Pogue: Antimicrobials I Flashcards
Clinically important bacteria
G+
o Streptococcus spp.
o S. aureus
o Enterococcus spp.
Clinically important bacteria
G-
Enteric (3):
Proteus spp.
E.coli
K.pneumoniae)
Clinically important bacteria
G-
Sneaky gram negatives (SPICE)
Sneaky gram negatives (SPICE)
Serratia Providencia Indole (+) proteus Citrobacter Enterobacter
Clinically important bacteria
G-
Nasty gram negatives(2):
Nasty gram negatives
- P. aeruginosa
- A. baumannii
Clinically important bacteria
Anaerobes:
C.difficile
Empiric vs definitive therapy
Empiric Therapy: therapy before the causative organism is known; based off of most common pathogens
Definitive Therapy: once cultures and sensitivities are known
Bacteriocidal vs bacteriostatic
Bacteriocidal: an antibiotic makes the number of bacteria decrease
Bacteriostatic: the number of bacteria stays the same upon exposure to an antibiotic
Synergy:
1 + 1= more than 2 (ie. adding 2 drugs together has synergistic effects that make the combination better than the sum of its parts)
Pharmacokinetics and Pharmacodynamics
- Pharmacokinetics: what the body does to the drug (absorption, distribution, metabolism, excretion)
- Pharmacodynamics: what the drug does to the body (concentration-dependent vs. time-dependent killing)
Minimal inhibitory concentration (MIC)
The lowest concentration of the antimicrobial that inhibits growth (bacteriostatic effect) in the test tube
Drugs that affect cell wall synthesis:
B-lactams, Vancomycin
Drugs that affect bacterial DNA replication
Fluroquinolones
Drugs that act as folic acid inhibitors
Trimethoprim (Stops DHF A –>THF A)
Sulfonamide (Stops PABA –> DHF A)
Drugs that affect the cell membrane
Daptomycin
Protein synthesis inhibitors
50s
30s
50s Macrolides Lincosamides Linezolid Streptogramins
30s
Aminoglycosides
Tetracyclines
Mechanisms of Resistance (3):
Antimicrobial Modifying Enzymes: an example is beta-lactamases
Target Site Alterations: an example is penicillin binding protein alterations
Decreased Concentrations in a Cell:
o Efflux pumps: pump drug out
o Outer membrane porin downregulation: less drug gets into the cell
BETA-LACTAMS:
General:
Bacteriocidal:
Time-Dependent Antimicrobials:
BETA-LACTAMS:
• General:
- Most commonly used antimicrobials
- First available in the 1940s (penicillin)
Bacteriocidal: leads to rapid cell death
Time-Dependent Antimicrobials: higher doses rarely the answer in treatment
BETA-LACTAMS
MOA:
Mechanism of Action:
Inhibition of the final step of cell wall synthesis
Blocks the cross-linking of peptidoglycan (essential for structural integrity)
Process normally carried out by enzymes called penicillin-binding protins (PBPs)
Beta-lactams bind PBPs and block transpeptidation
- Not lethal itself, but part of process that will lead to rapid cell death
BETA-LACTAMS
Elimination:
Exceptions:
Renal Dosing:
Nearly every beta-lactam is eliminated renally and requires renal dosing adjustment
Exceptions:
o Ceftriaxone
o Penicillinase-resistant penicillins (Nafcillin, Oxacillin, Methicillin, Dicloxacillin)
Penicillin
Spectrum of Activity (5):
o Streptococci (S.pyogenes, S.viridans) o Enterococci (E.faecalis) o Treponema pallidum o Clostridium spp. (not C.difficile) o Other mouth anaerobes
Beta-Lactamases:
Enzymes that are secreted by the organism that hydrolyze beta-lactam antibiotics
Likely evolved from PBPs
B-lactamases that only hydrolyze penicillin are called penicillinases
Initially, penicillin was DOC for S.aureus but it has created penicillinases making them resistant
- Now only 5-10% susceptable
Benzathine Penicillin:
Use:
Long acting depot preparation that must be given IM
Only used to treat extremely susceptible bugs (Treponema pallidum¸ which causes syphilis, is a classic example)
Current Use of Penicillin (4):
Syphilis
Dental coverage (Mouth anaerobes)
Necrotizing Faciitis (S.pyogenes)
Definitive therapy for streptococcal infections
Penicillinase-Resistant Penicillins/”Anti-Staphylococcal Penicillins”:
Nafcillin - Commonly used
Methicillin - Not clinically used
Oxacillin - Commonly used
Dicloxacillin - Oral
Penicillinase-Resistant Penicillins:
Designed to overcome:
DOC for:
Strep activity?
Lacks:
- IN GENERAL: o Designed to overcome penicillinase o DOC for MSSA o Some streptococcal activity o Lacks gram negative and enterococcus activity
MRSA (Methicillin Resistant Staph Aureus):
Results from PBP2A alteration, in which the PBP has a decreased affinity for beta-lactams and can still cross-link in their presence
Such a decrease in affinity leads to resistance against ALL beta-lactams**
Aminopenicillins:
Ampicillin (IV)
Amoxicillin (PO)
- Better absorption
Aminopenicillins
HELPS bugs:
H.infleunzae
E.faecalis
L.monocytogenes
P.mirabalis
Samonella and Shigella spp.
Aminopenicillins
Clinical use:
Only static against:
Used with what for synergy against serious enterococcus infection?
Meningitis:
Enterococcal Infections: static against E.faecalis; minimal activity against E.faecium
Use with gentamicin for synergy in serious infections
Meningitis: when concern for listeria, use high dose ampicillin
- Amoxicillin (PO):
o Better absorption (hence PO formulation)
o Same clinical use as ampicillin
Piperacillin
Expands coverage of ampicillin to include:
How does enterococcus susceptibility compare to ampicillin?
Piperacillin/tazobactam:
Expands coverage of ampicillin to include P.aeruginosa
IV only
If enterococcus susceptible to ampicillin, its susceptible to piperacillin
Piperacillin/tazobactam has no advantage over piperacillin alone for treatment of P.aeruginosa
No longer commercially available*
Beta-lactam/beta-lactamase inhibitor combinations
Basics:
o Better aerobic gram negative and anaerobic coverage (typically have beta-lactamases)
o Can treat MSSA
Beta-lactam/beta-lactamase inhibitor combinations (4):
Amoxicillin/Clavulanic Acid (Augmentin) –PO
Ampicillin/sulbactam (Unasyn) –IV
Ticaracillin/clavulanic acid (Timentin) –IV
Piperacillin/Tazobactam (Zosyn) –IV
What is ticarcillin?
Why teach us ticarcillin/clavulanic acid?
Similar class to piperacillin-however, not clinically use
Because of the clavulanic acid it has activity versus S.maltophilia (Nosocomial pathogen)
Amoxicillin/Clauvulanic Acid
(Augmentin)
Empiric regimens for broad coverage for community based pathogens (diabetic foot ulcers, intra-abdominal infections)
Ampicillin/Sulbactam
What does sulbactam have antimicrobial activity against?
(Unasyn)
Empiric regimens for broad coverage for community based pathogens (diabetic foot ulcers, intra-abdominal infections)
Sulbactam itself can be antimicrobial: activity against A.baumannii (makes Unasyn the DOC. Ampicillin is along for the ride.)
Piperacillin /Tazobactam (Zosyn)
Empiric broad spectrum for nosocomial infections (because it can treat pseudomonas)
What is the DOC against A. baumannii?
Ampicillin/Sulbactam (Unasyn)
Common Adverse Effects of Penicillins (6):
Allergic Reactions
Acute Interstitial Nephritis
Bone Marrow Suppression
Seizures
GI Effects
Contact Dermatitis
Penicillin allergy
Rash –> Anaphylaxis
- Related to beta-lactam ring or side chains? (important to make distinction to determine cross-reactivity)
Acute Interstitial Nephritis
Most common with: Triad of symptoms: Starts off as: Progresses to: What's seen on biopsy?
Most common with methicillin (but can be seen with all)
Fever, rash, eosinophilia
Starts as non-oliguric renal failure, but can progress to anuria and renal failure
Eosinophilic cells with tubular damage seen on biopsy
Common Adverse Effects of Penicillins
Seizures associated with:
Associated with high doses and non-renally adjusted doses
Common Adverse Effects of Penicillins
Most common with ampicillin:
GI Effects
Contact Dermatitis
Penicillin Drug Interactions:
What drug for gout can block renal excretion and increase the half-life of penicillins?
Minimal:
Potential for additive toxicities with other agents (rarely seen)
Probenecid: drug for gout that can block renal excretion and increase the half-life of penicillins
o Can be used clinically to increase drug concentrations
CEPHALOSPORINS:
Class: Structure: MOA: G+/- Coverage: Activity against enterococcus:
Beta lactam
Structure: similar to penicillins (6 membered ring attached to beta-lactam ring instead of 5 membered ring)
MOA: same as penicillin
Good Gram positive coverage
ENTIRE CLASS lacks activity against enterococcus (G+)
What are the subclasses of beta-lactams? (wiki)
penicillin derivatives (penams)
cephalosporins (cephems)
monobactams
carbapenems
First Generation Cephalosporin Activity against: G+ G- Anaerobes P.Aeruginosa
Gram (+) Activity:
Good vs. staphylococcus (MSSA)
Good vs. most streptococcus (S.pneumoniae variable)
Good skin coverage as long as MRSA is not a concern
Gram (-) Activity:
POOR
Some activity against PEK organisms (Proteus, E.coli, K.pneumoniae)
Anaerobic/P.Aeruginosa Activity: NONE
First Generation Cephalosporin
First Generation Agents (3):
o Cephalexin
o Cefazolin
o Cefadroxil
Second Generation Cephalosporin agents:
Cefaclor, cefuroxime (2A)
Cefotetan, cefoxitin (2B) “cephamycins”
Cefaclor and Cefuroxime (2A):
Activity against: G+ G- Anaerobes P.Aeruginosa Clinical Use:
Gram (+) Activity: improved against S.pneumoniae
Gram (-) Activity: a little better
Anaerobic/P.Aeruginosa Activity: NONE
Clinical Use: Respiratory tract infections (S.pneumo, H.flu, M.cattarhalis)
Cefotetan and Cefoxitin (2B; “Cephamycins”):
Activity against: G+ G- Anaerobes P. aeruginosa Clinical Use:
Gram (+) Activity: improved against S.pneumoniae
Gram (-) Activity: a little better
Anaerobic Activity: EXCELLENT
P.aeruginosa Activity: NONE
Clinical Use:
- Community acquired intra-abdominal infections (community acquired Gram (-) more likely to be susceptible)
- Surgical prophylaxis
Which type of cephalosporin has the best activity against anaerobes?
Cefotetan and Cefoxitin (2B; “Cephamycins”)
Third Generation Cephalosporin agents (4):
Cefotaxime
Ceftriaxone (IV):
Cefixime
Cefpodoxime (PO)
Third Generation Cephalosporin
Activity against: G+ G- Anaerobes P. aeruginosa Use caution with:
Gram (+) Activity: excellent S.pneumoniae coverage; variable MSSA
Gram (-) Activity: excellent vs. most nosocomial Gram negative bacilli
Anaerobic/P.Aeruginosa Activity: NONE
MUST USE CAUTION WITH ENTEROBACTER AND OTHER SPICE DRUGS
Ceftriaxone
DOC for:
What is it coupled with for intra-abdominal infections?
Also used for:
Ceftriaxone
DOC for CAP, meningitis (S.pneumo)
Intra-abdominal infections (+ metronidazole)
Urinary tract infections
Oral 3rd generation cephalosporins may be used for respiratory infections when oral therapy indicated
Unique 3rd Generation Agent- Ceftazadime
Activity against: G+ G- Anaerobes P. aeruginosa Clinical use:
Gram (+) Activity: less staphylococcus (MSSA) and streptococcus action
Gram (-) Activity: good
Anaerobic Activity: NONE
P.Aeruginosa Activity: YES
Clinical Use: limited due to its propensity to induce resistance mechanisms
Nosocomial meningitis (because of pseudomonas activity)
S.pneumoniae
Mechanisms of resistance to ß-lactams is mediated by:
How do 3rd generation cephalosporins overcome this?
How are MICs affected?
Exceptions:
Mechanisms of resistance to ß-lactams is mediated by small changes to PBPs
3rd generation cephalosporins overcome this by tighter binding to PBP
Minimum inhibitory concentrations (MIC) are higher, but can be overcome (this is not the case with second generation)
Exception meningitis (because sufficient concentrations would not be seen at the site of action)
Meningitis
What is the treatment of choice for CNS infection?
3rd generation cephalosporins are treatment of choice for CNS infections
What have excellent penetration into meninges?
Ceftriaxone and ceftazadime (high dose) have excellent penetration into meninges
What is standard for community acquired bacterial meningitis?
Ceftriaxone is standard for community acquired bacterial meningitis
What is often used for nosocomial organisms? Why?
Ceftazadime often used for nosocomial organisms because it adds pseudomonas
SPICE organisms: List: What do all of them have? What might happen if treated with 3rd gen cephs? Generally use what to treat?
Serratia, providencia, indole (+) proteus, citrobacter, enterobacter
All have a ß-lactamase that can be selected for
Initially the lab says susceptible to 3rd gen cephs
–If treated with 3rd gen cephs the b-lactamase is selected for which confers resistance, and the patient may get worse
Take home-use with extreme caution in these organisms in severe infections
–Generally use cefepime or carbapenems
4th generation:
Activity against: G+ G- P. aeruginosa Use caution with:
4th generation: Cefepime
Gram (+)
–Excellent strep and staph (MSSA)
Gram (-)
–Great against nosocomial organisms
–SPICE organisms,
–Questionable activity against Extended spectrum Beta lactamases (ESBL) organisms
P.aeruginosa: YES
Ceftaroline:
MOA:
G+
G-
Clinical use
Ceftaroline (“Fifth Generation Cephalosporin”):
MOA: binds PBP2A and PBP2X
Gram (+) Activity: can be used for MRSA; better S.pneumo coverage; activity against E.faecalis
Gram (-) Activity: Between 2nd and 3rd generation cephalosporins
Clinical Use: newer drug; CAP, skin infections?
Cephalosporin Side Effects:
What does ceftriaxone also cause?
Hypothrombinemia and Disulfiram-Like Reactions in Patients Taking Alcohol:
Similar to penicillins
Biliary Sludging in Neonates: Ceftriaxone
Hypothrombinemia and Disulfiram-Like Reactions in Patients Taking Alcohol: Cefotetan, Cefetazole, Cefoperazone (Cephalosporins with a methythiptetrazole/MTT group)
Cephalosporin Cross-Reactivity
5-10% cross reactivity with penicillins
However, true cross-reactivity much lower
–0-2%
–Side-chain vs. ß-lactam
–Ceftazadime and aztreonam
What are the broadest agents currently available?
Carbapenems
CARBAPENEMS
G+
G-
Anaerobes:
Cross-reactivity with penicillins:
Gram (+) Action: good, not great (imi > dori/mero > erta)
Gram (-) Action: excellent (dori/mero > imi > erta)
Anaerobes Action: excellent (but not C.diff)
Cross reactivity with penicillins exists (0-50%), but less likely than in cephalosporins
Group 1 Carbapenem
Drug
Holes:
DOC for:
Decrease selective pressure on:
Ertapenem
More narrow spectrum than group 2
Holes: APE (acinetobacter, pseudomonas, enterococcus)
Drug of choice for ESBL producing organisms
•Decrease selective pressure on pseudomonas
Where are ESBLs most commonly seen?
Ability to hydrolyze what?
DOC?
ESBL = Extended Spectrum B-Lactamase
Most commonly seen in E.coli and K.pneumoniae
– Can be transferred to other enterobacteraciae
Ability to hydrolyze extended spectrum ß-lactams
If present all penicillins, cephalosporins, and aztreonam are considered resistant
- Most are also resistant to other agents
Carbapenems are the drugs of choice
What carbapenems don’t cover:
- What they do NOT cover: o MRSA o Enterococci resistant to ampicillin o Stenotrophomas maltophilia o KPC o C.difficile o Fungi and viruses
Group 2 Carbapenems
Drugs: G- coverage: ESBL? Pseudomonas aeruginosa? A.baumannii Clinical use:
Imipenem, Meropenem, Doripenem
Great Gram (-) Coverage:
o ESBL
o Pseudomonas aeruginosa (including those resistant to cefepime and pip/tazo)
o A.baumannii
Clinical Use: multi-drug resistant organisms
Side Effects of Carbapenems:
What is cilastatin?
SEIZURES
Based off of old imipenem data (may have been related to cilastatin, a dihydropeptidase inhibitor added to imipenem to decrease toxicity and increase half life)
More likely at a higher dose
AZTREONAM
What is a monobactam?
G+/G- activity:
Pseudomonas aeruginosa?
ESBL?
Clinical use:
It is a monobactam
Monobactam: β-lactam compounds wherein the β-lactam ring is alone and not fused to another ring
Gram (-) Activity Only:
- Includes pseudomonas
- NO ESBL
Clinical Use: Empiric gram (-) nosocomial coverage in patients with a penicillin allergy (since no cross reactivity)
What is Acinetobacter Baumannii susceptible to?
Acinetobacter Baumannii and ß-lactams
Ampicillin/Sulbactam
Carbapenems
Often the only two agents this organism is susceptible to
- And now frequently resistant to these as well….
