Lesson 2.7 & 2.8 - Antimicrobial Resistance Flashcards
Define antimicrobials
Medications that kill microorganisms or inhibit their growth; grouped according to what they act against
Define antibiotics
- Treat bacterial infections
- Bactericidal (kill) vs. bacteriostatic (stop growth)
- ‘against life’
Define antifungal / antimycotic
- Kill fungi, prevent fungal infection (mycosis)
- i.e. athlete’s foot, ringworm, candidiasis, cryptococcal meningitis
Define antiviral
- Treat viral infections, don’t directly attack/kill viruses
- Target aspect of viral life cycle
- Attachment, penetration, uncoating, syntehsis, assembly, release
Plant products [before antibiotics existed]
- Opium, morphine
- Quinine, caffeine, cocaine
- Salicin, digitoxin
Amputation [before antbiotics existed]
Ulcerous wound, gangrene
Diptheria toxin serum ca. 1891 [before antibiotics existed]
Horse antibodies neutralize toxin (if allergic, then patient gets anaphylactic shock)
Salvarsan for syphilis ca. 1911 [before antibiotics existed]
Arsenic compound; high toxicity (risk for poisoning if too strong)
Prontonsil ca. 1932 [before antibiotics existed]
Red dye w/ antitmicrobial activity & low toxicitiy
1st sulfonamide; technically a antimicrobial
Paul Ehrlich
Coined term “magic bullets;” aka selective toxicity (killing microbes without harming human cells)
Spanish flu (1918-19)
- 675k U.S. deaths, 50 million worldwide
- Infecctious disease was main cause of death before antibiotics existed
Death rates 1901 vs. 1996
Deaths per 100,000
Alexander Fleming (1928)
Discovered Penicillium spp. (fungus) inhibited bacteria on Petri disk; named compound pencillin & was not widely available until after WWII
Nobel Prize in Physiology or Medicine (1945)
- Sir Alexander Fleming
- Physician; antimicrobial compounds, original observation
- Ernst Borin Chain
- Chemist; purification
- Sir Howard Walter Florey
- Pathologist; production & clinical trials
Nobel Prize in Chemistry (1964)
- Dorothy Crowfoot Hodgkin
- Structure of penicillin using x-ray crystallography
- +vit. B12 structure, insulin, etc.
Golden Age of Antibiotic Discovery
1940 - 1970
No need to memorize specific events
Sources of antibiotics
- Fungi & bacteria (natural product)
- Combinatorial chemistry = synthetic product made
- Small # by de novo
Phylum Actinobacteria
- Source of most antibiotics
- Ubiquitous soil microorganisms also in fresh/marine ecosystems
- Grow via hyphae
- e.g. Streptomyces (80% of antibiotics from this phylum)
Products of Phylum Actinobacteria
- Streptomycin, cephalosporin, tetracycline, vancomycin, chloramphenicol
- Antiviral, antifungals, antiparasitic, insecticidal compounds
Original Hypothesis of how Fungi / Bacteria produce antibioitcs
- Micoorganisms have geast or famine lifestyle
- r-selected (good = up & bad = down)
- Not k-selected (stable populations, i.e. elephants)
- r-selected (good = up & bad = down)
- Survival of the fittest paradigms
Contemporary Hypothesis of how Fungi / Bacteria produce antibiotics
- Antibiotics = signaling / communication molecules (like quorum sensing)
- Sub-lethal concentrations change transcriptional pattern of target organism
- Hormesis: positive response at low concentration; negative response at high concentrations (e.g. caffeine)
Targets of antibiotics (6)
- Cell wall synthesis
- Cell membrane
- DNA replication
- Transcription
- Translation
- Metabolic pathway
(6) Self-resistance mechanisms for producers
- Hidden by proteins
- Efflux pumps it out
- Target molecule protected
- Enzymes inactivate it within cytoplasm
- Binds to decoy molecules; it bypasses
- Modified during biosynthesis to be inactive to producer
BE METH!
Phases of Microbial Growth Cycle
- Lag phase
- Exponential phase
- Stationary phase
- Death phase
Lag phase
- Brief or extended, depending on start culture
- Cells adjust to medium; gene expression occurs
Exponential / logarithmic phase
- Cell population doubles every generation
- Time varies
- Shorter generation time = faster growth
- Vice versa
- Time varies
Stationary phase
- Cell growth limited
- Nutrient limitation (all C consumed) / buildup of waste
- Cryptic growth, but balanced by cell death
- Metabolism & biosynthetic functions continue
- Physiologically different from exponential phase
ANTIBIOTICS PRODUCED DURING THIS PHASE!
Death phase
- Viability decreases - lysis may or may not occur
- Rate of death slower than growth
- Metabolic & biosynthetic functions usually continue
- Cells physiologically different from exponential
Primary (1°) metabolite
- Produced during tropophase
- Thigns req. for growth, development, reproduction
- Nucleotides, AAs, FAs, monosaccharides, fermentation products
Secondary (2°) metabolite
- Producing during idiophase
- Not directly in growth, development, repro.
- Important in ecological / environmental situations
- Antibiotics, growth factors, toxins, pheromones, aromatic compounds, heat shock proteins
Bacteriostatic antibiotics
- Inhibit bacterial growth
- Requires higher concentration to kill bacteria
- Host immune system eliminates infection
- MBC/MIC ratio > 4
Bactericidal antibiotics
- Kill bacteria
- Inhibit /disrupt a vital cell function
- MBC/MIC ratio ≤ 4
Minimum inhibitory concentration (MIC)
- Lowest concentration that inhibits visible bacterial growth at 24 hrs.
- Specific medium, °C, & [CO2]
Minimum bactericidal concentration (MBC)
- Lowest concentration for a 1000-fold reduction (death) in bacterial density @ 24 hrs
- Specific medium, °C, & [CO2]
Which is better, bacteriostatic or bactericidal?
Bacteriostatic = superior & cost-effective; choice depends on what organism it is
Broad-spectrum antibiotics
- Effective against wide range (e.g. 30S subunits)
- Used when causative organism unknown
- Kills normal microbiome
- Higher risk of resistance
Narrow-spectrum antibiotics
- Effective against fewer range
- Used only if causative organism is identified
- Does not kill as many normal microbiomes
- Lesser chance of resistance
Antibiotic resistance sprectrum continuum (chart)
Tetracycline
Binds reversibly to 30S, inhibit aminoacyl-tRNA entry
Effective against Gram (-) & Gram (+)
Sulfa drugs
Effective against Gram (+) & Gram (-)
Streptomycin
Effective against Gram (-) & acid-fast bacteria
Erythromycin
Effective against Gram (+) & bacteria w/o cell walls (mycoplasma)
Penicillins
Original penicillin G mainly against Gram (+); newer have broader range, including Gram (-)
Isoniazid
- Effective against acid-fast bacteria only;
- Inhibit cell wall mycolic acid formation in Mycobacterium spp.
- Tuberculosis, leprosy, & atypical pneumonia
Antibiotic Reistance Crisis
- Nonsuscpetible
- ~2.8 million Americans acquire a resistant infection
- ~35,000 Americans die (CDC)
- $8 billion/year in healthcare costs
- Antibiotic resistance adds $1,383 in treatment costs
MDRO Infections (statistics)
- Multiple drug resistant organisms
- Estimated $2.9 billion to treat infection alone
- MDRO sepsis could cause 70,837 inpatient deaths/year
- 715k inpatient deaths
- 34.4% due to sepsis
- 28.8% due to MDR pathogens
- Would make MDR bacteria 3rd highest cause of death in US
- 715k inpatient deaths
ICD-10-CM
International Classification of Diseases, Clinical Modification
Codes relative to COVID-19 effective Jan 1, 2021. No codes in 2020.
Klebsiella pneumoniae (Reno in 2016)
- Resistant to 26 antibiotics
- Right femur fracture & osteomyelitis of femur & hip
- Travel to India
- New Delhi metallo-beta-lactamase (NDM)
Antibiotic Paradox
More antibiotics = misuse, overuse = more resistance and less effectiveness
Antibiogram
- Antimicrobial suspectibility profile; screening for resistance
- Advantages:
- Helps identify best antibiotic treatment plan
- Monitor trends (zone of inhibition)
- Limitations:
- Doesn’t take into account patient history
- May or may not apply to other patients
- Doesn’t demonstrate cross resistance
- Doesn’t take into account patient history
MSSA stands for
Methicillin sensitive S. aureus
High resistance to ciprofloxacin
MRSA stands for
Methicillin Resistant Staphylococcus aureus
CoNS
- Coagulase-negative staphylococci
- Nonpathogens that incite nosocomial infections
- Associated with intravascular catheter & immune compromised patients
Multiple Drug Resistance (MDR)
- Resistant to more than one antibiotic
- Nonsusceptibility to at least one agent in 3+ categories
- i.e. most MRSA are MDR
Extensively drug-resistant (XDR)
- Nonsusceptibility to at least one agent
- Susceptible to only 1-2 categories
- i.e. Mycobacterium tuberculosis
Mycobacterium tuberculosis
- Commonly resistant to isoniazid & rifampicin
- A fluoroquinolone
- 1/3 second-line parenteral drugs (non-oral method)
- i.e. amikacin, kanamycin, or capreomycin
Pan-drug resistant (PDR)
- Resistant to all antibiotics
- Nonsusceptibility to errrrrrythang
