio

n (

ug

/ml

)

0 1 2 3 4 5Weeks

Longer half-life antibiotics may create a greater windowof opportunity for the development of resistance

Guggenbichler JP, Kastner H Infect Med 14 Suppl C: 17-25 (1997)

Effect of Elimination KineticsEffect of Elimination Kineticson Bacterial Resistanceon Bacterial Resistance

“ I want you to take one of these with water every four years ”

HandwashingHandwashing• 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 .we have too many illusions

that we can… govern… the that we can… govern… the

microbes that remain our microbes that remain our

competitors of last resort for competitors of last resort for

dominion of the planet.”dominion of the planet.”

Lederberg J. JAMA 1988;260:684-5.

“…“….Pitted against microbial .Pitted against microbial

genes, we have mainly genes, we have mainly

our wits.”our wits.”

Joshua Lederberg, Ph.D. Nobel Laureate

JAMA 1996;276:418