Exam 2 lecture 2 Flashcards
Why were fluoroquinolones developed? Broad or narrow SOA? How did their PK properties change? Disadvantages
New group of synthetic antibiotics deveoped in response to growing bacetrial resistance.
The fluoro makes it broad spectrum and has excellent oral bioavailability.
Disadvantage- AE, development of resistance
Name fluoroquinolone drugs
Ciprofloxacin
Levofloxacin
Moxifloxacin
delafloxacin
MOA of fluoroquinolones?
Inhibit DNA synthesis by inhibiting bacterial topoisomerases
What are the two topoisomerases? How does Fluoroquinolones affect them? Primary targets of FQs in each type
DNA gyrase (topoisomerase II(+- Removes excess positive supercoiling
Topoisomerase IV- Essential for separation of interlinked daughter DNA molecules
In DNA gyrase- FQs form a stable complex with DNA and DNA gyrase, blocking DNA separation (primary target in gram negative bacteria)
Topoisomerase- FQs interfere with separation of daughter cells. (primarily target gram positive bacteria
are FQs time or concentration dependent? Speed of activity?
COncentration dependent bactericidal activity
Rapid activity
Mechanisms of resistance of bacteria against fluoroquinolones? Does cross resistance occur between FQs?
- Altered binding site (most important and most common)- chromosomal mutations in DNA gyrase or Topo IV lead to decreased binding affinity
- Expression of active efflux
- altered cell wall permeability (decrease in porin expression)
Name older FQs? Name Newer FQs? Why are Newer FQs called respiratory FQs?
Older- Ciprofloxacin
Newer- levofloxacin, moxifloxacin, delafloxacin
Called respiratory FQs because it is effective against strep pneumoniae
How does delafloxacin differ from the newer FQs
Has respiratpry activity to levofloxacin but has MRSA activity
Do we see cross reactivity with FQ?
Yes.
Especially for e coli, if resistant to one, will be resistant to all, same with pseudomonas
FQ spectrum of activity for gram positieves
Gram positive Aerobes
Older agents (ciprofloxacin) have poor activity against gram positive
Newer FQs and delafloxacin with enhanced activity against gram positive
FQ spectrum of activity for gram negative aerobes
All quinolones have activity against H influenzae, M. catarrhalis and Neisseria spp
Cipre, levo, dela have good activity against gram negatives (moxi is least active against gram negatives)
What are the specific gram positives FQ cover
Group and viridians and enterococcus- limited activity
Streptococcus pneumoniae- ENHANCED activity (thats why theyr ecalled respiratpry FQs)
What are target organsims for FQ
PRSP
MRSA only for delafloxacin
And pseudomonas aeruginosa
(exam) Which FQs have activity against pseudomonas aeruginosa? Which do not?
Cipro, dela and levo
Moxi does not have any activity against pseudomonas aeruginosa (neither does gemi)
Significant reistance has emerged, not moxi
What is a target organism for FQ?
Pseudomonas aeruginosa
FQs are the only oral drugs that we can give that are active against pseudomonas aeruginosa. If these do not work, next choice is IV
stenotrophomonas multifilia cure>
Levofloxacin
FQ spectrum of activity against Anaerobes? Atypical bacteria? Other bacteria?
Atypical bacteria- All FQs have excellent activity against atypical bacteria (drug of choice for legionella pneumophilia)
Anaerobes- moxi has limited activity against bacteroides spp
Other- mycobacterium tuberculosis, bacillus anthracis
Whata are antibiotics that cover atypicals
MAcrolides
FLuoroquinolones
tetracycline
When are FQs drugs of choice?
Legionella pneumophilia
Name atypical bacteria
Legionella pneumophilia
chlamydia
Mycioplasma
Ureaplasma ureakyticum
Describe the PK characteristics of FQ
Concentration dependent bacterial killing
AUC/MIC
Half life of ceftriaxone (exam)
Target AUC/MIC for quinolones in gram positive? Gram negative?
gram positive (strep pneumo)- 40-50
Gram negative- 100-125
We dose quinolone based on MIC
How long to get PAE for quinolones (post antibiotic effect against gram positie? Gram negative?
Gram positive- 2 hrs
Gram negative- 2-4 hrs
are FQ well absorbed orally? Norfloxacin bioavailability? What does this mean? Delafloxacin? Cipro? Levo? Moxi?
Yes
Norfloxacin- 50% (limited concentration in serum so only used for UTI) ,
delafloxacin- 59%, higher dose used to make up for bioavailability limitation
cipro- 70-75%, higher dose used for oral formulation
Levo, moxi- >90% availability, so oral and IV are pretty much similar doses for levo and moxi
How does concentration time profile of fluoroquinolones compare to B lactams? T max of FQ
Fluoroquinolones achieve concentration time profile lower than that of B lactams.
T max- 1-2 hrs
describe the distribution of quinolonesn(lung? Bone? CSF?)
Extensive tissue penetartion due to fluorine, they penetrate prostate because of this
Lung and bone as well
Minimal CSF penetration
Which FQs get into urinary ttract and prostate
Cipro, levo, dela
Elimination of FQ?
Renally eliminated (levo90%, cipro 60%, dela 64%)
Hepatically (moxifloxacin)
Are any of the fluoroquinolones removed during hemodialysis
NONE of the FQs are removed during hemodialysis
compare half life of FQ and B lactams
FQ have longer half lives
Which fluoroquinolones treat upper respiratory tract infection like sinusitis?
LRTI like community acquired pneumonia? Nosocomial (hospital) acquire dpneumonia
UTI (cystitis, pyelonephritis, prostatitis)
Skin and skin structure infections
SInusitis- Levo, moxi, cipro
Community acquired pneumonia- Levo, moxi and gemi
Nosocomial pneumonia- Cipro, levo
UTI (cystitis, pyelonephritis, prostatitis)- Cipro, levo
Skin and skin structure infections- delafloxacin
WHat is importat to know about handling intraabdominal issues with FQ? Why?
Use metronidazole with cipro and levo. Intraabdominal bacteria are usually polymicrobial
DO we see crossreactivity with penicillin and FQ
no
Adverse effects of FQ
Neurologic- BLACK BOX warning (headache, insomnia, dizziness, confusion, agitation) Dose limiting side effect
GI(N/V/D) and hepatotoxicity
QT prolongation (may lead to torsades)
Phototoxicity (uncommon with new FQs)
Tendonitis (tendon rupture)
When should we use FQ with caution
Hypokalemia, preexisting QT prolongation, concomitant antiarrhythmic
What is a contraindication to FQ? Why?
CI in pediatric pts and pregnant/breast feeding women
It also has an articular cartilage damage side effct
When does FQ cause tendonitis (tendon rupture)
When pt is >60 years old, on corticosteroids, transplant
WHat are some drug interactions of FQ? Describe the interactions and which FQ it affects
- Interaction with divalent and trivalent cations (zinc, iron, calcium, aluminum, magnesium, antacids, orange juice, sucralfate) interact with all PO FQs.
Cause clinical failure due to impairement of orally administered FQs
Administer 2-6 hrs apart
- Warfarin- All FQs, idiosyncratic rxn monitor INR)
Name macrolide drugs? Difference between them?
Erythromicin
Azithromycin
clarithromycin
Calrithromycin and azithromycin are structural derivatives of erythromycin
Why did we build azithro and clarithromycin from erythromicin
Broader spectrum of activity
Improved PK properties->better bioavailability-> better tissue penetration-> prolonged half life
explain the structural difference between erythromycin, clarithromycin and azithro
Erythro and clarithro have the same structure, but clarithro has a methoxy group while erythro has a hydroxy group
Azithro has an extra amino group on top (
MOA of macrolide? Bactericidal or bacteriostatic?
Inhibit protein synthesis by reversibly binding to the 50S ribosomal unit
Macrolides are bacteriostatic, but may be bactericidal when present at high concentrations against susceptible organisms
PK of erythro, clarithro or azithro
Erythro and clarithro display time dependent activity; azithro is concentration dependent
mechanism of resistance in macroide and level of resistance? What genes encode them?
- Active efflux- mef encodes for efflux pump that pumps macrolide out. Confers low level resistance to macrolides
2, altered binding sites- encoded by erm gene, which methylates macrolide bidning site on ribosome, confers high level resistance to all macrolides, clindamycin and syncercid
Does cross resistance occur between all macrolides
Yes
Macrolide spectrum of activity? Broad or narrow SOA
Gram positive aerobes- erythromycin and c larithromycin display best activity
narrow spectrum of activity
Rank macrolide spectrum of activity in order from best to last
Clarithro>erythro>axithromycin
Do macrolides display bactericidal or bacteriosatic
bacteriostatic
What organsims does macrolide act against gram positives? Wha is the target organism?
group and viridians streptococci
Streptococcus pneumoniae (about 70%, resistance is developing)
MSSA (Target organism)
Bacillus spp
are macrolides used in serious MSSA infections?
No, bacteriostatic so not used as much
What organisms does macrolide act on that are gram negative aerobes? What does it not cover? Which macrolides are good against gram negatives, which arent?
The whimpy gram negatives
-No activity against enterobacteriaceae
- H influenza (not erythro), M catarrharis, Neisseria spp
Azithro > clarithro> erythro
Do macrolides have any activity against upper airway anaerobes? Below diaphragm aerobes? Name the bacteria
Anaerobes- There is activity against upper airway anaerobes (pepto drugs)
No cover for below diaphragm organisms
Do macrolides have activity against atypical bacteria? If so name the organisms (exam)
Atypical- all macrolides have an excellent activity against atypical bacteria
-Legionella
- chlamydia
- mycoplasma
-Ureaplasma
are macrolides used for pen allergic patients? In waht diseases can we use them for pen allergic pts
Yes
syphillis, campylobacter, lyme
What are the different dosage forms of the macrolides
Azithro and erythro- Both PO and IV
Clarithro- Oral only
describe PK of PO macrolides in stomach? Serum concentrations compared to B lactams
Erythromycin- destroyed by gastric acid. Food decreases absorption.
Clarithromycin- Acid stable and well absorbed regardless of presence of food, ‘
Azithromycin- acid stable, regardless of presence of food
Low serum concentrations compared to B lactams
Describe distribution and elimination of macrolides? CSF penetration?
Distribution- clarithro and azithro VERY VERY LARGE Vd
- Minimal CSF penetration
Elimination- Erythromycin excreted in bile and metabolized by cyp450
- Azithro eliminated by biliary excretion
-Clarithromycin is metabolized and partially eliminated by Kidney so requires dose adjustment when Crcl<30
Which macrolide requires dose adjustment with CrCl<30? Azithromycin half lfe? Are macrolides eliminated during hemodialysis
Clarithromycin needs dose adjustment
68 hrs for azithro half life
None of macrolides are removed during hemodialysis
Clinical uses of macrolides
Community acquired pneumonia-> monotherapy in ourpatients and in combo with ceftriaxone for inpatients
Pharyngitis/tonsilitis in pen allergic pts, sinusitis, otitis media
STDs- single dose of azithro
MAC
What do clarithro and azithro cover really well
Pneumonia
What macrolide to use if H influenzae suspected
Azithro
When are macrolides used as alternative for pen allergic pts
Group A strep
Syphilis
Rheumatic fever prophylaxis
prophylaxis of bacterial endocarditis
Adverse effects of macrolides
GI- upto 33% (N/V/D)
Most common with erythro, less with azithro and clarithro. TAKE WITH FOOD IF POSSIBLE
Thrombophlebitis associated with IV erythro and azithro
Ototoxicity with high dose erythro
QTC prolongation (ALL of them cause QTc prolongation)
How to get around thrombophlebitis caused by macrolides
Dilution of IV eruthro and azithro, slow administration and using a large vein
Who should we use macrolides in caution with (exam)
Torsades de pointes/Qtc patients
On other QT prolonging drugs
Hypokalemia/Hypomagnesemia
WHat are the cytochrome P450 drugs that are inhibitors of cytochrome p450
Erythromycin and clarithromycin ONLY
What drugs do erythromycin and clarithromycin increase concentrations of (exam)
Theophyline
Carbamazepine
Cyclosporine
Phenytoin
Warfarin
Digoxin
Valproic acid
Does azithro cause P450 inhibition? What does it interact with
No it does not. Azithro may potentiate warfarin
Is there an adverse risk of combining Antacids with metals with macrolides?
No, you do not need to separate it
Out of macrolides, b lactams and Quinolones and tetracyclines, who has activity against atypical bacteria
Only B lactam combos do not have activity. The rest do
