Antimicrobials/antifungals Flashcards
What are 2 first line treatments for MRSA bacteremia?
-vancomycin
-daptomycin
What abx are first line therapy against ESBL organisms?
carbapenems
What is the treatment for mucormycosis or other invasive fungal infections in a soft tissue injury?
liposomal amphotericin B
-as efficacious as amphotericin B but w/ less nephrotoxicity and catheter associated side effects
What are the empiric abx of choice for bacterial meningitis? What if the pt is pregnant?
-vancomycin and a third generation cephalosporin (cefotaxime)
-if pregnant also have to worry about Listeria monocytogenes as an organism so add PCN G to the regimen
-L. monocytogenes is facultative anaerobe GPB transmitted via soft cheese and smoked meats
What is first line treatment for pts w/ fungemia or at risk for it (immunocompromised)?
echinocandins (micafungin, caspofungin, anidulafungin)
What is an appropriate treatment for cryptococcal meningitis?
amphotericin B and flucytosine
-also check for HIV
What class of drug is the first-line treatment for candidemia?
echinocandin (i.e. micafungin)
What is the treatment for VRE?
daptomycin
Which cephalosporins have anti-pseudomonal coverage?
-ceftazidime
-cefepime
Which carbapenems have anti-pseudomonal coverage?
-meropenem
-imipenem
-doripenem
Which penicillins have anti-pseudomonal coverage?
piperacillin
Which fluoroquinolone has anti-pseudomonal coverage?
levofloxacin
Which aminoglycosides have anti-pseudomonal coverage?
-gentamycin
-tobramycin
-amikacin
What are the treatment recommendations for PNA from K. pneumoniae?
-CAP = 14d course of 3rd of 4th generation cephalosporin (rocephin) monotherapy or quinolone monotherapy or either of those with an aminoglycoside
-for PCN allergic = aztreonam or a respiratory quinolone
-nosocomial = carbapenem
-ESBL = carbapenem
What should a pt be monitored for while taking linezolid?
-thrombocytopenia
-anemia
-peripheral neuropathy
-serotonin syndrome
What are examples of beta-lactams?
- penicillin
- cephalosporins
- carbapenems
- monobactams
What is the beta-lactams MOA?
Bactericidal
-inhibits cell wall via inhibiting peptidoglycan cross-linking
Are beta-lactams time or concentration dependent?
Time, ideally 100% T>mic
- especially for GN organisms
Are beta-lactams hydrophilic or lipophilic?
Hydrophilic
What bacterial species are 1st generation cephalosporins good coverage for?
GPC
- does have moderate activity against GNB
What bacterial species are 2nd generation cephalosporins good coverage for?
enhanced activity against E. coli K. pneumoniae and some Proteus
What bacterial species are 3rd generation cephalosporins good coverage for?
increased potency against GNB
What is unique about cedtriaxone’s metabolism compared to other cephalosporins?
hepatically metabolized and excreted
What bacterial species are 4th generation cephalosporins good coverage for?
wide spectrum of coverage to include pseudomonas
-cefepime
What bacterial species are 5th generation cephalosporins good coverage for?
similar to 3rd generation but only cephalosporin to have MRSA coverage
-ceftaroline
What drug is imipenem co-administered with and why?
-cilastatin
-prevents deactivation by dihydropeptidase w/in renal brush boarder
What is the coverage of carbapenems?
Inhibit must GPCs, Enterobacteriaceae, and GNR including pseudomonas and anaerobes
-except ertapenem has no pseudomonas coverage
What is the MOA of vancomycin?
glycopeptide that bonds w/ peptidoglycan precursors of the cell wall inhibiting its synthesis
What is the activity of vancomycin?
-broad spectrum against GP
-choice microbial for MRSA
-Most Streptococcus is susceptible
-good for Enterococcus but more resistance is developing
-has activity against GP anaerobes such as Peptostreptococcus, Propionibacterium, Clostridium
What is the dosing for vanco?
-loading dose 25-30mg/kg
-maintenance dose 15-20mg/kg q12hr for adults w/ healthy kidneys
What is the best predictor of adequate treatment dosing for vanco?
AUC : MIC ratio >/= 400 or a trough of 15-20mcg/mL
On what gene is the VRE resistance encoded?
VanA
What is the amino acid substitute that gives bacteria resistance to vancomycin?
D-lactate substituted for D-alanine in the peptidoglycan precursor for the cell wall
What are the most common/talked about adverse effects of vanco?
-red man syndrome
= rash and pruritis of head, face, neck
- treat by slowing the infusion and/or giving antihistamines
-nephrotoxicity
- risk factors = trough > 15mcg/mL, obesity, critically ill, concomitant use of zosyn
What is the MOA of daptomycin?
inserts a lipophilic tail into cell membrane of GP organisms causing membrane depolarization
What is the antimicrobial activity of daptomycin?
similar to vancomycin (broad spectrum against GP) but reserved for MRSA that fails vanc therapy or for VRE
Is daptomycin concentration or time dependent?
concentration
What is the dosing for daptomycin?
4-6mg/kg q24hrs or 8-12mg/kg if a deep seated infection
How is daptomycin excreted and how does this change its dosing?
-renally cleared
-dosing should be reduced to q48hr dosing if CrCl </= 30mL/min
What is daptomycin not a good choice for GP PNA infections?
it is inactivated by surfactant
What are the adverse effects of daptomycin?
muscle toxcity with BUE myopathy and increased CPK
-discontinue if CPK > 1000 and myopathy
-discontinue if CPK > 2000 even if no myopathy
can cause a falsely elevated PT
What is the MOA of oxazolindinones?
-inhibit 50s ribosome subunit
-bacteriostatic
What are examples of oxazolindinones?
-linezolid
-tedizolid
What is the antimicrobial activity of oxazolindinones?
similar to vanc and dapto
-use for vanc and dapto resistant infections
-does have activity against mycobacterium
What is the dosing and availability of oxazolindinones?
-600mg BID
-100% bioavailability so same dosing for both PO and IV formulas
-no adjustments needed for renal or hepatic failure
What are the adverse effects of oxazolindinones?
well tolerated, mostly GI upset
-can get hematologic and mitochondrial toxicities w/ prolonged use
What is the MOA of clindamycin?
inhibits ribosomal subunits
What is the antimicrobial activity of clindamycin?
-S. aureus
-most Streptococcus species
-anaerobic GP (to include Peptostreptococcus, Peptococcus, Clostridium)
-some GN activity against anaerobes
What resistance needs to be considered when prescribing clindamycin?
avoid in intra-abd infections d/t B. fragilis resistance
What tissue does clindamycin not have good penetration into?
CNS
-excellent for all other tissue penetration
What are the adverse effects of clindamycin?
C. diff colitis
What is the MOA for the fluoroquinolones?
interfere with DNA gyrase and topoisomerase to inhibit DNA synthesis
-bactericidal
What are examples of fluoroquinolones?
-ciprofloxacin
-levafloxacin
-moxifloxacin
-ofloxacin
What is the antimicrobial activity of fluoroquinolones?
broad spectrum
-aerobic GN (Enterobacterioceae, Haemophilus, Neisseria, Moraxella catarrhalis)
-cipro/levo have activity against Pseudomonas aeruginosa (cipro most potent)
-levo/moxi are best for respiratory pathogens (i.e. Streptococcus)
What are some pharmacology characteristics of fluoroquinolones (bioavailability, dependence, absorption, excretion, metabolism)?
-good bioavailability (70-100%)
-concentration dependent
-well absorbed by GI tract
-cipro/levo are renally excreted and require dose adjustments in renal failure
-moxi is hepatically metabolized and excreted in bile
When should fluoroquinolones be given in relation to tube feeds and why?
-separate by 2hrs from tube feeds
-cations in TF can reduce effectiveness of fluoroquinolones
What are the adverse effects of fluoroquinolones?
-QT prolongation
-potential arthropathy and tendonitis
What is the MOA of aminoglycosides?
-inhibit protein synthesis via an unknown mechanism
-bactericidal
-concentration dependent
What is the antimicrobial activity of aminoglycosides?
-GN activity
-primarily for resistant GN bacilli infections (Enterobacteriaceae, Pseudomonas, Acinetobacter)
-can use w/ a cell wall active agent to get GP coverage
-tobramycin has the best activity against Pseudomonas
Do aminoglycosides have anaerobic activity?
no- they require aerobic metabolism to work
What are examples of aminoglycosides?
-tobramycin
-gentamicin
-neomycin
-streptomycin
-amikacin
What are some of the common doses of aminoglycosides?
work best if concentration is about 10x higher than their MIC
-genamicin/tobramycin 5-7mg/kg/day
-amikacin 15mg/kg/day
What are some pharmokinetic characteristics of aminoglycosides (solubility, protein binding, organ failure adjustments)?
-highly water soluble
-low protein binding so wide extracellular distribution
-renal impairment needs prolonged dosing
-cystic fibrosis pts can have significant pharmokinetic alterations
What are the adverse effects of aminoglycosides?
-nephrotoxicity
-injury is to proximal renal tubule
-reversible
-ototoxicity
-injury is to cochlea, vestibule, or both
-irreversible
-risk increases w/ age, renal impairment, or concomitant vanc use
-neuromuscular blockade (rare)
-infusions >30min reduce risk of neuromuscular blockade
What is the MOA of sulfamethoxazole/trimethoprim?
-inhibits folic acid synthesis (sulfamthoxazole)
-dihydrofolate reductase inhibitor (trimethoprim)
-bacteriostatic
What is the antimicrobial activity of sulfamethoxazole/trimethoprim?
-wide GP and GN activity
-can also use for Stenotrophomonas, Pneumocystis jirovecii
What needs to be considered when dosing sulfamethoxazole/trimethoprim?
-dose based off the trimethoprim component
-can get sputum concentrations higher than those in the serum
-CNS concentrations are generally 25-50% of those in the serum
How is sulfamethoxazole/trimethoprim metabolized and excreted?
-hepatically metabolized
-renally excreted
-adjust dosing in renal dysfunction
What are the adverse effects of sulfamethoxazole/trimethoprim?
-can increase bleeding risks in pts on warfarin
-rare: SJS and TENS
-elderly can get hyperkalemia and Na disorders
What is the MOA of metronidazole?
-prodrug = must be activated by target pathogen
-inhibits DNA synthesis and causes oxidative DNA structural damage
-bactericidal
-concentration dependent
What is the antimicrobial activity of metronidazole?
-good for anaerobes (Bacteriodes and Clostridium)
-nonspore forming, GP anaerobic bacteria are naturally resistant (Actinomyces, Lactobacillus, Propionibacterium)
-good for Gardnerella bacterial vaginosis
-used in H. pylori regimens
What are some pharmokinetic properties of metronidazole (solubility, protein binding, bioavailability, penetration)
-lipophilic
-low protein binding
-large volume of distribution
-good bioavailability
-good CNS penetration
-good penetration into abscesses
What are the adverse effects of metronidazole?
-avoid in pregnancy
-can have a disulfiram like reaction if EtOH consumption within 3 days of medication
-inhibits warfarin metabolism and can increase risk of bleeding
-QT prolongation (rare)
What is the MOA of tetracyclines?
-reversible binding of 30s ribosomal subunit
-doxycycline can also bind to 70s subunit
-bacteriostatic
What are some examples of tetracyclines?
-doxcycline
-minocycline
-tigecycline (glycylcycline subclass)
What is the antimicrobial activity of tetracyclines?
-broad GP activity to include MSSA, MRSA, S. pneumoniae, and GP anaerobes
-highly active against atypicals (spirochetes and rickettsial families)
-GN activity only against Neisseria, Moraxella, Haemophilius, and Campylobacter
What are some pharmokinetic characteristics of tetracyclines (bioavailability, absorption, penetration, renal adjustments)?
-high bioavailability and can mostly use PO dosing
-cations found in TF can decrease absorption by up to 90%
-separate dosing from TF by 3hrs
-poor CSF penetration
-doxycycline doesn’t require dosing adjustments w/ renal dysfunction
What is polymixin E?
colistin
-bactericidal against GNB
-mostly used for resistant Pseudomonas, Acinetobacter, or CRE
-has high rates of nephrotoxicity
What is the MOA of azthiromycin (macrolides)?
-bind to 50s ribosomal subunit
-bacteriostatic
What is the antimicrobial activity of azthiromycin?
-good for community acquired upper and lower respiratory infections
-also has some anti-inflammatory activity too
-Streptococcus species
-MSSA
-H. influenzae
-Moraxella
-atypicals
-Chlamydia and Neisseria STIs
-Mycobacterium avium
What are some pharmokinetic characteristics of azthiromycin (protein binding, concentrations, bioavailability, metabolism)?
-low protein binding
-tissue concentration is > serum concentration
-bioavailability after a single PO dose only ~35%
-hepatically metabolized
What are the adverse effects of azthiromycin?
-GI upset
-QT prolongation
What is the MOA of amphotericin B?
-fungicidal
-binds to ergosterol and disrupts membrane function
What is the MOA of the azoles (imidazole/triazole)?
-CYP450 inhibitors
-inhibit C-14 alpha demthylation and impairs ergosterol synthesis and cell membrane integrity
What is the MOA of echinocandins (micafungin)?
-fungicidal
-disrupts cell wall synthesis via inhibiting 1,3-beta-glucan synthase
-good against all Candida species
-fungistatic against Cryptococcus, Mucormycosis, Fusarium
For antibiotics with activity that is a function of both time and concentration how do you monitoring appropriate dosing?
look at the area under the curve, or AUC/MIC ratio
How are hydrophilic antibiotics typically excreted?
renally
How are lipophilic antibiotics typically cleared?
hepatically
What happens to the volume of distribution of hydrophilic antibiotics during critical illness?
Vd is increased
-no change seen in Vd of lipophilic antibiotics
What type of antibiotic resistance is seen in tetracycline, macrolide, and aminoglycoside resistance?
acquired resistance
What type of antibiotic resistance is seen in beta-lactams and vancomycin?
both intrinsic and extrinsic mechanisms
-intrinsic = altered PCN-binding proteins
-extrinsic = beta-lactamase production
What are some mechanisms of resistance in GN bacteria?
-beta-lactamase production
-outer membrane impermeability and porins
-efflux pumps
-antibiotic degrading or altering enzymes
-DNA gyrase mutations
What are risk factors for developing antibiotic resistance?
-hospitalization > 5 days
-high frequency of abx resistance
-recent health care exposure
-hospitalization of 2+ days in the preceding 90 days
-home infusion therapy
-chronic dialysis w/in 30 days
-home wound care
-family member w/ multidrug-resistant pathogen
-immunosuppressed
What is the recommended treatment length for VAP?
randomized trials support 8 days
What is the recommended treatment length for bloodstream infections?
7 days
What are the recommended antibiotics for S. aureus or S. epidermidis?
-cefazolin or nafcillin
-vancomycin if MRSA
What are the recommended antibiotics for E. coli and Klebsiella?
-zosyn
-gentamicin
-cefotaxime
-ceftizoxime
-3rd generation cephalosporins (but no ceftriaxone d/t resistance)
What are the recommended antibiotics for Enterococcus?
-zosyn
-unasyn
What are the recommended antibiotics for bacteroides, clostridia, and anaerobic streptococci?
-flagyl
-clindamycin
What are the recommended antibiotics for Pseudomonas or Serratia?
gentamicin or amikacin w/ additional expanded spectrum zosyn
What is recommended emperic treatment for SBP?
-start abx w/in 48hrs
-cefoxitin or zosyn to start (most commonly E. coli then non-enterococcal streptococci)
-if neutrophil count in the fluid remains high after abx needs ex-lap
Triazoles (diflucan/fluconazole) is effective against all candida species except?
-glabrata
-krusei
What is the treatment for aspergillosis?
amphotericin or voriconazole
What oragnisms are NOT covered by carbapenems?
-MRSA
-Enterococcus
-Pseudomonas
Which antibiotics are cleared by the liver and don’t need to be adjusted in renal disease?
-nafcillin
-oxacillin
-ceftriaxone
What is the emperic treatment for early onset (on vent < 5 days) VAP?
early onset is likely E. coli
-2nd or 3rd generation cephalosporin (ceftriaxone 2gm daily; cefuroxime 1.5gm q8h; cefotaxime 2gm q8h)
or
-fluoroquinolones (levofloxacin 750mg daily; moxifloxacin 400mg daily)
or
-zosyn 3gm q8hr
or
-ertapenem 1gm daily
What is the emperic treatment for late onset (on vent > 5 days) VAP?
most likely pseudomonas:
-cephalosporin (cefepime 1-2gm q8h; ceftazidime 2gm q8h)
or
-carbepenem (imipenem+ cilastin 500mg q6h/1gm q8h; meropenem 1gm q8h)
or
-zosyn 4.5gm q6h + aminoglycoside (amikacin 20mg/kg/d; gentamicin 7mg/kg/day; tobramycin 7mg/kg/day)
or
-fluoroquinolone (ciprofloxacin 400mg q8h; levofloxacin 750mg daily) + vanc 15mg/kg q12h
