Antibiotic Classes and Resistance Flashcards
What are the 3 types/names of cell wall synthesis inhibitors?
- ß-lactams
- Glycopeptides
- Fosfomycin
What are the 3 Classes of ß-lactams?
- Penicillins
- Cephalosporins
- Carbapenems
What is the mode of action of ß-lactams? What stuctural feature do they all share? What are the analogous to?
competitive inhibition
All have a ß-lactam ring
Are analogous to D-ala-D-ala
What is the target of ß-lactams? How do they target them?
Penicillin binding proteins (PBPs)
- acts as D-ala-D-ala analogues and bind to the PBP
- the PBPs are now occupied and transpeptidation is inhibited
What are 4 methods of ß-lactam resistance? Which is the most common?
- Production of ß-lactamase (most common)
- Altered PBPs
- Novel PBP
- Altered permeability (mainly gram negatives)
How does ß-lactamase work?
Cleaves the ß-lactam ring which inactivates the drug
What are two important ß-lactamase inhibitors?
Clavulanic acid and Tazobactam
Which drug that we discussed is part of the Glycopeptides?
Vancomycin
What types of bacteria are susceptible to Vancomycin
Gram positives only
What is the mode of action for glycopeptides?
bind to the terminal D-ala of nascent cell wall peptides and prevents cross-linking of these peptide to form mature peptidoglycan
How have bacteria developed Vancomycin resistance?
- D-ala-D-ala target is altered - bacteria substitutes D-lac for D-ala- vancomycin CANNOT bind
What two bacteria are the primary concern for Vancomycin resistance?
- Staphylococcus aureus
2. Enterococcus
How does fosfomycin work?
Blocks the enzyme enol-pyruvyl transferase. Blocks condensation of UDP-N-acetylglucosamine with p-enolpyruvate
What is the spectrum of activity for fosfomycin?
Broad spectrum : both gram positives and negatives
What is fosfomycin used to treat primarily ? Caused by what organisms?
Uncomplicated cystitis in women
- caused by E.coli / E.faecalis
What does fosfomycin often retain activity against?
Bacteria that produce extended spectrum ß-lactamases (ESBLs)
What do the fluoroquinolones inhibit?
DNA synthesis
What is the difference between the classes of Cephalosporins? How do they differ in activity?
1st gen are very good against gram positive bacteria
As you increase generations you tend to lose gram positive activity and gain gram negative activity
Are fluoroquinolones time or concentration dependent? Bacteriocidal or bacteriostatic?
Concentration dependent and bactericidal
What is an example of a 2nd generation fluoroquinolone? what is it good against? what made it different from the 1st generation?
Addition of fluorine was a big change from the 1st generation
Ciprofloxacin is a good example
Broader spectrum and a very good anti-pseudomonal
What is an example of a 3rd generation fluoroquinolone? What is different between the 2nd generation and the 3rd?
The 3rd have better gram positive activity
- also have anaerobic activity (?)
Moxifloxacin is a good example
What are fluoroquinoles good acting against on the whole?
Atypical bacteria like mycoplasma (Chlamydia?)
What are the two specific targets of the fluoroquinolones?
- DNA gyrase
2. Topoisomerase IV
What do the fluoroquinolones do when they act on DNA gyrase?
prevent the DNA from reannealing
Both DNA gyrase and Topo IV are ___ enzymes
tetrameric
What causes “de novo” resistance to the fluoroquinolones ? (4 things)
- Spontaneous mutations in parC and gyrA - results in AA substitution = reduced affinity
- Over expression/up regulation of intrinsic efflux pumps
- Down regulation of porin channels in gram negatives
- Qnr production
What is Qnr?
protein that binds to and protects topoisomerase
How can bacteria acquire resistance to fluoroquinolones?
acquisition of resistance determinants from viridans streptococci
Fluoroquinolones have very good ___ bioavailability
oral
Where do the fluoroquinolones typically concentrate?
urine, kidney, prostrate, bile, lung, and macrophages
Which fluoroquinolone does not concentrate in the urine?
Moxifloxacin
What are two adverse effects of the fluoroquinolones? Who are they not used to treat?
- hyper/hypoglycemia
- cartilage toxicity and tendon rupture
Don’t use for children
What are two important situations to use fluoroquinolones?
- Atypical or gram negative infections like pseudomonas
2. Complicated UTIs
What are 4 other situations you would want to use fluoroquinolones?
- Intra-abdominal infections (rarely1st line) - combine with metronidazole
- Gastro-intestinal infections
- Hospital acquired Respiratory tract infections
- Community acquired (complicated) Respiratory tract infections
What is metronidazole the go to drug for? give some examples
Anaerobic or parasitic infections
C. difficile colitis
Trichmonas vaginitis and BV
H. pylori (in combination)
What is the mechanism of action of metronidazole?
Inhibits nucleic acid synthesis by disrupting /damaging DNA through the production of short lived toxic intermediates or free radicals under anaerobic (reducing) conditions
What are some side effects of Metronidazole use?
GI intolerance Antabuse effect Peripheral neuropathy Metallic taste Black/brown discoloration of urine
What are the 3 Macrolides we talked about?
Erythromycin, Clarithromycin, Azithromycin
What is the specific target of the macrolides?
Binds to the 50S subunit of the bacterial ribosome
What is the mechanism of action of the Macrolides
- blocks growth of nascent peptide chain by stimulating dissociation of the peptidyl-tRNA from the ribosome
- Also inhibits assembly of new ribosomes
What does MLS stand for?
Macrolide, Lincosamide, Streptogramin
What is the M phenotype?
presence of efflux pump, means that the bacteria are only resistant to macrolides
What is the MLS phenotype?
resistant to Macrolides, Lincosamides, Streptogramins due to activation of the erm gene which leads to AA substitutions/alterations in the 50S target site
What 3 first line uses for Macrolides?
- Mild-moderate community acquired pneumonia
- Pertussis
- Atypical pathogens like mycoplasma and chlamydia
What are 3 second line uses for Macrolides?
- Penicillin allergic patients
- URTIs
- C. jejuni gastroenteritis
What antibiotic is most often associated with C. difficile colitis
Clindamycin
What are 3 clinical uses of Clindamycin
- Anaerobic infections (typically gram neg)
- Gram positive infections (like staph)
- C. perfringens in penicillin allergic patient
What 5 drugs/group of drugs inhibit protein synthesis by binding to the 50S subunit?
- Macrolides
- Clindamycin
- Linezolid
- Chloramphenicol
- Streptogramins
What are the 3 Tetracyclines that we discussed?
Tetracycline, Doxycycline, Minocycline
Where do tetracyclines target? How do they bind?
Bind reversibly to the 30S subunit
What are 3 basic mechanisms of resistance that bacteria use against the tetracyclines?
- Energy dependent efflux
- Enzymatic inactivation
- Ribosomal protection
What are two types of infections that tetracyclines are excellent against?
- Atypical infections
2. Animal borne
What kind of infections are tetracyclines ok at combatting? What is an example?
most gram positives
ex: CA-MRSA
What are some adverse effects of tetracyclines?
discoloration of teeth
photosensitivity
depression of skeletal growth
esophageal ulceration
Who can’t be treated with tetracyclines? why?
Children under 12 or their teeth will be discoloured for life
What kind of antibiotics are the aminoglycosides?
Natural and semi synthetic
What are 4 examples of aminoglycosides?
Streptomycin, Gentamicin, Tobramicin, Amikacin
What are the spectra of activity for aminoglycosides?
excellent: gram negatives including pseudomonas
good: gram positives
What kind of killing do the aminoglycosides use?
Concentration dependent and bactericidal
What kinds of infections cannot be treated with aminoglycosides and why?
cannot be used for anaerobic infections or abscesses. Need to be actively transported into the cell in a process that required oxygen
What is the target of aminoglycosides? How do they bind?
Bind irreversibly to the 30S subunit
What is the mechanism of entry into the cell for the aminoglycosides? What is the rate limiting step? What blocks it?
Entry through inner membrane via an energy dependent transport system (electron transport)
This step is rate limiting and blocked by divalent cations and anaerobiosis
What is the most common form of resistance to the aminoglycosides?
Enzymatic modification
What are 2 other ways that bacteria have developed resistance to aminoglycosides?
- Altered ribosome binding sites
2. reduced uptake or decreased cell permeability
What are the two main adverse side effects of aminoglycoside use (hint: what are they toxic to?) What causes these side effects?
Can interfere with mammalian protein synthesis at high concentrations
- ototoxic: both cochlear and vestibular
- nephrotoxic: proximal tubule damage
What 5 situations would you want to treat with aminoglycosides?
- Complicated UTIs (Pyelonephritis)
- Mixed infections without abscess formation
- Endocarditis treatment (synergy Enterococcus)
- Pseudomonas infections
- For resistant Gram negative bacilli
What drug blocks folic acid synthesis?
Trimethoprim/sulfamethoxazole (Septra, TMP/SMX)
What bacteria are TMP/SMX effective against?
good gram negative, some gram positive
How does TMP/SMX work?
Blocks folic acid synthesis at two different steps
- not synergistic
What is the pathway to folic acid synthesis and which of TMP/SMX acts on each stage?
- PABA —-> dihydrofolic acid
- this step blocked by Sulfonamides (SMX) - Dihydrofolic acid —> tetrahydrofolic acid
- this step blocked by Trimethoprim (TMP)
What are the 2 mechanisms of resistance to TMP/SMX? Which is more common?
- Chromosomal:
- metabolic bypass
- over expression of dihydrofolate reductase - Plasmid (most common)
- drug resistant variants of DHFR / DHPS
What was TMP/SMX commonly used for but not has high rates of resistance?
uncomplicated UTIs
What is TMP/SMX a very active agent against?
anti-Staphylococcal agent (CA-MRSA)
What are two antibiotics that we discussed with activity against the bacterial cell membrane? What class of bacteria do they each act on?
- Colistin (gram negatives, some gram positive activity )
2. Daptomycin (gram positive agent)
How does Colistin work ? what is it best used to treat?
Displaces divalent cations from phosphate groups of membrane lipids
Disrupts outer membrane
Useful in treating MDR gram negative infections
What is Colistin toxic against?
Renally and neurologically toxic
What is the one kind of infection that only Colistin can be used to treat?
CRE infections
How does Daptomycin work? What is it useful in treating?
Insertion into bacterial cell membrane
Rapid membrane depolarization and K+ ion flux
Bactericidal concentration-dependent killing
useful against MRSA
What can Daptomycin not be used to treat? Why?
Cannot be used for RTIs because lung surfactin will inactivate the drug
