Cephalosporins Flashcards
Mechanisms of Resistance
- β-lactamase
- ↓ penetration through cell membrane
- Efflux
- Alteration of PBP
1 st Generation Cephalosporins
Parenteral
All cephalosporins have b lactam ring and the other ring
2 side chains
R1 on specturm of acitivity
R2 alter pharmacology, prolong half life
• Cephalothin (Keflin®) - t 1/2 0.6 hr - q 4 - 6 h dosing - Painful IM - Best staphylococcal coverage Not seen anymore
• Cefazolin (Ancef®)
- t 1/2 1.9 hr
- q8h dosing
- less painful IM
- Better Gram negative activity
1 st Generation Cephalosporins
Oral
• Cephalexin (Keflex®)
- t 1/2 0.5-1.2 hr
- q6h dosing
- 90% absorbed
- Better staphylococcal coverage
• Cefadroxil (Duricef®)
- t 1/2 1.3-1.6 hr
- q12h dosing
- Almost completely absorbed
- Better Gram negative coverage
1 st Generation Cephalosporins
Spectrum of Activity
• Increased stability to β-lactamases produced by
methicillin-susceptible Staphylococci (MSSA, MSSE)
• Not active against MRSA
• Moderately active against Streptococci
(poor activity against PRSP)
- Not active against enterococci
- Poor activity against Listeria
• Not active against M. pneumoniae, C. pneumoniae, or
Legionella
1 st Generation Cephalosporins
Spectrum of Activity
Relative to ampicillin
- Improved activity against MSSA
- Reduced activity against S. pneumoniae
- No activity against Enterococci
- Reduced activity against Listeria
- Similar/less activity against H. influenzae
• Improved activity against E. coli, Proteus mirabilis, K.
pneumoniae
2 nd Generation Cephalosporins
Spectrum of Activity
• Less activity than 1 st generation cephalosporins
against S. aureus and broader activity against Gram
negative organisms
- Greater activity against some cefazolin-resistant
E. coli, Klebsiella, Proteus mirabilis
• Cephalosporin group (cefuroxime) more active against
H. influenzae, S. pneumoniae than 1 st generation
• Cephamycins (Cefoxitin) active against B. fragilis
• No activity against Enterococci, Mycoplasma,
Chlamydia, or Legionella (as with all* cephalosporins)
2 nd Generation Cephalosporins
Cefuroxime (Zinacef®)
• Penetrates somewhat into CSF (initially recommended
for meningitis, but failures reported)
- t 1/2 1.2 -1.8 hr
- q8h dosing
• “Claim to fame” more resistant to β-lactamases
produced by H. influenzae
• concerns with intermediate and highly resistant
S. pneumoniae
2 nd Generation Cephalosporins
Cefuroxime axetil (Ceftin®)
- Oral ester of cefuroxime
- Hydrolyzed to cefuroxime after absorption
• 30 - 50% bioavailability (absorption increased with
food)
- t 1/2 1.2 hours
- BID dosing
• concerns with intermediate and highly resistant
S. pneumoniae
• (available as tablets and suspension 125 mg/5mL)
2 nd Generation Cephalosporins
Cefprozil (Cefzil®)
• Similar activity to cefuroxime
• Relatively good activity against S. pneumoniae (not as
good as cefuroxime)
- Good side effect profile
- Only available orally
- BID dosing
2 nd Generation Cephalosporins
Relative activity against S. pneumoniae
• Ampicillin / Amoxicillin > Cefuroxime > Cefprozil >
Cefixime* > Cephalexin*
• Cefixime or cephalexin not recommended if
S. pneumoniae resistance suspected or in treatment
of otitis media
2 nd Generation Cephalosporins
Cefoxitin (Mefoxin®)
• Active against Bacteroides fragilis
• More active than 1st generation against E. coli,
Klebsiella, Indole + & - Proteus, and Serratia
• Less active than cefazolin and cefuroxime against
Gram-positives and less active than cefuroxime
against H. influenzae
• Usually stable against Extended Spectrum
β-Lactamases (ESBL) (→ not AmpC, though)
- t 1/2 0.8 hr
- q6-8h dosing
3 rd Generation Cephalosporins
Cefotaxime (Claforan®)
Ceftriaxone (Rocephin®)
Spectrum of Activity
• Moderate activity against methicillin-susceptible
staphylococci, not effective against MRSA
• Good activity against Streptococci (was excellent)
- Resistance has been a concern with
S. pneumoniae
- UAH ceftriaxone 6% (2008); 12% (2019)(meningeal)
2% (2008); 4% (2019) (non-meningeal)
• Good activity against N. gonorrhoeae (especially
ceftriaxone)
• Poor activity against enterococci, M. pneumoniae,
C. pneumonia, and Listeria, as with all* cephalosporins
• 10-100x more activity against M. catarrhalis, H.
influenzae, E. coli, P. mirabilis, K. pneumoniae than 1 st
and 2 nd generation cephalopsorins
• Improved Gram-negative coverage, but not effective
against Pseudomonas (some variable e.g.,
Enterobacter)
3 rd Generation Cephalosporins
Cefotaxime (Claforan®)
Ceftriaxone (Rocephin®)
Problems with Resistance
Problems with Resistance
Inactivated by:
• Extended spectrum ß-lactamases (ESBLs)
(predominantly found in E. coli, Klebsiella)
• Use of cefotaxime/ceftriaxone to treat AmpC producing
‘SPICE A’ organisms may induce AmpC ß-lactamase
production during therapy (may result in clinical failure
despite in vitro susceptibility)
• Therefore not recommended for the treatment of ‘SPICE A’ organisms Serratia Providencia Indole-positive Proteus (e.g., P. vulgaris) Citrobacter Enterobacter Acinetobacter
3 rd Generation Cephalosporins
Cefotaxime (Claforan®)
- penetrates CSF well
- primarily excreted renally
• t 1/2 1 hr • active metabolite desacetylcefotaxime - 1/4 - 1/8 as active as parent - synergistic with parent - Effect of increasing t 1/2 to 1.5 hr • q8-12h dosing
3 rd Generation Cephalosporins
Ceftriaxone (Rocephin®)
• Adequate levels in CSF
• 40% excreted in biliary tract - (may cause biliary
sludge or pseudolithiasis with high doses)
- t 1/2 6.4-8 hours
- q12-24h dosing
• (no dose adjustment required in severe renal or
hepatic failure due to compensation of renal / biliary
excretion )
3 rd Generation Cephalosporins
Ceftriaxone (Rocephin®)
FDA Warning 4/21/2009 - Ceftriaxone/Calcium Interaction
• Concomitant use of ceftriaxone and intravenous
calcium-containing products is contraindicated in
neonates (<28 days of age).
• Ceftriaxone should not be used in neonates (<28
days of age) if they are receiving (or are expected to
receive) calcium-containing intravenous products.
• In patients >28 days of age, ceftriaxone and calcium-
containing products may be administered
sequentially, provided the infusion lines are
thoroughly flushed between infusions with a
compatible fluid.
• Ceftriaxone must not be administered simultaneously
with intravenous calcium-containing solutions via a
Y-site in any age group.
3 rd Generation Cephalosporins
Ceftazidime (Tazidime®, Fortaz®)
• Best antipseudomonal 3 rd generation
• least active 3 rd generation against Gram-positive
cocci
• otherwise similar spectrum to cefotaxime and similar
problems with resistance (AmpC β-lactamases
(SPICE A) and ESBLs (E. coli and K. pneumoniae))
• good penetration into CSF
- t 1/2 1.8 hr
- q8h dosing
3 rd Generation Cephalosporins
Cefixime (Suprax®)
• Spectrum of activity most similar to cefotaxime
• Poor activity against Staphylococci
• Variable - poor activity against Streptococci (S.
pneumoniae may be resistant) (less effective than
Cefotaxime/ceftriaxone) (use not recommended)
• No activity against Enterococci, Listeria, Chlamydia
pneumoniae, or Mycoplasma pneumoniae (as with all*
cephalosporins)
• Good activity against N. gonorrhoeae*, M. catarrhalis,
H. influenzae, Enterobacterales
• Only available orally
- t 1/2 3 - 4 hours
- Once or twice daily dosing
4 th Generation Cephalosporins
• Cefepime is a zwitterion (net neutral charge due to
quaternary N substitution) resulting in faster
penetration in Gram-negative organisms
• High affinity for PBPs
• lower affinity for β-lactamases including the inducible
AmpC β-lactamases produced by the ‘SPICE A’
organisms (but may be hydrolyzed by AmpC
β-lactamases)
• Effective against some but not all ESBL producing
organisms
• 70 - 80% organisms resistant to ceftazidime remain
susceptible to cefepime
4 th Generation Cephalosporins
Cefepime (Maxipime®)
• Retains good Gram positive activity (not effective
against MRSA and Enterococcus)
- Good activity against MSSA and streptococci,
including S. pneumoniae
• Good coverage of N. gonorrhea, N. meningitidis, H.
influenzae, Enterobacterales, Pseudomonas
( Sentry 1998 - 2003 )
• greater activity than Ceftazidime against SPICE A
organisms
• Some activity against ESBLs produced by E.coli and
K. pneumoniae
• May be effective against ceftazidime resistant P.
aeruginosa (similar activity to imipenem)
( Sentry1998 – 2003 )
• t 1/2 2; q8h dosing
5 th Generation Cephalosporins
• Broad spectrum activity
- MSSA, MRSA, VRSA (binds to PBP 2a)
- multidrug resistant S. pneumoniae
- Some vancomycin resistant E. faecalis (not E. faecium)
• Excellent activity against H. influenzae, M. catarrhalis
• Good Gram-negative activity similar to 3rd generation
cephalosporin ceftazidime
- limited activity against B. fragilis
- Excellent safety profile to date
- Low propensity for resistance
• Little is known about efficacy in meningitis and if they
will be useful for meningitis with MDR pneumococci
5 th Generation Cephalosporins
Ceftobiprole (Zeftera®)
• More resistant to inactivation by AmpC -lactamase
than ceftaroline (but both effectively inactivated by
ESBL)
• Activity against P. aeruginosa similar to that of
ceftazidime
• Indicated for community-acquired and hospital
acquired pneumonia (but not ventilator-associated
pneumonia)
• t 1/2 2.85; q8h dosing
5 th Generation Cephalosporins
Ceftaroline (Teflaro®)
• More active than ceftobiprole against Gram-positives
(except E. faecalis)
• Less active than ceftobiprole against some Gram
negatives (particularly against P. aeruginosa)
- t 1/2 2.6; q12h dosing
- FDA approved 2010 for
- Skin and Soft Tissue Infections (SSTIs)
- Community acquired pneumonia (CAP)
• (not currently available in Canada)
Cephalosporin
Rank Order of Activity for S. pneumoniae
• Ceftaroline > ceftobiprole > ceftriaxone, cefepime
> cefuroxime > cefixime* > cephalexin, cefadroxil
• * Use not recommended if resistant S. pneumoniae
suspected or if treating Otitis media
Cephalosporin / β-lactamase Inhibitor Combinations:
Ceftolozane / Tazobactam (Zerbaxa®)
• Only available as combination product
• Ceftolozane is antipseudomonal cephalosporin
- Improved stability against AmpC compared to
ceftazidime
• Active against most Pseudomonas strains, including
MDR ones
- And ~60% of carbapenem-resistant P. aeruginosa
• Active against most Enterobacterales
- Including most ESBL producing E. coli
Cephalosporin / β-lactamase Inhibitor Combinations:
Ceftazidime / Avibactam
• Avibactam inactivates susceptible β-lactamases by
covalent acylation of the β-lactamase active-site serine
residue (found only in Class A, C, and D β-lactamases)
• This binding is partially reversible and activity of the
active site of avibactam can be restored so that the
avibactam can be recycled, unlike the “suicide
inhibitors” clavulanate, tazobactam, sulbactam
Cephalosporin / β-lactamase Inhibitor Combinations:
Ceftazidime / Avibactam
Activity
Activity:
• Most Gram-negative Enterobacterales, including
AmpC producing strains & multi-drug resistant isolates
• Good activity against Pseudomonas aeruginosa
(although there are some resistant strains)
• Limited activity against Gram negative anaerobes
(where these organisms are suspected, metronidazole
should be added)
Cephalosporin / β-lactamase Inhibitor Combinations:
Ceftazidime / Avibactam
resistance
• Some resistance has developed to Avibactam
e.g., AmpC hyper-producing Enterobacter cloacae due
to point mutation(s)
• Gram-negative organisms may be resistant to
ceftazidime through other mechanisms
- e.g., porin alterations
- efflux pumps
- some have multiple resistance mechanisms and
may remain resistant despite inhibition of
β-lactamase with addition of avibactam
• Not active against metallo- β-lactamases (e.g., NDM-1)
Pharmacokinetic Parameters of Cephalosporins
see slide 42
Siderophore Cephalosporins
• New class of cephalosporins – mimics siderophores produced by bacteria to bind and bring iron into the cell
Name a Siderophore Cephalosporins:
Cefiderocol:
• Enters bacterial cell via passive diffusion and active
transport (“Trojan horse” effect), resulting in increased
intracellular concentrations
• Stable to breakdown by a wide variety of
β-lactamases, including Class B (metallo
β-lactamases)
• Therefore, may become an important drug in the
treatment of MDR (including carbapenem-resistant)
Gram-negative infections
• Not currently available in Canada
Adverse Effects of Cephalosporins
• Generally well tolerated
• Hypersensitivity reactions - rashes (1-3%), eosinophilia
(1-10%), rarely anaphylaxis (0.1- 0.0001%)
- Diarrhea (1-20%)
- Thrombophlebitis with IV use
- Interstitial nephritis (< 1%)
• Mild transient increases in serum transaminase
occasionally (1-7%)
• Neutropenia (< 1%), thrombocytopenia (1-3%),
anemia (< 1%)
- Neutropenia up to 5-15% with high dose
cephalosporins for greater than 10 days
• Seizures rarely with high doses in renal failure (<1%)
Adverse Effects of Specific Cephalosporins:
Ceftriaxone
Cefepime
Cefaclor
- Ceftriaxone - biliary sludge (pseudocholelithiasis)
- Cefepime – neurotoxicity
• (Cefaclor) - serum sickness in children (0.05%)
- (Related to metabolism defect)
• (Bleeding and disulfiram reaction associated with
methylthiotetrazole (MTT group) (cefamandole,
cefotetan, cefoperazone, moxalactam - no longer used)
Adverse Effects of Specific Cephalosporins:
Cephalexin
Cefaclor
Cefuroxime axetil
Cefprozil
Cefixime
see slide 49
