Antimicrobial Drugs (the stuff Dr. Figueroa didn’t tell you about in MIP) Jeffery A. Hobden, Ph.D.

Wonder Drugs Decreased morbidity and mortality in US after WWII from infectious diseases Decreased morbidity and mortality in US after WWII from infectious diseases Made practical some areas of medicine Made practical some areas of medicine Cancer chemotherapy Cancer chemotherapy Gut surgery Gut surgery Increased productivity in agriculture Increased productivity in agriculture

Antibiotics - Exploited In 2007, two antibiotics were in the top 20 drugs prescribed in the US In 2007, two antibiotics were in the top 20 drugs prescribed in the US Amoxicillin – 34,801,000 Amoxicillin – 34,801,000 Azithromycin – 23,782,000 Azithromycin – 23,782,000 In 2000, 24 million pounds of antibiotics were used in agriculture (chickens, pigs, cattle, etc) vs. 3 million pounds used to treat sick humans In 2000, 24 million pounds of antibiotics were used in agriculture (chickens, pigs, cattle, etc) vs. 3 million pounds used to treat sick humans Unrestricted access Unrestricted access

Top 20 Prescribed Drugs

Tainted Seafood Chinese seafood tested between 10/06 and 05/07 were repeatedly positive for Chinese seafood tested between 10/06 and 05/07 were repeatedly positive for Nitrofuran Nitrofuran Malachite green Malachite green Fluoroquinolones Fluoroquinolones Shipments banned from entering US Shipments banned from entering US Buy only local seafood! Buy only local seafood! Alabama officials hold a press conference – “Drugs in your seafood are bad, M’Kay?

The Consequences “That which does not kill us makes us stronger.” - Friedrich Nietzsche

Can’t we just get more? Screening natural or synthetic compounds for antibacterial activity Screening natural or synthetic compounds for antibacterial activity Preclinical studies (animals) Preclinical studies (animals) Safety (what is safe for animals may not be true for humans) Safety (what is safe for animals may not be true for humans) Efficacy (pharmacological parameters are different in animals) Efficacy (pharmacological parameters are different in animals)

Wait – there’s more… Clinical studies (humans) Clinical studies (humans) Phase 1 – short term studies in small number of healthy humans or patients with target disease, to determine metabolism and basic pharmacologic and toxicological properties of antibiotic Phase 1 – short term studies in small number of healthy humans or patients with target disease, to determine metabolism and basic pharmacologic and toxicological properties of antibiotic Phase 2 – first controlled clinical studies to assess the effectiveness of the antibiotic and to determine short-term side effects and risks. Phase 2 – first controlled clinical studies to assess the effectiveness of the antibiotic and to determine short-term side effects and risks. Phase 3 – expanded controlled and uncontrolled clinical studies to gather data regarding benefit – risk relationship. Phase 3 – expanded controlled and uncontrolled clinical studies to gather data regarding benefit – risk relationship. Phase 4 – marketing! Phase 4 – marketing!

Is it any wonder? Antibiotics are big businessfor pharm Antibiotics are big businessfor pharm Freebies Advertising Sponsorships Not as profitable as drugs for erectile dysfunction, cholesterol control, anxiety attacks, etc. Not as profitable as drugs for erectile dysfunction, cholesterol control, anxiety attacks, etc.

After MIP, what else is there to know about antibiotics? What’s the origin of that antibiotic? What’s the origin of that antibiotic? What’s special about it’s chemistry? What’s special about it’s chemistry? What happens to it after its in my body? What happens to it after its in my body? Will it kill or maim me if I take it? Will it kill or maim me if I take it?

Classification of Antibiotics by Mechanism of Action Inhibition of cell wall synthesis Inhibition of cell wall synthesis Beta-lactam drugs Beta-lactam drugs Penicillins Penicillins Cephalosporins Cephalosporins Carbapenems Carbapenems The others The others Cycloserine Cycloserine Vancomycin Vancomycin bacitracin bacitracin

Classification of Antibiotics by Mechanism of Action Disruption of cell membranes Disruption of cell membranes Polymyxin Polymyxin Polyenes (anti- fungal agents ) Polyenes (anti- fungal agents )

Classification of Antibiotics by Mechanism of Action Inhibition of protein synthesis Inhibition of protein synthesis Reversible inhibition (bacteristatic) Reversible inhibition (bacteristatic) Chloramphenicol Chloramphenicol The tetracyclines The tetracyclines The macrolides (erythromycin) The macrolides (erythromycin) Clindamycin Clindamycin Streptogramins Streptogramins Linezolid Linezolid Irreversible – the bactericidal aminoglycosides Irreversible – the bactericidal aminoglycosides

Susceptibility and Resistance In vitro values are guides, not rules In vitro values are guides, not rules In vivo, bug is resistant if cidal concentrations are toxic to the host In vivo, bug is resistant if cidal concentrations are toxic to the host Achievable serum concentrations are what determine susceptibility or resistance to drug Achievable serum concentrations are what determine susceptibility or resistance to drug Low pH, high protein concentrations, anoxia Low pH, high protein concentrations, anoxia Pharmacological parameters of drugs (serum versus other bodily fluids) Pharmacological parameters of drugs (serum versus other bodily fluids)

Bacterial Mechanisms of Resistance Prevent antibiotic from reaching its target Prevent antibiotic from reaching its target Destroy or inactivate antibiotic before it reaches target Destroy or inactivate antibiotic before it reaches target Alter target Alter target

Choosing the right antibiotic – is it really needed? Nature of the illness – is it a bacterial infection or something else? Nature of the illness – is it a bacterial infection or something else? Presumptive diagnosis (based on history and clinical symptoms) says yes! Presumptive diagnosis (based on history and clinical symptoms) says yes! Empiric therapy – broad spectrum drug Empiric therapy – broad spectrum drug Specific therapy – narrow spectrum Specific therapy – narrow spectrum

Choosing the right antibiotic – pharmacokinetic considerations. Location of infection Location of infection Some antibiotics may or may not reach therapeutic concentrations in certain bodily fluids (ex. CSF and urine) Some antibiotics may or may not reach therapeutic concentrations in certain bodily fluids (ex. CSF and urine) Degree to which antibiotic binds serum proteins Degree to which antibiotic binds serum proteins Excessive binding will affect passive diffusion of antibiotic from serum to tissue Excessive binding will affect passive diffusion of antibiotic from serum to tissue

Choosing the right antibiotic – host factors. Status of host immune system (cidal vs. static) Status of host immune system (cidal vs. static) Local environment of infected site (pus, foreign bodies, etc) Local environment of infected site (pus, foreign bodies, etc) Age (organ function in newborns and elderly) Age (organ function in newborns and elderly) Inherited metabolic disorder Inherited metabolic disorder Pregnancy (fetal or neonatal development) Pregnancy (fetal or neonatal development)

Choosing the right antibiotic – host factors. drug allergies drug allergies Rashes Rashes Anaphylaxis Anaphylaxis Co-morbid conditions are aggravated by some antibiotics Co-morbid conditions are aggravated by some antibiotics Seizures Seizures Blood disorders Blood disorders SJS Syndrome

First up…. The sulfonamides The sulfonamides The quinolones The quinolones The beta-lactams The beta-lactams Penicillins Cephalosporins Carbapenems Looking a-head….