(B) Lecture 13: Antibiotics and Antibiotic Resistance Flashcards
Antimicrobial agents
- disinfectants
- antiseptics
- antibiotics
Disinfectants
antimicrobial agents that are applied to INANIMATE OBJECTS (floors, tables, walls)
Antiseptics
antimicrobial agents that are sufficiently NONTOXIC to be applied to LIVING TISSUES (ex. hand sanitizers)
Antibiotics
antimicrobial agents produced by BACTERIA + FUNGI that are exploited by humans
- delivered topically + internally
Most effective therapeutic against bacterial infections
Major problems with antibiotics
- Low interest from pharmaceutical companies to develop new antibiotics (hard to make money when constantly making new antibiotics due to resistance)
- Bacterial resistance to antibiotics always happens
Misuse of antibiotics
- empiric use (blinded use): don’t know specific infection
- increased use of broad-spectrum agents: kills things you don’t want
- pediatric use for viral infections
- patients who don’t complete course (ex. TB)
- antibiotics in animal feeds
- global travel = resisted organisms/bacteria spread quickly
Measuring Antibiotic Activity
Minimum inhibitory concentration (MIC)
- MIC = point where bacteria can’t grow/ lowest conc of agent that inhibits growth
- series of culture tubes w/ diff conc. of agent + check for growth
How do antibiotics work?
Antibiotics target essential bacterial components:
- cell wall synthesis
- protein synthesis (ex. ribosomes)
- DNA/RNA synthesis
- folate synthesis
- cell membrane alteration
Targets are not present in eukaryotic cells
Beta Lactam Antibiotics
Ex. Penicillin, Methicillin
- contains a beta lactam ring
- INHIBITS CELL WALL SYNTHESIS in bacteria
Penicillin
a beta lactam antibiotic
Beta lactams bind bacterial “penicillin-binding proteins (PBPs)
- PBPs are transpeptidases and make peptide cross-links
- no peptide cross-links = weak cell wall = cell death
BUT some bacteria produce a beta lactamase (enzyme that destroyed ring and antibiotic)
Methicillin
a beta lactam antibiotic
- contains a beta lactam ring
- chemically modified penicillin
- CAN’T be cleaved by beta lactamases
BUT some bacteria can produce a different ‘penicillin-binding protein’ (PBP2a) encoded by ‘mec’
- PBP2a doesn’t bind methicillin (or other beta lactams)
Vancomycin
- not a great antibiotic
- a glycopeptide antibiotic
- inhibits cell wall synthesis in gram POSITIVES
- often a “last resort” (ex. MRSA)
Binds peptide linkage at terminal D-Ala-D-Ala residues and inhibits transpeptidation
- resistance genes change those to D-Ala-D-Lac and vancomycin can no longer bind
Resistance is encoded by van genes
Bacterial strategies for antibiotic resistance
- prevention of antibiotic entry (gram NEGATIVE outer membrane + mycobacteria cell envelope)
- antibiotic modification (beta lactamase)
- efflux of antibiotic (actively pump out the antibiotic)
- alteration of antibiotic target (PBPs, ribosome modifications)
- bypassing antibiotic action (use environmental folic acid)
Antibiotic resistance genes
- many mechanisms of antibiotic resistance are GENETICALLY ENCODED (ex. mec, beta lactamase, efflux pumps)
- can produce HIGH levels of antibiotic resistance
- often encoded on MOBILE genetic elements (ex. plasmids, transposons) that allow for horizontal gene transfer = SUPERBUGS
Superbugs
bacteria that are resistant to MULTIPLE antibiotics
Horizontal gene transfer
new genes are acquired from another source
- bacterial transformation: donor cell releases DNA and recipient picks it up
- bacterial transduction: phage infects bacteria and phage-infected donor cell releases phage to infect a recipient cell
- can pass on resistance genes - bacterial conjugation: donor cell and recipient cell combine and plasmid moves from donor to recipient
Klebsiella pneumoniae
Gram NEGATIVE
- important cause of nosocomial pneumonia
- produces a capsule
- commonly resistant to multiple antibiotics
- first documented source of NDM-1 (a carbapenemase)
- carbapenem antibiotics are beta-lactamase resistant beta-lactams w/ broad spectrum activity
Nosocomial
a disease acquired in a HEALTHCARE setting
NDM-1
a carbapenemase
- carbapenem antibiotics are beta-lactamase resistant beta-lactams w/ broad spectrum activity
Now widespread in other Gram NEGs = CRE (carbapenem-resistant Enterobacteriaceae)
Clostridia
- gram-POSITIVE, rod shaped
- endospore-formers
- strict ANAEROBES, vegetative cells killed by O2
- generally found in SOIL + INTESTINAL TRACTS of animals
- can cause life-threatening diseases mediated by EXOTOXINS
Examples
- C. difficile: pseudomembranous colitis
- C. tetani: tetanus
- C. botulinum: botulism
- C. perfringens: food-borne illness
C. diff
Clostridoides difficile
Can exist as
- asymptomatic carrier in large intestine
- cause of mild to moderate diarrhea
- cause of life-threatening pseudomembranous colitis (antibiotic-associated diarrhea)
NOSOCOMIAL environments (in nursing homes + hospital environments)
ENDOSPORES can be hard to get rid of
Mode of transmission: FECAL-ORAL ROUTE
Pseudomembranous colitis
- inflammatory condition of LARGE intestine
- most important risk factor: having recently received an antimicrobial agent
- antibiotics suppress normal microbiota = persistence of C. diff endospores
- when antibiotic is stopped, spores germinate; overgrowth of C. diff = toxins
- C. diff is not invasive but EXOTOXINS cause damage + inflammation to intestinal lining of large intestine
- diarrhea, ab pain, fever, nausea
How does C. diff work?
C. diff produces A-B toxins called the LARGE CLOSTRIDIAL CYTOTOXINS
“A-B” designates two domains
- A-domain: the ACTIVE portion of the toxin that carries the enzymatic activity
- B-domain: the portion of toxin responsible for BINDING + uptake by host cell
A-domain
the ACTIVE portion of the toxin that carries enzymatic activity
inactivates key regulatory proteins of host cells = dysregulation of cell processes like inflammation, cytoskeletal rearrnagements and cell death
Diagnosis and Treatment of C. diff
Diagnosis
- take history (antibiotic use)
- lab tests to confirm C. diff
- endoscopy and toxin detection
Treatment
- discontinue inciting antibiotic
- fluids
- antibiotics more specific for C. diff - oral vancomycin or I.V. metronidazole
- AVOID ANTIDIARRHEAL AGENTS - would cause decreased toxin clearance
Fecal microbiota transplantation
Take feces from a healthy person and transplants that into large intestine of infected person
Fixes microbiota
Study: Duodenal Infusion of Donor feces for Recurrent C. diff
Fecal microbiota transplantation
Methods
- 3 therapies randomly assigned: vancomycin + bowel lavage + donor feces infusion; standard vancomycin; vancomycin + bowel lavage
- goal: resolution of diarrhea w/ C. diff w/o relapse after 10 weeks
Results
- study stopped after interim analysis
- patients who got donor-feces infusion, showed increased fecal bacteria diversity, similar to healthy ppl
