Antimicrobial Antimicrobial DrugsDrugs

(the stuff Dr. Figueroa didn’t tell you (the stuff Dr. Figueroa didn’t tell you about in MIP)about in MIP)

Jeffery A. Hobden, Ph.D.Jeffery A. Hobden, Ph.D.

Wonder DrugsWonder Drugs• Decreased morbidity Decreased morbidity

and mortality in US and mortality in US after WWII from after WWII from infectious diseasesinfectious diseases

• Made practical some Made practical some areas of medicineareas of medicine• Cancer chemotherapyCancer chemotherapy• Gut surgeryGut surgery

• Increased productivity Increased productivity in agriculturein agriculture

Antibiotics - ExploitedAntibiotics - Exploited

• In 2007, two antibiotics In 2007, two antibiotics were in the top 20 drugs were in the top 20 drugs prescribed in the USprescribed in the US• Amoxicillin – 34,801,000Amoxicillin – 34,801,000• Azithromycin – Azithromycin –

23,782,00023,782,000

• In 2000, 24 million In 2000, 24 million pounds of antibiotics pounds of antibiotics were used in agriculture were used in agriculture (chickens, pigs, cattle, (chickens, pigs, cattle, etc) vs. 3 million pounds etc) vs. 3 million pounds used to treat sick used to treat sick humanshumans

• Unrestricted accessUnrestricted access

Top 20 Prescribed Top 20 Prescribed DrugsDrugs

Tainted SeafoodTainted Seafood• Chinese seafood Chinese seafood

tested between tested between 10/06 and 05/07 10/06 and 05/07 were repeatedly were repeatedly positive forpositive for• NitrofuranNitrofuran• Malachite greenMalachite green• FluoroquinolonesFluoroquinolones

• Shipments banned Shipments banned from entering USfrom entering US

• Buy only local Buy only local seafood!seafood!

Alabama officials hold a press Alabama officials hold a press conference – “Drugs in your seafood conference – “Drugs in your seafood are bad, M’Kay?are bad, M’Kay?

The ConsequencesThe Consequences

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

Can’t we just get more?Can’t we just get more?

• Screening natural or Screening natural or synthetic synthetic compounds for compounds for antibacterial activityantibacterial activity

• Preclinical studies Preclinical studies (animals)(animals)• Safety (what is safe for Safety (what is safe for

animals may not be true animals may not be true for humans)for humans)

• Efficacy Efficacy (pharmacological (pharmacological parameters are different parameters are different in animals)in animals)

Wait – there’s more…Wait – there’s more…

• Clinical studies (humans)Clinical studies (humans)• Phase 1 – short term studies in small number of Phase 1 – short term studies in small number of

healthy humans or patients with target disease, healthy humans or patients with target disease, to determine metabolism and basic to determine metabolism and basic pharmacologic and toxicological properties of pharmacologic and toxicological properties of antibioticantibiotic

• Phase 2 – first controlled clinical studies to Phase 2 – first controlled clinical studies to assess the effectiveness of the antibiotic and to assess the effectiveness of the antibiotic and to determine short-term side effects and risks.determine short-term side effects and risks.

• Phase 3 – expanded controlled and uncontrolled Phase 3 – expanded controlled and uncontrolled clinical studies to gather data regarding benefit clinical studies to gather data regarding benefit – risk relationship. – risk relationship.

• Phase 4 – Phase 4 – marketing!marketing!

Is it any wonder?Is it any wonder?

• Antibiotics are big Antibiotics are big businessbusiness for pharmfor pharm• FreebiesFreebies• AdvertisingAdvertising• SponsorshipsSponsorships

• Not as profitable Not as profitable as drugs for as drugs for erectile erectile dysfunction, dysfunction, cholesterol cholesterol control, anxiety control, anxiety attacks, etc.attacks, etc.

After MIP, what else is After MIP, what else is there to know about there to know about

antibiotics?antibiotics?•What’s the origin of that antibiotic?What’s the origin of that antibiotic?•What’s special about it’s What’s special about it’s

chemistry?chemistry?•What happens to it after its in my What happens to it after its in my

body?body?•Will it kill or maim me if I take it?Will it kill or maim me if I take it?

Classification of Classification of AntibioticsAntibiotics

by Mechanism of Actionby Mechanism of Action• Inhibition of cell Inhibition of cell

wall synthesiswall synthesis• Beta-lactam Beta-lactam

drugsdrugs• PenicillinsPenicillins• CephalosporinsCephalosporins• CarbapenemsCarbapenems

• The othersThe others• CycloserineCycloserine• VancomycinVancomycin• bacitracinbacitracin

Classification of Classification of AntibioticsAntibiotics

by Mechanism of Actionby Mechanism of Action

• Disruption of Disruption of cell cell membranesmembranes• PolymyxinPolymyxin• Polyenes (anti-Polyenes (anti-

fungal agentsfungal agents))

Classification of Classification of AntibioticsAntibiotics

by Mechanism of Actionby Mechanism of Action• Inhibition of protein synthesisInhibition of protein synthesis

• Reversible inhibition (bacteristatic)Reversible inhibition (bacteristatic)• ChloramphenicolChloramphenicol• The tetracyclinesThe tetracyclines• The macrolides (erythromycin)The macrolides (erythromycin)• ClindamycinClindamycin• StreptograminsStreptogramins• LinezolidLinezolid

• Irreversible – the bactericidal Irreversible – the bactericidal aminoglycosidesaminoglycosides

Susceptibility and Susceptibility and ResistanceResistance

• In vitroIn vitro values are values are guides, not rulesguides, not rules

• In vivoIn vivo, bug is resistant , bug is resistant if cidal concentrations if cidal concentrations are toxic to the hostare toxic to the host

• Achievable serum Achievable serum concentrations are what concentrations are what determine susceptibility determine susceptibility or resistance to drugor resistance to drug• Low pH, high protein Low pH, high protein

concentrations, anoxiaconcentrations, anoxia• Pharmacological Pharmacological

parameters of drugs parameters of drugs (serum versus other (serum versus other bodily fluids)bodily fluids)

Bacterial Mechanisms Bacterial Mechanisms of Resistanceof Resistance

• Prevent Prevent antibiotic from antibiotic from reaching its reaching its targettarget

• Destroy or Destroy or inactivate inactivate antibiotic before antibiotic before it reaches targetit reaches target

• Alter target Alter target

Choosing the right Choosing the right antibiotic – is it really antibiotic – is it really

needed?needed?• Nature of the illness – is it a Nature of the illness – is it a

bacterial infection or something bacterial infection or something else?else?

• Presumptive diagnosis (based on Presumptive diagnosis (based on history and clinical symptoms) history and clinical symptoms) says yes!says yes!• Empiric therapy – broad spectrum Empiric therapy – broad spectrum

drugdrug• Specific therapy – narrow spectrumSpecific therapy – narrow spectrum

Choosing the right Choosing the right antibiotic – antibiotic –

pharmacokinetic pharmacokinetic considerations.considerations.• Location of infectionLocation of infection

• Some antibiotics may or may not Some antibiotics may or may not reach therapeutic concentrations reach therapeutic concentrations in certain bodily fluids (ex. CSF in certain bodily fluids (ex. CSF and urine)and urine)

• Degree to which antibiotic binds Degree to which antibiotic binds serum proteinsserum proteins• Excessive binding will affect Excessive binding will affect

passive diffusion of antibiotic from passive diffusion of antibiotic from serum to tissueserum to tissue

Choosing the right Choosing the right antibiotic – host factors.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 Local environment of infected site (pus, foreign

bodies, etc)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 Choosing the right antibiotic – host factors.antibiotic – host factors.

• drug allergiesdrug allergies• RashesRashes• AnaphylaxisAnaphylaxis

• Co-morbid Co-morbid conditions are conditions are aggravated by aggravated by some antibioticssome antibiotics• SeizuresSeizures• Blood disordersBlood disorders

SJS SJS SyndromeSyndrome

First up….First up….

• The The sulfonamidessulfonamides

• The quinolonesThe quinolones• The beta-The beta-

lactamslactams• PenicillinsPenicillins• CephalosporinsCephalosporins• CarbapenemsCarbapenems

Looking a-Looking a-head….head….