Mechanisms of Resistance: Penicillin/Cephalosporins

Detoxification by hydrolysis of  β-lactam ring by

  β-lactamase enzyme.   For β-lactamaseresistant   penicillins,altered PBPs that do not bind the penicllins.

Mechanism of Resistance: Tetracycline 

Interference with transport (efflux pump) 

Mechanism of Resistance: Chloramphenicol

Detoxification by acetylation of hydroxyl groups 

Mechanism of Resistance: Aminoglycosides

Enzymatic modification of drug; adenylation, phosphorylation, acetylation

Mechanism of Resistance: Sulfonamides/Trimethoprim

Drug resistant replacement enzyme

 (e.g. dihydrofolatereductase)

Mechanism of Resistance: Erythromycin/Lincomycin

Enzymatic modification (methylation) of 23S  ribosomal RNA

Mechanisms of Resistance: (Fluoro)quinolones (FQs)

How Do Bacteria Become Resistant?

Mutation or Inheritance

• Chromosomal Mutations
• For example, alteration of ribosomal protein to give streptomycin resistance
• Can be one step, high level resistance or multistep low-level increases.
• Generally, altered envelopes that prevent access into the cell or a change in target.
• Probably impart some growth disadvantage
• Single species, single parent
• 
  
• In nature, 
• inheritance plays a large role
• Multiresistant transfer
• Inter-species transfer
• Inter-genera transfer

Elements of Antibiotic Resistance

Plasmids

Insertion Sequences/Transposons

Integrons

Integron - genetic unit that includes genes of a site-specific recombination system capable of capturing and mobilizing genes contained in mobile elements called gene cassettes.

Genetic exchange: conjugation, transformation, transduction

Ways to Control Antibiotic Resistance

• Control, reduce, and cycle antibiotic usage; reduce time course?
•  Improve hygiene in hospitals and among hospital personnel andreduce movement of patients to reduce dissemination of resistantorganisms.  
• WASH YOUR HANDS!!!  Be extra vigilant if you are a carrier of antibiotic resistant Staph or others
• Generate new antibiotics
• Modify existing antibiotics to produce agents inert to known bacterial resistance mechanisms
• Maintain adequate drug levels/compliance
• Elimination of  antimicrobial agents from animal feeds
• Educate public and prescribers alike on prudent use- preserve
• Do NOT give antibiotics for viral infections (colds, most ear infections)
• Contain patients harboring resistant strains
• Limit foreign bodies (catheters, prosthetics, etc)
• Use appropriate prophylaxis (eg., surgery)

Proper diagnosis and treatment for an infection (misdiagnosis= wrong antibiotic)

Multiple Drug Resistance

• A plasmid, transposon, or integron carries genes  for resistance to several different antibiotics
• A single gene can encode a biochemical mechanism that results in resistance to a class of antibiotics  e.g. macrolides (erm), aminoglycosides (aac, aph, ant), ß-lactams (bla), or export (smr).
• A single resistance gene determines resistance to structurally unrelated antibiotics (aad) or efflux systems.
• Use of disinfectants selects for the genetically linked antibiotic resistance genes.
• Mutations in multiple, independent targets
•   (Mycobacterim tuberculosis)

Side effects of Antimicrobial Therapy

Johnson Syndrome- MUST ask patient if known allergy

2.Nephrotoxicity, ototoxicity- Aminoglycosides/Amphotericin B

(contraindicated for pregnant women and children- stains teeth)

 Chloramphenicol- rarely used

common side effects- nausea, cramping, loose stools, etc)

  **Pseudomembranous colitis- killing of normal flora in gut

allows Clostridium difficle to overgrow

6.  Non-compliance leading to antimicrobial resistance