Exam 1 DPT III

How long has bacteria been around?

3.5 billion years

What are some similarities between bacteria and cyanobacteria?

both can produce toxins

What is a key difference between bacteria and cyanobacteria?

bacteria are a key group of infection causing and drug producing organisms while cyanobacteria is not

BMAA

crosses the BBB

smoking gun for guamanian "lytico-bodig disease"

not exclusive cause but can contribute to neurodegenerative disease

Microcystin-LR

can lead to oxidative stress, cell death, and cytoskeletal disruption

can also lead to damaging liver

Okadaic acid and dinophysistoxins can cause...

diarrheic shellfish poisoning

can lead to neurotoxicity

Domoic acid

can be found in some shellfish and cause seizures

"sea lion seizure"

Saxitoxin

can lead to paralytic shellfish poisoning

0.5 mg can cause death in humans

can enter as aerosol, through skin or seafood

Na channel acting toxin

Arsphenamine (Salvarsan)

"magic bullet" for treatment of syphilis and trypanosomiasis

Vancomycin

inhibits proteins associated with membrane structural integrity and associated function of stress response protein, oxidoreductase, and transporter ATP protein binding

binds to D-Ala-D-Ala preventing cell wall biosynthesis

What are the different approaches to develop of therapeutics?

phenotypic

targeted

drug design

polypharmacologic

Phenotypic approach

known molecules but unknown targets

most antibiotics are discovered this way

Targeted Approach

known target (purified) screen molecule libraries

Drug Design Approach

known target and use of computer modelling to design a ligand

works well with protein targets but less effective for other targets

Polypharmacology Approach

design drug to act on multiple targets to delay resistance development

Beta Lactam Antibiotics

binds to penicillin binding proteins, inhibit the synthesis of the peptidoglycan sheets in cell wall

Peptide antibiotics

vancomycin

bind to peptidoglycans preventing formation of the peptidoglycan layer

Sulfonamides

inhibit dihydropteroate synthase enzyme that stops the synthesis of vitamin B9 (inhibits bacterial metabolism)

Quinolones

inhibits DNA synthesis by inhibiting DNA gyrase

Aminoglycosides and tetracyclines

inhibit protein synthesis by binding to the small subunit of ribosomes

Lincosamides MOA

inhibit protein synthesis by binding to the large subunit of ribosomes

ESKAPE pathogens

Enterococcus faecium, Staphylococcous aureus, Klebsiella pneuomniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter

group of pathogen with high rate of antibiotic resistance

Bacterial Cell Wall

thick and rigid polymer that surrounds cytoplasmic membrane

protects cytoplasmic membrane from physical and osmotic changes

helps maintain shape

What does the peptidoglycan layer consist of?

N-acetyl glucosamine

N-acetyl muramic acid

crosslinked tetrapeptides

What are the 4 mechanisms of antimicrobial resistance?

inactivation

efflux

modification of target

impermeability

Carbapenem Resistant Acinetobacter baumannii (CRAB)

Gram - bacteria

can cause pneumonia, wound, bloodstream, and UTI

longer hospital stays are at risk

What can you treat CRAB with?

polymixins, tigecycline, aminoglycosides

Persisters

bacterial survivors that can survive treatment from beta lactams, aminoglycosides, and fluoroquinolones

Candida auris

multi drug resistant yeast

possible link to the use of azoles

treatment: echinocandins, amphotericin B and triazoles OTHER than fluconazole

How can you treat Candida species?

clotrimazole, nystatin, fluconazole, voriconazole, amphotericin B, echinocandins

immunocompromised or critically ill: IV fluconazole or echinocandin

C. Diff

Gram + that causes life threatening diarrhea and colitis

produces toxins called Enterotoxins

composed of S-layer that has at least 28 proteins that may provide unique targets

Prevention of C Diff

controlling antibiotic use, isolation, cleanliness

rarely occurs without antibiotic use

Treatment of C Diff

vancomycin or fidaxomicin orally

stool transplant

probiotics

Neisseria gonorrhoeae

G - diplococci

causes sexually transmitted disease that can be life threatening, ectopic pregnancy and infertility

grown resistant to penicillin, tetracycline, and fluoroquinolones

What is the last line of defense for N. gonorrhoeae?

ceftriaxone, third generation cephhalosporin

Campylobacter

gram -

causes bloody diarrhea, fever

spread from contaminated food

treatment: self resolving in about one week, azithromycin in high risk infections

ESBL Producing Enterobacteriaceae Treatment option

carbapenems due to it breaking down penicillins and cephalosporins

VRE

gram +

cell membrane remodeling mediates resistance

treatment: linezolid, Lactobacillus rhamnosus GG (probiotic for gastrointestinal)

Pseudomonas aeruginosa

gram -

virulence factors: proteases, exotoxins, phospholipase-C, pyocyanin, siderophores, and alginate

produces B lactamases, efflux pumps and down regulates expression of porins which contributes to its resistance

Treatment for Pseudomonas aeruginosa

carbapenems, polymxins, and tigecycline

Salmonella Nontyphoidal

gram -

can spread from animals to people from food

Salmonella Typhi

typhoid fever

prevention: vaccination

treatment: cipro, ceftriaxone

Shigella

gram - related to E coli

spreads through feces through direct contact or contaminated surfaces

produces shiga toxin that can damage small vessels

Treatment for Shigella

ampicillin, amoxicillin, third-generation cephalosporins, azithromycin, ciprofloxacin, norfloxacin

MRSA Treatment

bactrim, clindamycin, minocycline, and doxycycline

Streptococcus pneumoniae

gram +

causes pneumococcal disease

causes sepsis with sickle cell disease

treatment: amoxicillin

Tuberculosis

caused by M. tuberculosis and most common infectious disease and frequent cause of death worldwide

Group A Strep

treatment: amoxicillin or azithromycin

can cause strep throat, pneumonia, flesh eating infections and sepsis

How does GAS evade?

M and F proteins of pili with hyaluronic acid capsule can inhibit phagocytosis and help avoid killing GAS

secreted GAS factors can inhibit complement activation, induce apoptosis of phagocytes, interfere with cytokines, destroy NETs

Group B Strep Treatment

B-lactams

M. genitalium

sexually transmitted and can cause urethritis in men and cervicitis in women

treatment: doxycycline and azithromycin

Bordetella pertussis

gram - respiratory illness known as whooping cough

treatment: erythromycin and other macrolides

vaccines

Mutational Resistance

subset of bacterial cells derived from susceptible populations develop mutations in genes that affect the activity of the drug resulting in preserved cell survival in the presence of the antimicrobial molecule

Horizontal gene transfer

can acquire genetic material through transformation, transduction, or conjugation

What are the different ways of antimicrobial resistance genetically?

mutations, horizontal gene transfer

Fluroquinolone resistance

1. mutations encoding target site of FQ

2. over expression of efflux pumps

3. protection of FQ target site

What are the different ways that a antibiotic can be chemically altered?

acetylation, phosphorylation, and adenylation

Antimicrobial Resistance Mechanisms

1. modifications of the antibiotic molecule

2. decreased penetration and increased efflux

3. changes in target site

4. resistance due to global cell adaptations

What do all beta lactams inhibit?

penicillin binding proteins

Amoxicillin

commonly prescribed with clauvanic acid

used to treat: middle ear infection, strep throat, pneumonia, skin infections, and UTI

binds to PBP and inhibits the third and last stage of bacterial wall synthesis

Ampicillin

can work against VRE

side effects: C diff colitis

MOA: inhibits 3rd and final stage of bacterial cell wall synthesis

Clavulanic acid

beta lactamase inhibitor frequently combined with amoxicillin or ticarcillin

suicide inhibitor

Class B beta lactamases

metalloenzymes that utilize zinc

Class A C D Beta lactamases

hydrolyzes serine

Vaborbactam

beta lactamase inhibitor

can reversibly bind to serince carbapenemases and act as a transition state analog

What is special about the nucleus of a cephalosporin?

7-ACA helped produce thousands of cephalosporins and can be effective in treatment of serious infections of both gram + and -

Cefazolin

used to treat cellulitis, UTI, pneumonia, endocarditis, join infection

side effects: pregnancy cat B

MOA: cell wall interfering, PBP binding

Mechanisms of B-lactam resistance

porin mutations that decrease entry

increase in efflux pumps

degrade antibiotics through beta lactamases

PBP mutations of target site

Ceftaroline

can be used for MRSA, pneumonia, skin infections

Ceftolozane

in combination with tazobactam

MOA: inhibit of PBPs of Pseudomonas aeruginosa and E coli where as tazobactam is a potent beta-lactamase inhibitor

Sulfamethoxazole

used in combination with trimethoprim

can be used in UTI, bronchitis, prostatitis

WHO med for UTI

MOA: interferes with folic acid

Trimethoprim

used in combination with dapsone for pneumocystis pneumonia with HIV/AIDS

MOA: disrupts folate synthesis, starves bacteria of nucleotides

bactericidal activity

Quinolone Class

can be used as both an antimalarial drug and food flavoring agent

cinchona tree is the only active source

Ciprofloxacin

second generation

MOA: acts of DNA gyrase and topoisomerase and inhibits DNA synthesis

Fluoroquinolone Toxicity

tendon rupture, nervous system disturbances, heart kidney and liver damage, diabetes, and FQAD

What is the treatment for FQAD?

antioxidants, mineral replacement, mitochondria repair, restoring cellular energy

What are the main mechanisms of fluoroquinolone toxicity?

oxidative stress

binding metals

damage to mitochondria

disruption of cellular energy pathways

damage to DNA

Delafloxacin

used to treat acute bacterial skin infections

MOA: interferes with bacterial DNA synthesis

side effects: C diff associated diarrhea

broad coverage MRSA and Pseudomonas

Nitrofurantoin

primarily used to treat uncomplicated bladder infections and UTI (second line behind bactrim)

side effects: NOT to be used in kidney disease or pregnancy

Fosfomycin

primarily used for bladder infections and occasionally prostate infections

MOA: inhibition of cell wall biogenesis by inactivating MurA, mediated by epoxide which alkylates Cys 115

Clindamycin

useful for MRSA and malaria when combined with quinine

side effects: risk of C diff

MOA: inhibits bacterial protein synthesis, bacteriostatic effect

Neomycin

used as a preservative in some vaccines

prevents hepatic encephalopathy

MOA: irreversibly binds to protein to inhibit synthesis

Doxycycline

second generation

side effects: tooth development discoloration

MOA: protein synthesis inhibitors

Chloramphenicol

binds to 50S and inhibits formation of peptide bond

Linezolid

binds to 50s and prevents formation of the 50/30s ribosomal complex

Tetracyclines

bind to 30s and interfere with binding of tRNA to ribosomal complex

Aminoglycosides

bind to 30s and causes mRNA codon to be misread

Macrolides, Clindamycin

block polypeptide exit tunnel on 50s and prevent peptide chain elongation

Daptomycin

side effects: potential for hepatotoxicity and nephrotoxicity

MOA: inserts the cell membrane and causes cellular depolarization and loss of membrane potential (messes with Ca)

bactericidal

Which drugs MOA are at cell wall?

beta lactams, vancomycin

Which drugs MOA are at cell membrane?

polymyxins

Which drugs MOA are with nucleic acid synthesis?

folate: sulfonamides and trimethoprim

DNA gyrase: quinolones

RNA polymerase: rifampin

Which drugs work at the 50S subunit and inhibit protein synthesis?

macrolides, clindamycin, linezolid, chloramphenicol

Which drugs work at the 30s subunit and inhibit protein synthesis?

tetracyclines

aminoglycosides

mRNA Vaccines

side effect: reactogenicity

DOES NOT ALTER DNA

MOA: transported into dendritic cells by phagocytosis and makes a viral antigen, then the mRNA is destroyed

Enterococcus faecalis daptomycin resistance

LiaX tells the bacteria to remodel protective cell envelope that way the drug cannot bind

Infection

invasion of the body with organisms that have the potential to cause disease

Infectious disease

disease resulting from tissue destruction or damage which is directly attributable to invasion of the body by a microorganism

What are the 4 D of antimicrobial stewardship?

right Drug

right Dose

De-escalation to pathogen specific therapy

right Duration of therapy

Pharmacokinetics

what our bodies do the antimicrobials