Pharmacology of Antimicrobials: Everything Else Flashcards
What is the mechanism of action of aminoglycosides and how do you remember this?
Bind the 30S subunit of the ribosome to decrease protein synthesis
AT = small, AT base pairing, both aminoglycosides and tetracyclines bind the small 30S subunit
Are aminoglycosides cidal or static, and why don’t they have activity against anaerobes?
Cidal - exception to rule of protein synthesis inhibitors
No activity against anaerobes because they require active transport into the cell
What are aminoglycosides mainly used for?
They have a synergistic effect, combine with a Beta-lactam because cell wall interruptors help more enter the cell
Expands Beta-lactam spectrum to enterococcus (Facultatitive anaerobes), typically only used in serious infections
What is gentamicin’s route and when is it used?
Typically IV - used synergistically for serious staph / enterococcal infections (i.e. endocarditis)
What is tobramycin’s route and when is it used?
IV - empiric coverage of nosocomial infections (used with Zosyn or mirapenem or cefepime)
What is amikacin’s route and when is it used?
Also empiric coverage of nosocomial infections, but has some role in mycobacterial infections
What is Neomycin’s role and why?
Neomycin is taken PO to decontaminate GI tract prior to surgery since it is not absorbed PO
Topically, it is neosporin
When is streptomycin used?
IV, when gentamycin resistant, and like amikacin for mycobacterial infections
Why are aminoglycosides good for UTI’s?
Hydrophilic (limited tissue penetration), but good for high urine concentrations and kidney excretion
What are two resistance mechanisms for aminoglycosides?
- Enzymatic modification - add a side chain which prevents 30S ribosomal binding = drug specific
- Target-site modification - modification of 30S ribosome, loss of entire class
What is the most common side effect of aminoglycosides and how can this be reduced?
Nephrotoxicity -> reduce trough levels at end of dosing intervals, letting tubules regrow
Less commonly: irreversible deafness due to vestibular / ototoxicity
What is the mechanism of action of fluoroquinolones, and is it cidal or static?
Inhibit bacterial DNA replication via inhibition of topoisomerases
It is bactericidal
What are the fluoroquinolones of clinical significance?
Ciprofloxacin
Levofloxacin
Moxifloxacin
What are levofloxacin and moxifloxacin also called and why?
Respiratory fluoroquinones -> good against all streptococcus, and all CAP organisms
Should not be relied on vs Staph / Enterococcus due to easy mutation
What is Ciprofloxacin good for?
Good against gram negative, with anti-pseudomonal activity (resistance in place in respiratory bugs, unfortunately)
So is levofloxacin, so we don’t carry it for its overuse potential
What is B. fragilis and what fluoroquinone is good against it?
An anaerobe commonly targeted in therapies
Only moxifloxacin
Unfortunately, it lacks anti-pseudomonal activity
What is the route of delivery for fluoroquinones?
Orally -> excellent bioavailability
How are the fluoroquinolones cleared and why is this relevant?
Cleared via kidney, however moxifloxacin is not so it can’t be used versus UTIs
What are the common fluoroquinolone side effects?
CNS toxicity - headaches, seizures, neuropathies
Tendon ruptures due to cartilage damage
Dysglycemia
Cardiac arrythmias / prolonged QT, especially moxifloxacin
What is a critical drug interaction with FQ?
Reduced divalent cation absorption due to chelation
-> separate 2-4 hours
Why are FQ so dangerous for developing resistance?
Cause development of efflux pumps which can also efflux Abx of unrelated structures
What class is vancomycin and what is its mechanism of action? Cidal or static?
Glycopeptide, works by binding D-ala,D-ala portion of peptidoglycan, preventing further cross-linking
Very slowly cidal (weak killing)
What organisms does vancomycin cover?
Gram positive only, used for empirical MRSA coverage (inferior for MSSA), in patients with Beta-lactam allergy who need gram + coverage
Very broad spectrum
When would you not need to empirically treat for MRSA with vancomycin?
Whenever the condition of the patient is not that serious and you can wait for a culture
What is Red-Man’s Syndrome?
Histamine-response to vancomycin often caused by too rapid infusion
Prevented by diphenhydramine or not infusing greater than 1g/hr
What is the side effect of concern for vancomycin?
Nephrotoxicity - 10-15%, especially in obese patients
What is the second generation glycopeptide and why isn’t it used?
It is a LIPOglycopeptide called telavancin, also disrupts membrane barrier function.
Not used due to even higher nephrotoxicity + interference with coagulation tests
What are dalbavancin and oritavancin?
Long-acting glycopeptides which are being studied for skin infections, huge potential for single dose therapies being entire drug course
What is daptomycin’s mechanism of action and killing activity? How is it given?
IV only - highly bactericidal to gram + organisms only
It uses its lipid tail to build a pore in cell membrane (like MAC) and osmotically lyse the cell
What is the major clinical use of daptomycin?
MRSA and VRE bloodstream infections (only with high levels of resistance, intermediate = VISA = cell wall thickening giving cross-resistance), endocarditis, soft tissue infections
What are daptomycin’s issues and when is it absolutely contraindicated?
Causes CPK elevations and rhabdomyolysis (muscle breakdown)
Irreversibly binds pulmonary surfactant, avoid in pneumonia
In what class is oxazolidinone and what is its mechanism of killing / activity?
Linezolid
Inhibits protein synthesis via 50S ribosome, bacteriostatic effect
What is the clinical application of Linezolids?
VRE infections - but keep in mind it’s only static
MRSA - pneumonia (when vanco-resistant, dapto can’t be used)
Why are linezolid’s so perfect?
IV / PO dose is the same, and it’s not renally eliminated so dosage is not needed to be adjusted
What is the major side effect of concern for linezolid?
Thrombocytopenia, especially in long courses
What is the major drug interaction of linezolid?
It is a weak MAOI, so can cause serotonin syndrome with SSRIs (fever, agitation, mental status change)
What are VRE and what is the most common species for it? How is it typically treated?
Vancomycin-resistant enterococcus
Common in Enterococcus faecium
Treated via Linezolid / Daptomycin usually
What is the VRE mechanism?
D-ala, D-ala becomes D-ala, D-lac (or D-ser), which Vanco cannot bind
Why is Oritavancin still useful against VRE?
Can bind D-lac as well
Why is VRSA very rare? What is good against it?
very expensive for resistance mechanism
Daptomycin is good against it
What was the first drug for treatment of VRE? Why has it fallen out of favor?
A streptogramin called Synercid (quinupristin / dalfopristin), binds 50S ribosome
Fallen out of favor due to high rates of infusion reactions
What are the macrolides / mechanism of action / killing?
- Azithromycin (IV/PO)
- Clarithromycin (PO)
- Erythromycin (IV/PO)
Bind 50S ribosome
Bacteriostatic
What are the macrolides mostly active against?
Respiratory pathogens, including pneumococcus, Hemophilus, mycobacterium
Also: Chlymadia / gonorrhea
Mycobacterium avium complex seen in HIV
What is Clarithromycin mainly used for?
Standard therapy for H. pylori
What is Azithromycin used for? Why is it chosen most often?
Chlymadia, gonorrhea, non-TB mycobacteria, and 1st line for CAP
It has a long half life, allowing for shorter drug course
Why is erythromycin not really used anymore?
Binds to motilin receptor in GI tract and causes diarrhea
What are the side effects of concern for the macrolides?
Nausea, vomiting, and diarrhea are very common
Also QT prolongation
Why is azithromycin chosen most often?
Has a long half life for short regimens, IV dose = PO dose, and it has the fewest CYP3A4 interactions
What is the mechanism of action and killing of tetracyclines?
Works on 30S ribosome, bacteriostatic
What are the clinical tetracyclines and their route?
Tetracycline - PO
Doxycycline / Minocycline (IV/PO)
Demeclocycline - PO
What is Demeclocycline used for?
Treatment of SIADH (inappropriate ADH release)
What are the side effects of tetracyclines?
- Bind to growing teeth and bones (do not use in patients under 8 years)
- Photosensitization
What are the drug interactions with tetracyclines?
Chelate with divalent and trivalent cations (like FQs)
What are doxycycline / minocycline typically used for?
Respiratory tract infections, including CAP
Skin infections, especially when CA-MRSA is a concern
Good against animal bites / lyme disease
What is minocycline emerging as good for?
Carbapenem-resistant A. baumannii
What is Tigecycline?
A glycylcycline, a derivative of minocycline binding 30S ribosome which can overcome tetracycline resistance mechanisms
What are the two big problems with tigecycline?
- Highly lipophilic - poor for treating blood, lung, and urine infections
- Causes nausea/vomiting in 20% of patients
What is the spectrum of tigecycline activity? When is it used clinically?
Very broad in both gram positive and negative, just misses PP = pseudomonas and proteus
Used as last line for resistant gram-negative like Acetinobacter and Klebsiella
Used often in POLYMICROBIAL WOUNDS including MRSA or VRE
What is the major lincosamide and its killing type?
Clindamycin
50S subunit -> bacteriostatic
What does clindamycin ideally cover, and what is one fun fact about it?
Staph, strept, and oral anaerobes (unfortunately minus B. fragilis), (no gram negative), though effectiveness is waning
Has toxin suppression activities against necrotizing gram + infections
What is the major side effect of clindamycin?
C. difficile diarrhea -> was once the number one antibiotic associated with it
What are the major intended uses of Clindamycin?
Skin infections Aspiration pneumonia (especially because anaerobes are thought to be players, but no gram negative coverage)
What is the significance of the “erm” gene?
Encodes “MLS” resistance to Macrolides-Lincosamides-Streptogramin, which all act on 50S ribosome, and give S. aureus a huge resistance mechanism
What should be done if something is found to be erythromycin resistant but clindamycin susceptible?
Special “D test”, since resistance may be latent and inducible
How do sulfonamides work? Most common one?
Structural analogs of PABA, blocking DHF synthesis from PABA competitively
Sulfamethoxazole, bacteriostatic
What is Sulfamethoxazole often combined with and how are they synergistic?
Combined with trimethoprim, another static inhibitor working on DHF reductase for DNA synthesis
As TMP / SMX, it is called bactrim and BACTERICIDAL
What is the major clinical role for TMP/SMX?
Outpatient UTIs, good against MRSA but poor for Strept (not good for skin infections)
What two nasty infections can TMP/SMX treat?
Pneumocystic (jirovecii) pneumonia, and Stenotrophomonas maltophilia pneumonia
What are the side effects of “sulfa drugs” = TMP/SMX?
Hypersensitivity, often severe skin reactions
Stops kidney creatinine excretion, causing creatinine to rise
What can Trimethoprim cause?
Hyperkalemia -> blocks K+ excretion, so beware with K+ sparing diuretics
Also anemia, leukopenia, and granulocytopenia
Increased bleeding when given with warfarin
What is the main nitro-imidazole given? How does it relate to clindamycin?
Metronidazole - good for GI anaerobes vs clindamycin which was good for oral anaerobes
What are three main uses of metronidazole?
- Empiric anaerobic coverage for intra-abdominal infections
- Drug of choice for mild-moderate C. difficile
- Trichomonas vaginalis coverage
What is the major side effect of metronidazole?
Peripheral neuropathy if given cumulatively
What are the drug interactions with metronidazole?
- Warfarin reaction (increased bleeding)
2. Alcohol - Disulfiram reaction with any consumption (like MTT-containing cephalosporins)
What is the mechanism of action of Rifampin?
Binds the DNA-dependent RNA polymerase, blocking bacterial mRNA synthesis
What is Rifampin’s spectrum of activity?
Good against all gram +, including MRSA, but not used as a monotherapy
Ineffective against gram negative unless in combination
Excellent against TB
In what clinical scenarios is Rifampin actually used?
Part of standard TB regimen, against staph infections complicated by hardware / biofilms, and against MDR gram negative
Give two reasons why Rifampin is not typically used
- Hepatotoxicity
- Induces multiple Cytochrome P450 enzymes, including CYP3A4. Contraindicated in many HIV meds because it causes subtherapeutic levels of the drugs (quicker metabolism)
What is one side effect you must warn patients of with Rifampin?
They will have discolored fluids
How do polymyxins work? Static or cidal?
Cationic detergents which interact with LPS on gram negative organisms, displacing divalent cations and disrupting outer membrane
Has anti-endotoxin effect and is bactericidal
What is the major polymyxin used and why did it stop being used?
Polymyxin B, can be IV, PO, or topical
Stopped being used due to nephrotoxicity (like vanco and aminoglycosides) and neurotoxicity
Why is polymyxin used clinically?
Last line treatment against multi-drug resistant gram negative:
P. aeruginosa, A. baumanii, K. pneumoniae, E. coli
Why is chloramphenicol not used anymore?
Caused bone marrow suppression, aplastic anemia, and gray-baby syndrome (toxic phase 2 metabolite)
What is nitrofurantoin used for, and its main contraindication?
Urinary tract organisms (gram negative, narrow spectrum)
Contraindicated if GFR < 60 mL/min (compromised kidney function)
What is the mechanism of action of dapsone and when is it used?
antagonist of PABA
Used in prevention and treatment of pneumocystic pneumonia when patient has sulfa allergy (can’t used TMP/SMX)
What is the major side effect of dapsone?
Hemolysis which is much worse in G6P dehydrogenase deficiency
