Cephalosporins, Carbapenems and Monobactams Flashcards
What distinguishes cephalosporins from penicillins (think mech. or action/resistance)?
Cephalosporins are stable against b-lactamases
Mechanism of Action: cephalosporins
Cephalosporins, like penicillins, interfere with cell wall synthesis by binding to and inhibiting enzymes called penicillin-binding proteins (PBPs) that are located in the cell wall of bacteria, thus inhibiting peptidoglycan cross-linking. This kills the cell.
Mechanism of Resistance: cephalosporins (3)
B-lactamases: less of a problem for 3rd and 4th generations
Changing the PBPs themselves so the drug can’t bind, ie. in MRSA or penicillin-resistant S. pneumo
Antibiotic can’t reach target because it can’t cross outer membrane (in Gram-negative bacteria).
Spectrum of Activity: 1st generation cephs
G+ most aerobes: ex. MSSA, Penicillin-susceptible Streptococcus pneumoniae, S. pyogenes and S. agalactiae (GBS), S. viridans
G- : “PEK:” Proteus mirabilis, E. coli, Klebsiella pneumonaie
Spectrum of Activity: 2nd generation cephs
G+ aerobes: (equal or slightly higher MICs than 1st generations)
G-: “HEN PEK:” H. influenzae, Enterobacter, Neisseria spp., Proteus mirabilis, E. coli, Klebsiella
Which 2nd generation agents have activity against anaerobes?
The cephalomycins, esp. Cefoxitin
Which 2nd generation agents work against B. fragilis?
Cefoxitin
Do any other generations of cephalosporins have activity against anaerobes, besides the 2nd generation?
No, just the second generation
Spectrum of activity: 3rd generation cephalosporins
G+ aerobes: ceftriaxone and cefotaxime are two of the only cephs to work against pen-resistant S. pneumo, but other than that, relatively poor activity
G- aerobes: “HEN PECKSSS:” H. influenzae, Enterobacter, Neisseria spp., Proteus mirabilis, E. coli, Citrobacter, Klebsiella, Serratia, Salmonella, Shigella
Which 3rd gen. cephs have activity against pen-resistant Strep. pneumo?
Ceftriaxone and cefotaxime
Which 3rd gen. cephs have activity against Pseudomonas?
Ceftazidime and cefoperazone
Which 3rd generation ceph induces b-lactamase activity in Enterococcus
Ceftazidime
Spectrum of activity: 4th gen cephs
G+ aerobes: coverage against staphylococci and
streptococci similar to ceftriaxone and cefotaxime
G- aerobes: similar to 3rd gens, incl. Pseudomonas aeruginosa, b-lactamase-producing enterococcus, and E. Coli
Which G+ aerobes do ceftriaxone and cefotaxime show activity against
Staph. and strep
Do 4th gen cephs induce b-lactamases in G- bacteria? To which class of bacteria does this expand coverage?
No, and b-lactamase producing enterococcus
Spectrum of activity: 5th gen cephs
Extended activity against respiratory pathogens, MRSA, multidrug resistant organisms (MDROs)
Spectrum of activity: ceftaroline (5th)
MRSA - (Skin & skin structure infections, or Community acquired bacterial pneumonia)
Spectrum of activity: ceftolozane + tazobactam (5th)
Beta-lactam resistant G- Rods, including Pseudomonas (complicated UTI including pyelonephritis, or complicated intra-abdominal infections, with metronidazole)
What do cephs not affect?
Overall, cephalosporins are not active against MRSA*, coagulase-negative staphylococci, Enterococcus spp., Listeria, Legionella, C. difficile, Stenotrophomonas
maltophilia, and Campylobacter jejuni.
*exception is ceftaroline
Which cephalosporins are active against MRSA
Ceftaroline
Which cephalosporins are active against pseudomonas?
4th gens, as well as ceftazidime and cefoperazone
Ceph Absorption and Bioavailabilty?
Good, not great.
Ceph Distribution?
Widely distributed
Ceph Elimination?
Most are eliminated unchanged by the kidneys via glomerular filtration and tubular secretion.
They require dosage adjustment in the presence of renal insufficiency.
The exceptions include ceftriaxone and cefoperazone,
which are eliminated by the biliary system and the liver, respectively.
Which ceph generations can cross the BBB?
Parenteral cefuroxime, parenteral 3rd, and 4th
gens can cross the BBB, especially when the meninges are inflamed
Which cephs are indicated by meningitis?
Parenteral 3rd and 4th gens - better for G- etiologies
NO LISTERIA MONOCYTOGENES ACTIVITY!
Cefuroxime crosses the BBB but is not bactericidal in the CSF
Which cephs don’t require dose adjustments in renal failure?
ceftriaxone and cefoperazone
Which ceph is eliminated by the liver?
Cefoperazone
Which cephalosporin is not cleared by hemodialysis?
ceftriaxone
Which ceph is eliminated by the biliary system?
Ceftriaxone
On average, are ceph half-lives long or short?
Short
Which ceph can you give 1-2 times a day?
Ceftriaxone
Indications for 1st gens:
- Orally-administered 1st gens have bad bioavailability and should only be used for the treatment of mild to moderate skin infections or uncomplicated UTIs
- MSSA- or Strep-mediated skin and soft tissue infections, septic arthritis, osteomyelitis, and endocarditis
- Cefazolin is the drug of choice for surgical prophylaxis against surgical site infections because of its activity against Staph; can usually be administered as a single preoperative dose.
- UTIs and bacteremias due to “PEK”
Indications for 2nd gens:
- Oral agents, such as cefuroxime, are useful for the treatment of pharyngitis, tonsillitis, sinusitis, otitis media, bronchitis and mild to moderate community-acquired pneumonia. This is due to expanded G- coverage
- Useful for the treatment of mild to moderate skin and soft tissue infections, and uncomplicated urinary tract infections due to susceptible bacteria.
- Although cefuroxime does penetrate the CNS, it is not bactericidal enough when it gets there, so IT IS NOT USED for meningitis
- The cephamycins, esp. cefoxitin, have activity against G-‘s, incl. anaerobes such as B. fragilis, so they are useful for prophylaxis in abdominal surgical procedures and for the treatment of polymicrobial infections such as intraabdominal infections
(diverticulitis, appendicitis, bowel perforation), pelvic infections (pelvic inflammatory disease), and skin and soft tissue infections in patients with diabetes.
Indications for 3rd gens:
- Due to expanded activity against gram-negative aerobes, can treat of bacteremia, pneumonia,
complicated UTIs, peritonitis, intraabdominal infections, skin and soft tissue infections, bone and joint infections, and meningitis caused by gram-negative bacteria (nosocomial infections). - If Pseudomonas aeruginosa is known or suspected, ceftazidime or cefoperazone should be used.
- If anaerobes are known or suspected,
metronidazole or clindamycin should be added. - Ceftriaxone is used as a single IM dose for uncomplicated gonorrhea.
- Cefotaxime and ceftriaxone have good activity against gram-positive aerobes, and may be used for the treatment of infections due to pen-resistant
Strep. pneumo (meningitis, pneumonia). - Ceftriaxone can be used for the treatment of viridans strep endocarditis in clinically stable
patients as outpatient parenteral therapy. - Oral third agents are used for the treatment of uncomplicated UTIs, acute otitis media, minor soft tissue infections, and acute sinusitis.
- IV agents can cross the BBB
Indications for 4th gens:
Community- and hospital-acquired pneumonia Bacteremia Uncomplicated and complicated UTIs Skin and soft tissue infections Intraabdominal infections Gram-negative meningitis Empiric therapy for febrile neutropenia Pseudomonas
If anaerobes are known or suspected, clindamycin (above diaphragm) or metronidazole (below diaphragm) should be added.
Indications for 5th gens:
- Ceftaroline is used for community acquired pneumonia and skin and skin structure infections. It has minimal gram negative activity: Haemophilus,
Moraxella – respiratory pathogens - Activity against staphylococcus and streptococcus, including multidrug resistant pneumococcus and MRSA.
- Ceftolozane-tazobactam is used for intraabomdinal infections and complicated UTIs, particularly due to drug resistant gram negative rods.
Would you adjust the dose of ceftaroline in renal failure?
Yes
Cephalosporin adverse effects
- Hypersensitivity - 5%
Allergic-type reactions occur most frequently in patients with a history of penicillin allergy. Cross-reactivity is 5 to 15%, and clinicians must consider whether the allergic reaction to penicillin is IgE mediated and the degree of cross-reactivity when deciding if a cephalosporin should be used in a patient with a history of allergy to penicillin. If previous reactions led to immediate or accelerated hypersensitivity reactions (anaphylaxis, laryngeal edema, hives, bronchospasm) – avoid other cross-reactive b-lactams. If they are delayed hypersensitivity reactions (rash, pruritus) – give other b-lactams with caution, keeping in mind the degree of cross-reactivity. - Some cephalosporins have a 5-NMTT side chain (nitromethylthiotetrazole) that confers unique adverse effects. They can cause hypoprothrombinemia with or without bleeding due to blocking of enzyme in vitamin K metabolism or reduction of vitamin K producing bacteria in the GI tract. Moxalactam also reduces platelet aggregation that significantly increased the incidence of bleeding. Finally, these drugs can cause a disulfiram reaction with alcohol.
- Hematologic
β-lactam-specific cytotoxic IgG or IgM antibodies are developed that bind to circulating WBC or platelets. This causes cell lysis when antigen (penicillin) is
encountered by activation of the complement system. Leukopenia, neutropenia or thrombocytopenia - especially in patients receiving long-term (> 2 weeks) therapy.
D. Gastrointestinal
- Transient increases in liver enzymes.
- Biliary sludging with ceftriaxone therapy.
- Nausea, vomiting.
- Pseudomembranous colitis (Clostridium difficile diarrhea). Some cephalosporins may cause diarrhea that is not due to C. difficile.
E. Precipitation of ceftriaxone with IV calcium products – avoid coadministration.
What precipitates ceftriaxone?
Calcium. Avoid taking with milk.
What changes in activity result from the structural differences between b-lactams and carbepenems
The structural difference results in increased antibacterial activity and greater stability against most b-lactamase enzymes.
Small zwitterions, can penetrate the outer membrane of most gram-negative bacteria
Carbepenem’s mechanism of action:
Like other b-lactam antibiotics, carbapenem antibiotics display time-dependent bactericidal activity (except against Enterococcus), by binding to PBPs.
Carbepenem’s mechanism of resistance:
A. Decreased permeability in G-‘s, particularly Pseudomonas.
B. Hydrolysis of carbapenem antibiotics by carbapenemase enzymes
C. Alterations in PBPs that lead to decreased binding affinity of the carbapenem.
Spectrum of activity, overall
The carbapenems are currently the most broad-spectrum antibiotics, with good activity against many gram positive AND gram-negative aerobes AND anaerobes. All have equally good anaerobic activity.
Spectrum of activity, imipenem
G+ aerobes: MSSA, pen-susc. Strep. pneumo, other Strep, E. faecalis
G- aerobes: intermediate activity
Spectrum of activity, doripenem
G+ aerobes: MSSA, pen-susc. Strep. pneumo, Groups A, B, and C streptococci, S. viridans, E. faecalis
G- aerobes: lots of activity, HEN PECKSSS +
Pseudomonas aeruginosa, Morganella morganii, Providencia spp.,
Yersinia spp., Acinetobacter spp.,
Moraxella catarrhalis, Campylobacter jejuni,
Spectrum of activity, meropenem
G+ aerobes: 2 to 4 times less effective than imepenem
G- aerobes: lots of activity, HEN PECKSSS + Pseudomonas aeruginosa
Morganella morganii, Providencia spp.,
Yersinia spp., Acinetobacter spp.,
Moraxella catarrhalis, Campylobacter jejuni,
Spectrum of activity, ertapenem
G+ aerobes: 2 to 4 times less effective than imepenem
G- aerobes: least effective, NO pseudomonas or acinetobacter activity
Which anaerobes do the carbepenems have activity against?
Gram+ anaerobes: Peptostreptococcus sp., Peptococcus spp., Clostridium perfringens and tetani
Gram- anaerobes: Bacteroides spp., Prevotella bivia,
Fusobacterium spp., Veillonella parvula
What DON’T the carbepenems have activity against?
The carbapenems do NOT have activity against MRSA, coagulase-negative Staph, some enterococci, C. diff, Nocardia, atypicals, and Stenotrophomonas maltophilia
Are there oral carbepenems?
No
Distribution (excluding CNS)?
Great, it gets everywhere
Elimination, overall?
All of the carbapenems are excreted in the urine as an uncharged drug. Both filtered and secreted.
What danger does imipenem pose towards the kidney?
How does cilastatin protect against this?
Hydrolysis by DHP in the kidney converts imipenem to microbiologically inactive and potentially
nephrotoxic metabolites. A DHP inhibitor called cilastatin is added to imipenem to prevent nephrotoxicity.
How well do carbepenems cross the blood-brain barrier?
Meropenem penetrates into the CSF better than imipenem and ertapenem, with CSF concentrations up to 52% of simultaneous serum concentrations in patients with meningitis
Do carbepenems require dose adjustments in renal failure? If so, which ones
All carbapenems require dosage adjustment in renal dysfunction
Are carbepenems removed during hemodialysis?
Yes, all of them.
Indications for carbapenems, overall
- As very broad-spectrum antibiotics, they are used on polymicrobial infections (ie. intraabdominal or skin and skin structure infections in diabetics) and as empiric therapy for nosocomial infections (ie. serious lower respiratory tract infections, septicemia, and complicated urinary tract infections)
- Infections due to resistant bacteria, especially those organisms that produce β-lactamases.
Which carbepenems would you use in febrile neutropenia?
Imipenem or meropenem
Which carbepenem(s) would you use in pediatric meningitis?
Meropenem
Serious adverse effects - carbepenem
A. Hypersensitivity - 3% (sim. to cephalosporins)
- Allergic-type reactions occur most frequently in patients with a history of penicillin allergy. Cross-reactivity is 5 to 15%, and clinicians must consider whether the allergic reaction to penicillin is IgE mediated and the degree of cross-reactivity when deciding if a cephalosporin should be used in a patient with a history of allergy to penicillin. If previous reactions led to immediate or accelerated hypersensitivity reactions (anaphylaxis, laryngeal edema, hives, bronchospasm) – avoid other cross-reactive b-lactams. If they are delayed hypersensitivity reactions (rash, pruritus) – give other b-lactams with caution, keeping in mind the degree of cross-reactivity.
B. Gastrointestinal
- Nausea, vomiting, and diarrhea have been reported in up to 5% of patients
- C. diff
C. Central nervous system – direct toxic effect
1. Insomnia, agitation, confusion, dizziness, hallucinations, and depression.
2. Seizures - usually with imipenem (1.5%). Since imipenem dosing now adjusts for renal dysfunction, seizures are less prevelent
Pre-existing CNS disorders, high doses (>2 g/day), and renal dysfunction are all risk factors.
List the four carbepenems in order from broadest to narrowest bacterial coverage?
Imipenem> doripenem»meropenem»ertapenem
What is the only monopenem available today?
Aztreonam
Monobactam’s mechanism of action?
Binds PBPs, stops cell wall synthesis, bactericidal.
Monobactam’s mechanism of resistance?
Aztreonam is hydrolyzed by some b-lactamases produced by Klebsiella spp., Enterobacter spp., and
Pseudomonas aeruginosa.
Changes in porin proteins, stopping drug from entering cell
Monobactam’s spectrum of activity?
G- aerobics, incl. HEN PECKSSS, Pseudomonas aeruginosa
Moraxella catarrhalis
Morganella morganii
Providencia spp.
Is aztreonam oral or IV?
IV
Aztreonam’s distribution (not including CNS)?
Great, it goes everywhere
Can aztreonam enter the CNS?
Aztreonam DOES penetrate into the CSF, especially in meningitis.
Aztreonam’s elimination?
Excreted principally in the urine as unchanged drug.
Aztreonam: adjustment for renal insufficiency?
Yes
Aztreonam: removed during hemodialysis?
Yes, completely
Aztreonam: indications?
Infections caused by G-‘s. Add clindamycin or metranidazole if anaerobic infection is suspected.
Gram-negative infections in patients with a history of a severe penicillin allergy.
Adverse reactions seen in aztreonam
A. Hypersensitivity -
(rare). Because of a low to negligible incidence of crossreactivity, aztreonam can be used in a patient with a history of penicillin allergy.
B. Gastrointestinal - diarrhea, nausea, vomiting in 1 to 2% of patients
