Ch 14. Antimicrobial Drugs

sulfonamides (sulfa drugs)

discovered in the later 1920s by screening libraries of synthetic compounds

first broad spectrum treatment

sulfa drugs

• “magic” bulletin capable of treating many types of bacterial infections

• mass marketed by Bayer as “Prontosil” in 1932

• classified as an antimicrobial drug

• severe side effects in some patients (allergic reactions)

impact of sulfa drugs

cheap & widely available in the 1930s

• radically changed medicine & public health

  • widely used during WWII - reduced overall global mortality by ~3%

discovery of penicillin

• early work by Alexander Fleming focused on antisepsis

  • discovered lysozyme in tears, saliva, etc.

• 1928: when working with Staphylococcus, noticed contamination of colony of Penicillium mold inhibiting bacterial growth nearby

penicillin

true antibiotic; antibacterial agent - naturally occurring compound that kills microbes

• killed gram-positive, but not gram-negative bacteria

isolation of penicillin

• 1st findings discovered by Fleming in 1929, couldn’t purify

• 1938, Florey & Chain worked to isolate penicillin from mold

  • 1st clinical trial in 1941

• 1945: penicillin industrially produced for allied forces

golden age of antibiotic discovery

• global public health impacts cannot be overstated

• in US, mortality from infection plummeted

• discovery of penicillin launched search for more antibiotics

• streptomycin (treats Tb) discovered in 1945

• new classes of antibiotics discovered in ‘40s - ‘60s

chemotherapeutic

a chemical used to treat a disease

antimicrobial

a chemotherapeutic that kills (or inhibits growth of) microbes

antibiotic

an antimicrobial natural product, or derivative

semisynthetic antibiotic

modified derivative of a natural antibiotic

penicillin

natural product of Penicillium mold

• antibiotic

sulfonamides

not a natural product - are antimicrobial, but not antibiotics

amoxicillin & ampicillin

synthetic, modified derivative of penicillin - semisynthetic antibiotic

characteristics of antimicrobials

• selectively toxic

• therapeutic index/window

• broad/narrow spectrum

selectively toxic

are more toxic to pathogens than to host cells

• why antimicrobial are clinically useful

therapeutic index/window

difference between amount that is therapeutic vs amount that is toxic

• ex. bleach & rifamicin both kill E. coli,but only one is therapeutic

broad-spectrum

• targets a wide variety of bacteria

• useful to treat infections by more than one pathogen, or when pathogen is unknown

• may be used to prevent infections (ex. after surgery)

• may be used after a narrow-spectrum antibiotic fails

narrow spectrum

• targets a limited set of bacterial classes (ex. only gram-positive)

• may treat a specific infection without killing off the normal microbiome)

superinfection background info

• bacteria colonize most body surfaces, cavities, & digestive tract

• microbial community composition varies across the body

• a healthy, normal microbiome protects against some pathogens

• treatment with broad-spectrum antibiotics can kill most of protective microbiome → gives pathogens an opportunity to colonize host

superinfection

consequence of antibiotic treatment

1. normal microbiota keeps opportunistic pathogens in check

2. broad-spectrum antibiotics kill non resistant cells

3. drug-resistant pathogens proliferate & can cause a superinfection

*common with Clostridium in the gut

C. difficile

• opportunistic spore forming pathogen

• normally absent or present as a very minor component

• healthy microbiome keeps C. difficile in check, suppressing growth

• broad-spectrum antibiotics kill much of biome, reducing diversity → gives C. difficile opportunity to colonize GIT

• active infection is self-sustaining

  • takes over GI microbiome - antibiotic treatment cannot clear infections → C. difficile recolonizes GIT

fecal transplant

fecal transplantation from healthy patient can restore microbial balance & stop recurrent C. difficile. infection

• probiotics & transplants are emerging as possible treatments for other diseases: obesity, T2 diabetes, autoimmune disease, depression

bactericidal

kills bacteria

bacteriostatic

inhabits growth of bacteria

cidal vs static

• either may be successful in treating infection in a healthy patient

• bacteriostatic treatments block bacterial growth & rely on the immune system to fight off infection

• infections in immunocompromised patients - or infections in locations that are difficult for immune cells to access - may require bactericidal treatments

testing sensitivity to antimicrobials

• MIC: minimum inhibitory conc.

• MLC: minimum lethal conc.

treating susceptibility to different antimicrobials

• Kirby-Bauer disk diffusion test

  • impregnated filter disks

  • inhibition zone measured

  • diameter correlates with resistance or susceptibility

• plate-based assays to test MIC against multiple compounds at once