“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  -Lactam Antibiotic Porin Outer Membrane Protein Inner Membrane

Penicillins Adapted from Denver LA, Dermody TS. Arch Intern Med  -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  -Lactam Antibiotic Inner Membrane Porin Altered Penicillin Binding Protein 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

Antimicrobial agent Penicillins Cephalosporins Aminoglycoside Imipenem Ciprofloxacin No. of studies No. of infections Development of Resistance 9 % 13 % 5 % 12 % Therapeutic failures 5 % 4 % 11 % 3 % 4 % Summary of Resistance Development During Antibiotic Treatment

‘82 ‘84 ’86 ‘88 ’90 ‘92 ‘94 YEAR 20,000 16,000 12,000 8,000 4,000 0 Number of Organ Transplants, United States,

Penicillin-resistant S. pneumoniae Canadian isolates

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

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

Clarithromycin Azithromycin Selective Window MAC MIC Concentration ( ug/ml ) 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: (1997) Effect of Elimination Kinetics on Bacterial Resistance

“ 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