Cephalosporins Flashcards
(34 cards)
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
