Cephalosporins, Carbapenems, Monobactams Flashcards
Cephalosporins are the only ones to cover what?
Below the diaphragm anaerobes
1st generation cephalosporins
cefazolin, cephalexin
Spectrum of activity of 1st generation cephalosporins
- Best activity of all cephalosporins against gram-positive aerobes – penicillin-susceptible streptococcus pneumoniae (PSSP) and methicillin-susceptible staphylococcus aureus (MSSA)
- Activity against some gram-negative aerobes: proteus mirabilis, Escherichia coli, klebsiella pneumoniae (PEK).
- Ex. cefazolin, cephalexin; cefazolin is drug of choice for surgical prophylaxis.
2nd generation cephalosporins
cefuroxime, cefoxitin, cefotetan, cefprozil
Spectrum of activity of 2nd generation cephalosporins
slightly less active than 1st gen cephalosporins against gram-positive aerobes such as staphylococci and streptococci but are more active against gram-negative aerobes.
1. Gram-positive aerobes: same as 1st gen, cefprozil and cefuroxime are the best options
2. Gram-negative aerobes: activity against proteus mirabilis, Escherichia coli, klebsiella pneumoniae, haemophilus influenzae (only beta-lactamase negative strains), Moraxella catarrhalis, Neisseria spp, Citrobacter and Enterobacter (HENPECK).
3. Anaerobes: only cefoxitin, cefotetan, and cefmetazole are active against anaerobes including Bacteroides fragilis. Treat polymicrobial infections.
4. Ex. cefuroxime, cefprozil, carbacephems (loracarbef), cephamycin (cefoxitin)
3rd generation cephalosporins
ceftriaxone, ceftazidime, cefpodoxime
Spectrum of activity of 3rd generation cephalosporins
these are the 1st set of drugs with activity against PRSP; less active than 1st or 2nd generation agents against gram-positive aerobes, but have enhanced activity against gram-negative aerobes.
1. Gram-positive aerobes: ceftriaxone and cefotaxime have the best activity and are among the only cephalosporins that have activity against penicillin resistant streptococcus pneumoniae (PRSP).
2. Gram-negative aerobes: expanded spectrum of activity compared to 2nd generation agents (HENPECKSS and more) – P mirabilis, E coli, K pneumoniae (better than 1st and 2nd gen), H influenzae, Neisseria gonorrhoeae (including beta-lactamase producing strains), Citrobacter spp, Enterobacter spp, Serratia marcescens, salmonella spp, shigella spp, pseudomonas aeruginosa (only ceftazidime and cefoperazone)
1. Ceftriaxone does NOT cover pseudomonas. Used for uncomplicated gonorrhea.
2. If pseudomonas aeruginosa is known/suspected, ceftazidime or cefoperazone.
3. Cefotaxime and ceftriaxone for penicillin-resistant streptococcus pneumoniae.
3. Anaerobes have limited activity – usually add metronidazole.
4. Select 3rd generation cephalosporins (especially ceftazidime) are strong inducers of extended spectrum beta-lactamases (AmpC) in gram-negative aerobic bacteria (Enterobacter spp).
5. Ex. ceftriaxone, ceftazidime, cefpodoxime
4th generation cephalosporins
cefepime
Spectrum of activity of 4th generation cephalosporins
active against gram-positive and gram-negative aerobes.
1. Cefepime: similar coverage to ceftriaxone against gram-positive aerobes; displays similar coverage against gram-negative aerobes as 3rd gen agents including pseudomonas aeruginosa and beta-lactamase producing Enterobacter and E coli. Also, poor inducer of extended spectrum beta-lactamase (AmpC) in gram-negative aerobic bacteria.
1. Has antipseudomonal activity
Anti-MRSA cephalosporin
ceftaroline
Spectrum of activity of ceftaroline
- anti-MRSA cephalosporin; only beta-lactam to cover MRSA! Gram positive aerobes – coverage against staphylococci and streptococci similar to ceftriaxone (including PRSP). Gram-negative aerobes – coverage similar to 3rd generation agents like ceftriaxone but does NOT cover pseudomonas aeruginosa.
- For skin and soft tissue infections (including those caused by MRSA).
Spectrum of activity of cefiderocol
- Gram-positive aerobes – no activity; gram-negative aerobes – pseudomonas aeruginosa, MDR strains that produce ESBLs, AmpCs, and carbapenemases.
Spectrum of activity of cephalosporins with beta-lactamase inhibitors
- Ceftolozane-tazobactam: most active against pseudomonas aeruginosa. Gram-positive aerobes – coverage against streptococci; gram-negative aerobes – coverage similar to cefepime but includes some ESBL-producing gram-negative bacteria and also covers AmpC-producing pseudomonas aeruginosa.
- Ceftazidime-avibactam: gram-positive aerobes – coverage against streptococci; gram-negative aerobes – coverage similar to cefepime but also includes many ESBL-producing gram-negative bacteria, some AmpC-producing enterobacterales and pseudomonas aeruginosa and some KPC producing and OXA-48 producing enterobacterales.
Overall, cephalosporins are NOT active against…
MRSA (except ceftaroline) and coagulase negative staphylococci, enterococcus spp, legionella pneumophila, C diff.
What cephalosporins penetrate the CNS and achieve therapeutic concentrations in the CSF?
- Penetrate the CNS: NOT obtained with 1st and most 2nd generation cephalosporins or the beta-lactamase inhibitors. Parenteral cefuroxime, parenteral 3rd, and parenteral 4th generation cephalosporins are attained in the CSF.
What cephalosporins have the longest elimination half-life?
ceftriaxone (8 hrs)
Which cephalosporins do NOT require dosage adjustment in presence of renal insufficiency?
- No dosage adjustment in renal insufficiency: Ceftriaxone and cefoperazone, which are eliminated by the biliary system and the liver. Most are removed during hemodialysis and require supplemental dosing after except for ceftriaxone.
What are the major AEs of cephalosporins?
Hypersensitivity reactions; leukopenia, neutropenia, thrombocytopenia; biliary sludging (ceftriaxone), pseudomembranous colitis; nonconvulsive status epilepticus (cefepime, ceftazidime, cefiderocol).
What is the risk of cross-reactivity between penicilins and cephalosporins?
cross reactivity between penicillins and cephalosporins is associated with similarities in the R1 side chain. Rate of cross-reactivity is estimated to be 1-5%; 1st generation cephalosporins (except cefazolin because it has a unique R1 side chain) demonstrate the highest risk.
When should a penicillin-allergic pateint receive a cephalosporin? When should they not?
- ICU admission due to allergy (anaphylaxis), interstitial nephritis, delayed severe skin allergic reactions –> avoid ALL beta-lactams (cephalosporins, carbapenems)
- Immediate or delayed hypersensitivity reactions (general rash, pruritus) –> avoid cephalosporins with identical or similar R1 side chains, use other cephalosporins with caution.
What cephalosporins contain an MTT (methythiotetrazole) side chain?
This confers unique adverse effects. This include cefamandole, cefotetan, cefmetazole, cefoperazone, and moxalactam.
1. Hypoprothrombinemia, disulfiram reaction (ethanol intolerance)
Spectrum of activity of carbapenems
- Carbapenems are the most broad-spectrum antibiotics, displaying activity against many gram-positive and gram-negative aerobes and anaerobes.
- Gram-positive aerobes: imipenem and doripenem exhibit the best activity, then meropenem and ertapenem – PSSP, MSS, enterococcus faecalis only (NOT faecium)
- Gram-negative aerobes: doripenem and meropenem are the best, followed by imipenem and ertapenem. Carbapenems display activity against beta-lactamase producing strains that display resistance to other beta-lactam antibiotics – drugs of CHOICE for ESBL and AmpC producing bacteria. Meropenem-vaborbactam and imipenem-relebactam also have activity against KPC-producing enterobacterales. HENPECKSS; pseudomonas aeruginosa (NOT ertapenem) but imipenem, meropenem, and doripenem. Acinetobacter spp (NOT ertapenem).
- Anaerobes: all carbapenems display activity against gram-positive and gram-negative anaerobes, including Bacteroides spp.
- They do NOT have activity against MRSA, C diff, Stenotrophomonas maltophilia and atypical bacteria.
- Aztreonam: Has poor affinity for PBPs of gram-positive and anaerobic bacteria but binds preferentially to PBP-3 in aerobic gram-negative bacilli. ONLY has activity against gram-negative aerobes. Active against pseudomonas aeruginosa and HENPECKSS.
What are the carbapenems?
imipenem, meropenem, ertapenem, doripenem
What carbapenem has the longest elimination half-life allowing for once daily dosing?
elimination half-life of ertapenem is approximately 4 hours.
What carbapenems and monobactams achieve therapeutic concentrations in the CSF?
only low concentrations of imipenem diffuse into the CSF following IV administration; meropenem penetrates into the CSF better then imipenem and ertapenem. Aztreonam does penetrate into the CSF.
What is the purpose of co-formulating imipenem with cilastatin?
Imipenem undergoes hydrolysis in the kidney by an enzyme called dihydropeptidase (DHP) to microbiologically inactive and potentially nephrotoxic metabolites. Cilastatin is a DHP inhibitor added to prevent renal metabolism and protect against potential nephrotoxicity.
What carbapenems and monobactams require dosage adjustment in renal insufficiency?
All carbapenems require dosage adjustment in patients with renal dysfunction and are removed during hemodialysis procedures so they are usually dosed after hemodialysis. Aztreonam also requires dose adjustment in renal insufficiency.
What are the major adverse effects associated with the carbapenems and aztreonam?
Hypersensitivity
1. ICU admission due to allergy (anaphylaxis), interstitial nephritis, delayed severe skin allergic reactions avoid ALL beta-lactams (cephalosporins, carbapenems)
2. Immediate or delayed hypersensitivity reactions (general rash, pruritus) avoid cephalosporins with identical or similar R1 side chains, use other carbapenems with caution.
3. Pseudomembranous colitis; seizures in imipenem, meropenem, ertapenem, and doripenem; thrombophlebitis, neutropenia, thrombocytopenia, transient LFT increases, yeast infections.
4. For aztreonam: hypersensitivity, GI – N/V, diarrhea; neutropenia, thrombocytopenia, eosinophilia, transient LFT increases, phlebitis.
Describe the risk factors associated with the development of central nervous system toxicity with the carbapenems.
risk factors for the development of seizures during carbapenem therapy include preexisting CNS disorders (h/o seizures, brain lesions, head trauma), high doses (>2 g imipenem per day), and the presence of renal dysfunction.
Describe the risk of cross-reactivity between penicillins and the carbapenems or aztreonam.
- ICU admission due to allergy (anaphylaxis), interstitial nephritis, delayed severe skin allergic reactions avoid ALL beta-lactams (cephalosporins, carbapenems)
- Immediate or delayed hypersensitivity reactions (general rash, pruritus) avoid cephalosporins with identical or similar R1 side chains, use other carbapenems with caution.
List the β-lactam antibiotic that can be safely used in a patient who experiences anaphylaxis to penicillin.
Aztreonam
Clinical uses of 1st generation cephalosporins
infections due to MSSA, group and viridans streptococci; cefazolin is the drug of choice for surgical prophylaxis; do NOT use for meningitis.
Clinical uses of 2nd generation cephalosporins
pharyngitis, tonsillitis, sinusitis, otitis media, bronchitis, and mild-moderate community-acquired pneumonia. Cephamycins, cefoxitin, cefotetan, and cefmetazole have activity against gram-negative aerobes and anaerobes including Bacteroides fragilis, and are useful in treating polymicrobial infections.
Clinical uses of 3rd generation cephalosporins
Infections caused by gram-negative bacteria (including nosocomial infections); if pseudomonas aeruginosa is known or suspected, ceftazidime or cefoperazone should be used. Ceftriaxone for uncomplicated gonorrhea. Cefotaxime and ceftriaxone for penicillin-resistant streptococcus pneumoniae.
Clinical uses of 4th generation cephalosporins
cefepime for antipseudomonal activity.
Clinical uses of ceftaroline
for skin and soft tissue infections (including those caused by MRSA).
Clinical uses of cefiderocol
infections from multidrug resistant gram-negative bacteria.
Clinical uses of cephalosporin-beta-lactamase inhibitor combo
complicated UTIs.
Clinical use of carbapenems
- Typically used for polymicrobial infections. Ertapenem does NOT have activity against pseudomonas aeruginosa.
- Empiric therapy for nosocomial infections due to gram-negative bacteria.
- Infections due to resistant gram-negative bacteria, especially those organisms that produce ESBLs or type 1/classC/AmpC beta-lactamase enzymes.
- Meningitis: meropenem; febrile neutropenia: imipenem or meropenem
- Complicated UTIs including pyelonephritis caused by KPC-producing Enterobacterales – meropenem/vaborbactam and imipenem/relebactam
Clinical use of aztreonam
- Can only be used for the treatment of infections caused by gram-negative aerobes (including pseudomonas aeruginosa). It is especially useful for the treatment of gram-negative infections in patients with a h/o a severe penicillin or beta-lactam allergy.
Carbapenems with beta-lacatamase inhibitor
meropenem-vaborbactam
imipenem-relebactam
