L5 Pharm: Cephalosporins/Carbepenems/Monobactam Flashcards
Beta-lactam Characteristics
- Bacteriostatic or Bactericidal?
- Mechanism of Action?
- Half life- short or long?
- Eliminated by what organ?
- Cross allergenicity -except _______?
- Bactericidal
- Inhibit cell wall synthesis
- Typically short half life (except Cephalosporin & one Carbapenem)
- Eliminated unchanged by the kidney (except nafcillin, oxacillin, ceftriaxone, cefoperazone)
- Cross allergenicity except aztreonam
Cephalosporins
- Beta lactam ring connected to what structure?
- Cephamycins have a methoxy group at C7 that are active against what bacteria group?
- Beta lactam ring connected to 6-membered dihydrothiazine ring
* *Confers greater stability against many beta-lactamase enzymes that render penicillins inactive** - Anaerobes
- How do Cephalosporins interfere with cell wall synthesis?
2. What are the 3 primary mechanisms of resistance to cephalosporins?
- Interfere with cell wall synthesis by binding to PBP (transpeptidases)
- Inhibition of PBPs leads to inhibition of the final transpeptidation step of PG synthesis - Bacteria confer resistance by:
- Production of B-lactamase enzymes (many gram negative, some gram positive and anaerobic bacteria)
- Change PBP protein- decrease binding affinity
- Gram negative can change porin- inability of antibiotic to reach PBP target due to poor penetration through outer membrane
- How are Cephalosporins grouped?
2. What are divisions based upon?
- Generations (5 total)
- Cephalosporins divided into Generations based on:
- Antimicrobial activity
- Resistance to Beta Lactamase
First Generation Cephalosporins
- Best activity against what bacteria group?
- Good activity against a few…?
- What are the two most common ones used?
- Gram Positive Aerobes
- MSSA
- Penicillin Susceptible S. Pneumoniae
- Group Streptococci
- Viridians Streptococci - Good activity against a few gram negative aerobes (PEK)
- P. Mirabilis
- E. Coli
- K. Pneumoniae -
Cefazolin & Cephalexin
* = bolded in the handout
Second Generation Cephalosporins
- What are the three subgroups?
- Compared to First Generation: less active/more active against what bacteria?
- What subgroup has activity against anaerobes?
- Cephalosporins, Cephamycins, Carbacephems
- Less active against gram positive aerobes (staphylococci and streptococci- MICs are higher)
- More active against gram-negative aerobes - Cephamycins target anaerobes
Second Generation is more active against gram-negative aerobes, such as:
- H. Influenzae
- Enterobacter spp. (some)
- Neisseria spp.
- P. Mirabilis
- E. Coli
- K. Pneumoniae
(Hint: HENPEK)
Also have expanded coverage against Moraxella Catarrhalis
Second Generation Cephalosporins
- The cephamycins (cefoxitin, cefotetan, and cefmetazole) are the only cephalosporins that have activity against what species?
- Cephamycins can be used as a prophylaxis before what type of surgery?
-
Anaerobes
- Bacteroides fragilis
- Bacteroides fragilis group - Prophylaxis before abdominal surgery- kills anaerobic bacteria
Cefuroxime, Cefprozil and Cefoxitin belong to what generation of Cephalosporins?
Second Generation
- expanded gram negative aerobic coverage
- anaerobic coverage (bacteriodes group)
- less gram + coverage than first generation
Cefoxitin, Cefotetan, and Cefmetazole are apart of the __________ subgroup of ____________ generation cephalosporins.
Cephamycin subgroup of 2nd generation
-kill anaerobic bacteria
How do Third Generation Cephalosporins compare to first and second generation with regards to gram +/- bacteria?
- Less active than 1st or 2nd generation agents against gram positive aerobes
- Enhanced activity against gram negative aerobes, including B-lactamase producing strains
What two 3rd Generation Cephalosporins can be given to treat pseudomonas aeurginosa?
ONLY ceftazidime and cefoperazone
Does Ceftriaxone have activity against pseudomonas?
NO.
-Only 3rd generation that do: Ceftazidime and Cefoperazone
Ceftriaxone and Cefotaxime have the best activity against what type of aerobes?
- Gram postive aerobes.
- 3rd generation Cephalosporins- these two drugs have less activity against gram positive agents than 1st or 2nd generation cephalosporins
- Third generation Cephalosporins have bactericidal activity against what gram negative aerobes?
- Do they have activity against anaerobes?
H. Influenzae, E. Coli, Neissiera meningitis and gonorrhea (including B-lactamase producing strains), P. Mirabilis, Enterobacter spp., Citrobacter spp., Salmonella, Shigella, Serratia Marcescens
Pseudomas Aeruginosa is only treated with Ceftazidime and Cefoperazone
- Very little activity against anaerobes
- Ceftizocime has marginal activity
Ceftriaxone, Ceftazidime, and Cefpodoxime are commonly used….
Third Generation Cephalosporins
Select 3rd generation cephalosporins are strong inducers of what enzymes found in gram-negative aerobic bacteria (Enterobacter spp)?
Extended Spectrum B-Lactamases (Type 1 or Class C)
Fourth generation Cephalosporins
- Extended spectrum of activity against what species? What species are not covered?
- What is an example of a 4th generation Cephalosporin?
- Good or poor inducer of Extended Spectrum Beta Lactamases?
- How stable are 4th generation Cephalosporins against B-lactamase hydrolysis?
- Extended spectrum of activity against gram positive and gram negative aerobes
- Gram positive aerobes: coverage against staphylococci and streptococci similar to ceftriaxone and cefotaxime
- Gram negative aerobes: similar coverage to 3rd generation, but has activity against:
- Pseudomonas Aeruginosa & B-lactamase producing Enterobacter & E.Coli - Cefepime (only drug listed)
- Poor inducers
- Excellent stability (most stable against b-lactamase)
Unlike Penicillins, what bacteria are Cephalosporins NOT active against?
- MRSA
- Coagulase Negative Staphylococci
- Enterococcus spp.
- Listeria monocytogenes, Legionella pneumonia, C. diff (atypical bacteria- intracellular pathogens)
- Stenotrophonomonas maltophilia
- Campylobacter jejuni
Cephalosporins
- How well are they absorbed?
- Distribute where? What generation distributes to CSF?
- How are they eliminated? What are they exceptions?
- Long or short half life?
- Well absorbed orally from GI tract, serum concentrations lower than IV dosing
* Food influences absorption - Widely distributed into tissues & fluids
- 3rd and 4th generation adequately distribute to CSF- can be used to treat meningitis (1st & 2nd generation do not reach adequate concentrations!) - Renal elimination; Exceptions:
- Ceftiaxone- biliary system
- Cefoperazone- liver
* Always watch renal function when giving pts these abx! - Short half life (
What type of infections are First Generation Cephalosporins used to treat?
- Skin and soft tissue infections
- Septic arthritis
- osteomyletis
- endocarditis
- UTI
- Bacteremia
Can be used as a prophylactic in surgery
What generation Cephalosporin would you use to treat the following: sinusitis, otitis, upper and lower respiratory infections, polymicrobial infections?
Second Generation
- Bactericidal to anaerobic bacteria
- Can be used as a prophylactic in abdominal surgery
Bolded in Handout:
Second generation cephalosporins are no longer recommended in treatment of meningitis
**Cephamycins treat the whole Bactericides fragilis family & polymicrobial infections (intra-abdominal infections)
What clinical use does 3rd Generation Cephalosporins have?
Used to Treat: (Bolded in Hanodut)
- *Pseudomonas Aeruginosa- Ceftazidime or Cefoperazone
- *Uncomplicated Gonorrhea- Ceftriaxone (single IM dose)
- *Pen-Resistant Strep. Pneumoniae (meningitis, pneumonia)- Use Cefotazime and Ceftriaxone
Others:
- Bacteremia
- Pneumonia
- Complicated UTI
- Abdominal infection
- Bone and joint infection
- Meningitis
What is an important property of Cefepime? What other infections does it treat?
Anti-Pseudomonal Activity
Also Treats: community & nosocomial acquired pneumonia, bacteremia, uncomplicated & complicated UTIs, skin & soft tissue infections, intraabdominal infections, empiric therapy for febrile neutropenia
- What drug is a 5th generation Cephalosporin?
- What two gram positive strains does it have activity against?
- What is it used clinically to treat?
- What is important in really impaired patients?
- Ceftraoline
- Activity against staphylococcus and streptococcus, including multi drug resistant pneumococcus and MRSA
- Clinically: CA-pneumonia, skin & skin structure infections
- DOSE ADJUST in renally impaired patients
Adverse Effects- Cephalosporins
- Hypersensitivity: _____%
- What patient population does hypersensitivity reactions to cephalosporins typically occur in? What is the degree of cross reactivity (%)?
- Hypersensitivity: 5%
- Rxns occur most frequently in pts with penicillin allergy
- Cross Reactivity- 5-15%
- If a patient has an IgE mediated response to penicillin, DO NOT give cephalosporins!*
- If a patient just gets a rash/pruritus- give other beta-lactams with caution keeping in mind the degree of cross reactivity*
Adverse Effects- Cephalosporins
1. Some cephalosporins have a NMTT side chain- what unique adverse effects can these produce?
- What 5 Cephalosporins have this side chain?
- ->Hypoprothrombinemia
- With or without bleeding, due to blocking of an enzyme in Vit. K metabolism or reduction of Vit. K producing bacteria in the GI Tract
- > Disulfiram Reaction (ethanol intolerance)
- NMTT blocks alcohol dehyrdogenase
- Cefamandole, Cefotetan, Cefmetazole, Cefoperazone, and Moxalactam (reduces platelet aggregation that significantly increases the incidence of bleeding)
Adverse Effects- Cephalosporins
- Hematologic effects?
- GI?
- Avoid giving Ceftriaxone to a patient receiving IV __________?
- Beta-Lactam Specific Cytotoxic IgG or IgM antibodies develop & bind WBC or platelets- cause cell lysis when antigen (penicillin) encountered by activation of the complement system
- Leukopenia, neutropenia, thrombocytopenia- especially in patients undergoing long term (>2 wks) treatment - GI: Pseudomembranous colitis- C. diff diarrhea Some cephalosporins may cause diarrhea that is not due to C. diff
- Nausea/vomiting
- Biliary sludging (ceftriaxone therapy)
- transient increase in liver enzymes - IV Calcium
- Precipitation of Ceftriaxone with IV Calcium products- AVOID giving these two together!
Other adverse effects: phlebitis, drug fever, interstitial nephritis (rare), neurotoxicity, non convulsive status epilepticus
Carbapenems
- What are the 4 Carbapenem drugs?
- Carbapenems have a trans configuration hydroxyl group at carbon 6 compared to the cis configuration acylamino group at carbon 6 of penicillin. What does this structural difference result in (aka how are carbapenems better than penicillins?)
- Imipenem, Meropenem, Ertapenem, Doripenem
- Structural change allows for:
- Extended spectrum of activity
- Increased antibacterial activity
- Greater stability against most beta-lactamase enzymes (even more than cephalosporins)
* *Question might be more detail than we need to know- might just be important to know they both have beta-lactam attached to a 5 membered ring & that trans configuration is more stable because there’s less steric hindrance- Orgo chem 101 bitches**
- Do Carbapenems display time dependent or concentration dependent bactericidal activity?
- How do they cause cell death?
- What PBP do they have high affinity for?
- Carbapenems are small zwitterions- how does this influence their activity?
- Time-dependent (all beta-lactams)
- Bind PBP proteins
- PBP-2 (Imipenem, Meropenem, Doripenem)
- Small zwitterion- enable them to penetrate the outer membrane of most gram-negative bacteria and gain access to PBPs more readily
How do bacteria confer resistance to Carbapenems?
- Alter outer membrane porins
- Hydrolysis of carbapenem antibiotics by beta-lactamase or carbapenamase enzymes
- all of the carbapenems display intrinsic resistance to nearly all beta-lactamases - Alterations in PBPs (decreased binding affinity)
- Carbapenems are currently the most _______-spectrum (broad or narrow?) antibiotics
- Which 2 Carbapenems are good against gram-positive aerobes?
- Which 2 are the best against gram negative aerobes?
- Most BROAD SPECTRUM
- gram +/- aerobes AND anaerobes - Gram + aerobes: use Imipenem and Doripenem
- MSSA, PSSP, Group A-C streptococcus, viridians strep, Enterococcus Faecalis only (E. Faecium are resistant) - Gram Negative Aerobes- Doripenem & Meropenem are the best
* *Carbapenems display activity against B-lactamase producing strains that display resistance to other B-lactam antibiotics**
- E. Coli, Klebsiella spp., Serratia Marcescens, Morganella Morganii, Yersinia spp, Citrobacter freundii, Enterobacter spp, proteus spp, providencia spp, acinetobacter spp.
All carbapenems have activity against pseudomonas except…
ERTAPENEM TEST
All carbapenems display activity against gram + & - anaerobes
- What gram postive anaerobes?
- What gram negative anaerobes?
- Peptostreptococcus spp., peptococcus sp., Clostridium perfringens & tetani
- NOT C. Diff! -
Entire Bacteroides family
- Prevotella spp, Veillonella parvula, Fusobacteriums
Carbapenems do NOT have activity against what 7 bacteria strains/species?
- *TEST Q**
1. MRSA**
2. Coagulase negative staph
3. Some enterococci
4. Clostridium difficile**
5. Stenotrophomonas maltophilia**
6. Nocardia
7. Atypical bacteria (Listeria, chlamydia)** - *=bolded in handout
- This list was mentioned twice in lecture- she said it’s important to know*
What carbapenem penetrates CSF best?
- Meropenem*
- Penetrates better than Imipenem (only low concentrations diffuse into CSF following IV administration) & Ertapenem
- What is the major route of elimination of all of the carbapenems?
- What carbapenem undergoes hydrolysis in the kidney? What enzyme causes hydrolysis? What drug inhibits this?
- Kidney- Urinary excretion of unchanged drug (glomerular filtration/tubular secretion)
- IMIPENEM
- Undergoes hydrolysis in the kidney by DHP enzyme
- Causes Imipenem to become inactive & potentially nephrotoxic
- Prevent this by giving Imipenem with DHP-Inhibitor CILASTATIN
- ->This prevents renal metabolism & protects against nephrotoxicity!
“Cilastin makes Imipenem last…im”
- What carbapenem has the longest half life?
2. All carbapenems require dosage adjustments in patients suffering from what?
- Ertapenem- 4 hours; all others have a t1/2 of 1 hour
2. Renal dysfunction
- What are three infections carbapenems are used to treat?
2. If a patient presents with pseudomonas aeruginosa, what carbapenem would NOT be used?
- Used to treat:
- Nosocomial infections (empiric therapy)
- Polymicrobial infections
- Infections due to resistant bacteria- especially organisms that produce type 1 or class C beta-lactamase enzymes - ERTAPENEM
Carbapenems can also be used to treat febrile neutropenia & meningitis in children
Carbapenems
- Hypersensitivity- ____%
- Cross reactivity in patients with what allergy?
- 3%
- Penicillin allergy
Same rules as cephalosporins:
- If a patient has an IgE mediated response to penicillin, DO NOT give carbapenems!*
- If a patient just gets a rash/pruritus- give other beta-lactams with caution keeping in mind the degree of cross reactivity*
How do Carbapenems adversely effect:
- GI system?
- CNS? What risk factors do they pose?
- GI: nausea/vomiting in 5% of patients
- Abx associated pseudomembranous colitis (predisposes pt to c. diff) - CNS: insomnia, confusion, dizziness, hallucinations, dpression
- Increase risk for SEIZURES
- ->Reported in 1.5% of pts receiving Imipenem, Meropenem (0.5%), Ertapenem (0.5%) and Doripenem (patients with preexisting CNS disorders are more likely to develop seizures (brain lesions, recent trauma, history of seizures)
Other adverse effects: thrombophlebitis, neutropenia, thrombocytopenia, transient LFT increases, yeast infections
Monobactrams
- What is the only clinically used monobactram?
- Time dependent or concentration dependent killing?
- Can only bind to what PBP? What species does this limit monobactrams to?
- Aztreonam
- Time-dependent bactericidal action
- PBP-3, which is only found on gram negative aerobes
- Is Aztreonam stable against beta lactamases?
2. What is a significant gram negative aerobe that assertional is active against?
- Aztreonam is relatively stable against hydrolysis by some plasmid/chromosomally mediated beta-lactamases
- Hydrolyzed by some beta lactamases produced by Klebsiella, Enterobacter and pseudomonas aeruginosa - Has activity against PSEUDOMAS AERUGINOSA
- What is the only way Aztreonam can be administered?
- Does it penetrate into CSF?
- How is Aztreoname eliminated?
- Only administered in IV form
- Aztreonam is widely distributed into body tissues & fluids- DOES penetrate CSF, especially in the presence of inflamed meninges
- Eliminated by kidneys- unchanged in urine
- t1/2= 1.3-2.2 hours
* *adjust dose in patients with renal dysfunction!**
Aztreonam is especially useful for treatment of gram-negative infections in patients with what severe allergy? Why is this?
Penicillin allergy. Aztreonam has no cross reactivity!
What are the only 2 3rd generation cephalosporins that target Pen-Resistant Strep Pneumo?
What is the MOST active cephalosporin against Pseudomonas?(2 actually)
Ceftriaxone & Cefotaxime
CEftazidime & Cefoperazone
What is the main clinical use for 1st generation cephalosporins?
Surgical prophylaxis for ABDOMINAl surgery
______ is used for uncomplicated gonorrhea (single IM dose), CAP, PRSP, viridans strep endocarditis
CEFTRIAXONE
