Antibiotics Flashcards
How do Penicillins work?
They bind to PBP resulting in the inhibition of PG synthesis and activation of autolytic enzymes in the cell wall
They break down the wall and prevent wall repair
Bactericidal
How do bacteria become resistant to penicillins?
Production of beta-lactamases - destroy the drug
Lack of PBPs or altered PBPs - no target for drug
Efflux of drug out of cell - pump the drug out
Failure to synthesize PG such mycoplasmas or metabolically inactive bacteria - org not growing or maintaining cell walls
What is the structure that penicillins share?
6-aminopenicillanic acid (thiazolidine ring attached to a beta-lactam ring)
bonds need to be intact for AB to work
What is penicillin G most active against?
gram positive bacteria and spirochetes
ex) syphilis
What can penicillin G be destroyed by?
Beta-lactamases and stomach acids
Which Pen Gs are special? How?
Procaine and benzathine Pen G
They are both salts and administered Intramuscularly only
The salt prolongs their activity
If given thru IV, then you will kill the pt due to toxicity
What is Pen V? What is special about it?
It is an oral formulation
It is more acid stable but needs to be taken on an empty stomach
What are some groups/families that pen is good for?
streptococci, pneumococci, meningococci, spirochetes, clostridia, anaerobic +ve rods, actinomyces
enterococci
Explain Methicillin and its members
Isoxazolyl peniciliins “anti staph”
Designed for Staph aureus
Relative resistance to beta-lactamases
less gram +ve activity otherwise
IV and oral forms
Staphylococcal
What is MRSA
Methicillin resistant staph aureus (resistant to the whole class + penicillins too)
A lab marker
What is MSSA?
Methicillin susceptible staph aureus
Which antibiotic of the methicillin class is made in Canada?
Cloxacillin is from Canada
What types of organisms are aminopenicillins active/effective against?
gram positive and gram negative organisms (more broad than prev two)
What is a resistance strategy of orgs against aminopenicillins
Destroyed by beta-lactamases
What are the two main aminopenicillins?
ampicillin and amoxicillin
What is the difference between ampicillin and amoxicillin?
Ampicillin - used IV, more stable than natural pens but they have poor bioavailability (F)
amoxicillin - used orally, but they have better abs. than ampicillin, they are available combined with clavulanic acid (b-lactamase inhibitor)
Name some organisms that aminopenicillins works well against
Streptococci, enterococci, Neisseria sp., non-b-lactamase prod H. influenzae, E.coli, P mirabilis , Salmonella, etc
How do beta-lactamases work against penicillins and cephalosporins?
They open up the beta-lactam ring and render the AB no longer active
What does classification of beta-lactamases depend on?
genetics, biochemical properties and substrate affinity for a beta-lactamase inhibitor
What are ESBLs?
Extended-spectrum beta-lactamases found in e.coli and klebsiella pneumoniae
can deactivate lots of beta-lactams
What are NDM-like organisms? Provide an example
New Delhi metallo-beta-lactamase. Liinked to metals
Acinetobacter baumannii
(human pathogen)
MAY NEED TO UPDATE THIS CARD
What is the activity profile of ureidopenicillins?
Increased activity against gram negative rods
Also active against PSEUDOMONAS AERUGINOSA - The v. pathogenic gram -ve rod that not alot of ABs effective against
What is an example of a ureidopenicillin?
piperacillin
What is so special about piperacillin?
It is active against the pathogenic Pseudomonas aeruginosa
Parenteral administration only - IV only
What are ureidopenicillins combined with? Provide an example
Combined with a beta-lactamase inhibitor such as tazobactam (no activity against bacteria)
Discuss the pharmacokinetics of penicillins
oral bioavailability (F) varies
wide tissue distribution including CNS
Most are excreted by the kidney (if there are kidney probs, then adj the dose)
What is the only penicillin that can be taken with food?
Amoxicillin
What are some pharmacokinetic properties of penicillins?
Generally short half-lives, so there needs to be frequent dosing
They have concentration-independent pharmacodynamics
What are concentration independent pharmacodynamics? How about dependent ones?
They are effective above a certain threshold, so we want to maintain the drug above this level. For penicillins we want to maintain this level thru continuous IV drip infusion
Dependent means that the higher the concentration, the better the killing action or effectiveness. They need the highest dose possible, no maintenance really
Are penicillins safe in pregnancy? How about during breastfeeding? How about with oral contraceptives?
Safe in pregnancies
Distributed in breast milk, so may affect baby’s microflora
There is a drug interaction with oral contraceptive -> destruction of estrogen, no entero recirculation
What are the adverse effects of penicillins?
Allergic rxns - many ppl report allergies, most aren’t real ones tho
Anaphylactic shock
Serum sickness -> fever and joint stiffness
Rashes
Fever, nephritis (nephron inflammation), eosinophilia
Seizures, encephalopathy delirium
electrolyte imbalances
neutropenia, thrombocytopenia in longer courses of therapy
Diarrhea, GI upset = these are the most common side effects
What is the main structure of cephalosporins?
7-aminocephalosporanic acid
What is a structural difference in cephamycins?
There is an oxygen in place of the sulfur in the ring
ppl say that this isn’t a true cephalosporin
What is the mechanism of action for cephalosporins?
Same as penicillin, so they bind to PBP’s disrupt the cell wall, PG inhibition
They are also bactericidal
What are some of the resistance strategies employed by bacteria against cephalosporins?
Lack of PBP or altered PBP with reduced affinity
Production of beta-lactamases (produced by staph aureus and gram negative bacilli)
Efflux - pumping out the AB
Inability of the drug to penetrate
What are examples of first generation cephalosporins? How is the first gen ceph cefazolin administered?
oral - cephalexin (common) and cefadroxil
Cefazolin - IV/IM
What are first gen cephalosporins effective against?
Active against gram positive cocci (but not enterococci or MRSA) and some gram negative bacilli such as E. coli, proteus and klebsiella
What are the exceptions for gram positive cocci bacteria that are not affected by first generation cephalosporins?
enterococci or MRSA
True of false 1st gen cephs penetrate the CNS
They don’t penetrate the CNS
What is the only drug of choice in the 1st gen gen cephs for surgical prophylaxis?
Cefazolin
What are the second generation oral cephalosporins?
Cefuroxime axetil, cefprozil (cefaclor)
What is an IV/IM second generation cephalosporin?
Cefuroxime
What is the second generation cephalosporin cephamycin?
cefoxitin, it has good anaerobic coverage
What is the coverage of second generation cephalosporins?
Active against the same orgs from the first gen cephs
There is a greater coverage of gram negative bacteria, but it DOES NOT cover Pseudomonas aeruginosa
When are cephamycins used? Provide an example
in mixed aerobic and anerobic infections
In the gut or diabetic foot infxn - there are lots of aerobic and non-aerobic species here
How are third generation cephalosporins administered?
IV or IM injections
What are examples of third generation cephalosporins? Which one is an oral agent? Which one do we reserve for Ps. aeruginosa?
Cefotaxime, ceftriaxone, ceftazidime, cefixime
Ceftazidime for aeruginosa
Cefixime is the oral agent
What is the spectrum for third generation cephalosporins?
The feature enhanced activity against gram negative bacilli
Decreased activity against gram-positive cocci extra strep pneumoniae
Which third generation cephalosporin has the ability to penetrate the CNS?
All of them
What are the three main fourth generation cephalosporins?
Cefepime, Ceftaroline and ceftobiprole
What is the activity of cefepime?
Enhanced activity against Enterobacter and Citrobacter
Active against Ps. aeruginosa
What is so special about ceftaroline and ceftobiprole?
they are broad spectrum and have activity against MRSA, ampicillin sensitive E. faecalis and penicillin resistant S. pneumoniae
What are the adverse effects of cephalosporins?
Hypersensitivity
Diarrhea
Skin rash
Other - fever, granulocytopenia, hemolytic anemia
Biliary pseudolithiasis for ceftriaxone
What is biliary pseudolithiasis and what AB is responsible for this condition?
The crystallization of the drug, which mimics a gallstone
Ceftriaxone - because it is eliminated thru the biliary and has a long half-life
What class of antibiotics are structurally related to beta-lactams?
carbapenems
What are some examples of carbapenems?
Imipenem-cilastatin, meropenem, ertapenem
What is the spectrum of carbapenems?
gram positive, gram negative
including pseudomonas, and other anaerobes
What is so special about ertapenem?
Long half life
dosed once daily
poor activity against enterococcus sp and P. aeruginosa
monkey-cillin because it doesn’t cover APE
*Gorilla = APE = meropenem
Explain monobactams
Monocyclic beta-lactam ring
Resistant to beta-lactamases
Aztreonam not available in Canada
What is the spectrum of monobactams?
Gram-negative bacilli
Includes Ps. Aeruginosa
What do monobactams not cover?
ESBL or AmpC producers
What are the macrolides?
Erythromycin, clarithromycin, and azithromycin
How macrolides work?
They attach to the 23s rRNA on the 50S subunit of the bacterial ribosome resulting in the inhibition of protein synthesis
Bacteriostatic, time dependent killing
How do organisms evade macrolides?
Methylation of the rRNA receptor
inactivating enzymes
active efflux
What is the spectrum of macrolides?
Gram positive pneumococci, streptococci and corynebacterial (reserved for penicillin allergic patients)
M penumonias
Chlamydia trachomatis
C. penumophilia
Bordatella pertussis
Campylobacter jejuni
Helicobacter pylori
Do erythromycin base penetrate the CNS?
No, they are super big molecules
How is erythromycin administered?
IV or oral
the IV causes severe phlebitis which is characterized by pain in the veins
What are the adverse effects of erythromycin?
GI - nausea, acid burning, dyspepsia
Increased liver function tests (LFTs)
Cholestatic hepatitis
QT prolongation and cardia arrhythmias
What causes increased cholestatic hepatits?
Using estolate and/or if pregnant
What is the drug interaction with erythromycin that causes QT prolongation or cardiac arrhythmias?
When combined with CYP3A inhibitors
What is the dosing for clarithromycin and azithromycin?
BID and OD
What enhanced activity do clarithromycin and azithromycin have?
Chlamydia, Moraxella, H. influenzar, mycobacteriums
Useful for some MRSA
What can be said if an organism is resistant to erythromycin?
it is resistant to clarithromycin and azithromycin too
Which antibiotic(s) of the macrolides have a higher rate of GI adverse effects?
erythromycin
What is the erythromycin base with the longest half life?
azithromycin
What are the main uses for macrolides?
URTIs
STI
Acne
Of the three erythromycin bases, which one has the least drug interactions?
Azithromycin
Which erythromycin bases are substrates and inhibitors for CYP 3A4?
erythromycin and clarithromycin
What are some drugs that are metabolized by CYP3A4?
antiarrhythmics, antidepressants, benzodiazepines, anticonvulsants, statins
Using with E or C will increase these drugs’ toxicity
What is the mechanism of action of clindamycin?
Same as macrolides
What is the mechanism of action of clindamycin?
Same as macrolides
They attach to the 23s rRNA on the 50S subunit of the bacterial ribosome resulting in the inhibition of protein synthesis
What is the spectrum of clindamycin?
anaerobes, S. aureus, MRSA, streptococci
Clindamycin is not the drug of choice for any infections. When would it be an appropriate time to use them in patients?
When the patient has a penicillin allergy or when dealing with resistant organisms
How is clindamycin administered?
Orally or parneteral
True or False: Clindamycin is associated with antibiotic-associated diarrhea
Ture, and its called C. difficile diarrhea
What are the adverse effects of clindamycin?
nausea, vomiting, diarrhea
rash
elevated LFTs
esophageal irritation
C. difficile diarrhea
How to prevent esophageal irritation?
Always take the med with water and sit upright
What are examples of tetracylines?
tetracycline, monocycline, doxycycline
What is the mechanism of action for tetracyclines?
inhibit binding of aminoacyl-tRNA to the 30s unit of ribosome to inhibit protein synthesis
bacteriostatic
What are strategies employed by bacteria against tetracyclines?
Unknown
What is the spectrum for tetracyclines?
many gram positive and negative orgs
Very broad spectrum
there are high rates of resistance
What are tetracyclines the drug of choice for?
rickettsiae, bartonella, chlamydiae, m. pneumoniae
Nocardia
P. acnes
What are the adverse effects of tetracyclines?
GI upset (nausea, vomiting, diarrhea)
Skin rashes
Photosensitivity
Yeast overgrowth
Deposited in bones and teeth so there may be teeth yellowing
Hepatitis
Vestibular toxicity (dizziness, vertigo, ataxia) seen in minocycline
Does minocycline have more or less hypersensitivity?
More hypersensitivity
Who do we avoid using tetracyclines in?
Children less than 8 years old
What are the drug interactions with tetracyclines?
Anticonvulsants (phenobarbital, phenytoin, carbamazepine) may reduce Tetra levels
Divalent and trivalent cations reduce abs; need to dose separately
Increase INR and bleeding seen with warfarin
What are glycylcyclines?
synthetic analogue of tetracycline - tigecycline
active against many gram positive and negative orgs including MRSA, s.pneumoniae, enterococci, salmonella, shigella, Acinetobacter, anaerobes
How are glycylcyclines administered?
IV or IM
eliminated thru biliary tract and feces
When are glycylcyclines used?
reserved for resistant organisms
What is the main glycopeptide?
Vancomycin
What is the MOA of glycopeptides?
inhibits cell wall PG synthesis
bactericidal
DIFFERENT THAN THAT OF PENICILLIN
What is the spectrum of glycopeptides/vancomycin?
gram positive cocci in particular enterococci, Penicillin resistant strep pneumoniae, MRSA
Active against clostridia, clostrioides, and some bacilli
What are resistant species to vancomycin?
vanco-resistant enterococci (VRE) and S. aureus (VISA)
How can vancomycin be administered?
IV - for serious infxn
PO - only for C. difficile (as not orally absorbed)
What are the adverse effects of vancomycin?
Nephrotoxicity (kidney damage) especially in combination with nephrotoxins
Ototoxicity - heating loss and off balance
Red man syndrome - person turns red + uncomfortable due to hypotension
Granulocytopenia
How to prevent ototoxicity in vancomycin?
Avoid the use with furosemide, which can increase oto effects
How to avoid or prevent red-man syndrome?
reduce the infusion rate of vancomycin
What is a similar structure drug to vancomycin?
Teicoplanin
What is daptomycin?
lipopeptide (same class as vancomycin)
parenteral
OD dosing
major adverse effect is myopathy
What class of drugs is considered to be the opposite of vancomycin?
Aminoglycosides
What happens if vancomycin is administered alongside an aminoglycoside?
the nephrotoxicity is synergistic = dangerous for the pt
What are examples of aminoglycosides?
streptomycin, gentamicin, tobramycin, and amikacin
The work horse drug is gentamicin
What is the MOA of aminoglycosides?
inhibit protein synthesis by inhibiting the 30S subunit of bacterial ribosome
What are the resistance strategies against aminoglycosides?
mutation or methylation of the 16s rRNA-binding site
Enzymatic destruction of the drug
lack of permeability of the drug molecule
active efflux (or lack of active transport)
Aminoglycosides are not effective against gram +ve species. What could we do to help with activity?
Destroy the cell wall first and then use the aminoglycoside to attack the ribosome
Seen in endocarditis
What is the spectrum of aminoglycosides?
aerobic gram negative bacilli
Discuss the pharmacokinetics of aminoglycosides
IV/IM
penetrate the tissues relatively poorly, no CNS
Renal elimination (adj the dose with renal dysfxn)
Are aminoglycosides synergistic with penicillins for enterococci and streptococci?
Yes
What are the adverse effects of aminoglycosides?
Nephrotoxicity
Ototoxicity
Neuromuscular blockade
allergies rare
What are some drug interactions with aminoglycosides?
Other nephrotoxic drugs
other ototoxic drugs
neuromuscular blocking agents
What are examples of fluoroquinolones?
Ciprofloxacin, levofloxacin, moxifloxacin
What is the MOA of fluoroquinolones?
Inhibit DNA gyrase or topoisomerase II and IV
Bactericidal; conc dependent killing
What are the strategies for fluoroquinolone resistance?
alteration of the A or B subunit of DNA gyrase
mutation in ParC or ParE of topoisomerase IV
Change in outer membrane permeability
efflux pumps
What is the spectrum of fluroroquinolones?
highly active against gram negative bacteria
Haemophilus sp, Neisseriae, chlamydiae, etc
Of the fluroquinolones what is the most active against P. aeruginosa? S. pneumoniae? Anaerobes?
P. aeruginosa -> ciprofloxacin
S. pneumoniae -> levofloxacin
anaerobes -> moxifloxacin
What conditions are commonly treated with fluoroquinolones?
UTI, STI, lower resp tract infxn, enteritis or travelers diarrhea, drug resistant mycobacterial infection
How are fluoroquinolones administered?
IV or PO, parenteral use not commonly required
Excellent oral bioavailability
How are ciprofloxacin, levofloxacin, and moxifloxacin eliminated?
ciprofloxacin and, levofloxacin - eliminated renally
moxifloxacin - biliary pathway (doesn’t get to the urine and not for UTI’s)
What are the adverse effects of fluoroquinolones?
Nausea, vomiting, diarrhea
insomnia, headache, dizziness
Other CNS effects including seizures (goes to the brain and causes jitters, dizzy, scattered thoughts)
skin rashes
impaired liver fxn
tendinitis, tendon rupture
QTc interval prolongation
Hypo/hyperglycemia - hypo is linked to the seizures
C. difficile diarrhea
Peripheral neuropathy = tingles and numbness in extremities
What are the drug interactions with fluroquinolones?
They bind to di and tri-valent cations
QTc prolongation
CYP 1A2 inhibition -> increased levels of many drugs
Increase INR with warfarin
Is the use of fluroquinolones common?
No, many toxicities and a lot have been removed from the market
Only for resistant organisms, not really a drug of choice overall
Not used in children under 18 years
True or false: sulfamethoxazole and trimethoprim are commonly combined together as TMP/SMX
True, normally they are static drugs, but when combined, they become cidal drugs
What is the mechanism of SMX?
structural analogue of PABA and competitively inhibits dihydrofolic acid synthesis
What is the mechanism of TMP?
binds to dihydrofolate reductase therefore inhibiting the reduction of dihydrofolic acid to tetrahydrofolic acid
What is the resistance for SMX and TMP?
the ability for the cell to use preformed folic acid, don’t need to make it
What is the spectrum of SMX and or TMP?
wide spectrum of gram positives, gram negatives, chlamydia, nocardiae, and protozoa
What are some examples of organisms affected by SMX/TMP?
staphylococci including MRSA
Streptococcus pneumonia, not group A strep
S. maltophilia
Moraxella
H. influenza
Enterobacteriaceae
Brucella
pneumocystis jirovecii
What is Pneumocystis jirovecii?
An opportunistic pathogen in HIV infected patients
What are the uses of SMX/TMP?
UTI, MRSA infections, PJP, other
What are the adverse effects of SMX and TMP?
skin rashes, which can be severe/ life-threatening
Hypersensitivity - due to the sulfa component
headache
GI issues (N,V,D)
bone marrow suppression - decreases in WBC and platelets, anemia too
Hyperkalemia and hyponatremia
photosensitivity
What are the drug interactions of TMP/SMX?
2C9 inhibitor and 3A4 substrate causing increased levels of carvedilol, digoxin, and phenytoin
Increased INR and bleeding with warfarin
Hypoglycemic agents - increased risk of hypoglycemia
Drugs that increase potassium levels
What are some cautions and contraindications with TMP/SMX?
Caution with those with renal dysfunction (folic acid development and unbinding to bilirubin causing increased toxic free forms)
Contraindicated in first and third trimester of pregnancy
What is the MOA of metronidazole?
Unknown, possible inhibition of nucleic acid synthesis and disruption of DNA
Resistance is unknown
What is the spectrum of metronidazole?
anaerobes including C. difficile
protozoa - trichomonas, Giardia, etc.
Propionibacterium are resistant
How is metronidazole administered?
IV and PO
The PO has excellent bioavailability
What are the adverse effects of metronidazole?
GI
metallic taste
headache
dark urine
peripheral neuropathy (after a couple weeks of use)
Disulfiram-like rxn with alcohol
Insomnia
stomatitis - mouth sores
What are disulfiram-like reactions and which anitbiotic may cause this?
You feel sick -> nausea, vomiting, sweating
Can be seen in patient who use metronidazole
What are the drug interactions with metronidazole?
alcohol - disulfiram rxn
warfarin - increased INR and bleeding
What is the MOA of linezolid?
inhibits protein synthesis
bacteriostatic, but cidal for strptococci
What is the spectrum for linezolid?
Streptococci, enterococci( includes VRE), Staphylococci (including MRSA)
Reserved for multi-drug resistant organisms
An alternative for vancomycin
expensive
What is the administration for linezolid?
IV and Oral
What are the adverse effects of linezolid?
Headache
nausea, vomiting, diarrhea
Rash
increased LFT’s
myelosuppression - low platelets and anemia
Optic or peripheral neuropathy
Lactic acidosis
decreased seizure threshold
What are some drug interactions with linezolid?
Increased serotonin syndrome risk with SSRIs and MAOIs
Rifampin decreases linezolid levels
