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Cephalosporins
Cephalosporins are grouped into generations according to their effectiveness against different organisms,
their characteristics, and their development.
A. Antibacterial spectrum / Pharmacotherapeutics
Cephalosporins have been classified as first, second, third, and fourth generation, based largely on their
bacterial susceptibility patterns and resistance to β-lactamases.
1. First generation: The first-generation cephalosporins act as penicillin G substitutes. They are
resistant to the staphylococcal penicillinase (that is, they cover MSSA) and also have activity against
Proteus mirabilis, E. coli, and Klebsiella pneumoniae (the acronym PEcK has
been suggested).
2. Second generation: The second-generation cephalosporins display greater activity against three
additional gram-negative organisms: H. influenzae, Enterobacter aerogenes, and some Neisseria species,
whereas activity against gram-positive organisms is weaker (the acronym HENPEcK has been suggested
with the second generation’s increased coverage). Antimicrobial coverage of cefotetan and cefoxitin also
includes the anaerobe, Bacteroides fragilis. However, neither cefotetan nor cefoxitin is the preferred
treatment because of the increasing prevalence of resistance amongst B. fragilis to both agents.
3. Third generation: These cephalosporins have assumed an important role in the treatment of
infectious diseases. Although inferior to first-generation cephalosporins in regard to their activity against
MSSA, the third-generation cephalosporins have enhanced activity against gram-negative bacilli, including
those mentioned above, as well as most other enteric organisms plus Serratia marcescens.
Ceftriaxone [sef-trye-AKS-own] and cefotaxime [sef-oh-TAKS-eem] have become agents of choice in the
treatment of meningitis.
Ceftazidime [sef-TA-zi-deem] has activity against P. aeruginosa, however, resistance is increasing and
appropriate use should be evaluated on a case-by-case basis. Third generation cephalosporins must be
used with caution, as they are associated with "collateral damage," essentially meaning the induction and
spread of antimicrobial resistance.
4. Fourth generation: Cefepime [SEF-eh-peem] is classified as a fourth generation cephalosporin and
must be administered parenterally. Cefepime has a wide antibacterial spectrum, being active against
streptococci and staphylococci (but only those that are methicillin susceptible). Cefepime is also effective
against aerobic gram-negative organisms, such as Enterobacter species, E. coli, K. pneumoniae, P.
mirabilis, and P. aeruginosa. When selecting an antibiotic that is active against P. aeruginosa, clinicians
should refer to their local antibiograms (laboratory testing for the sensitivity of an isolated bacterial strain
to different antibiotics) for direction.
Representative Drugs
First -generation cephalosporins include cefadroxil, cefazolin sodium, and cephalexin monohydrate.
Second -generation cephalosporins include cefaclor, cefprozil, cefoxitin, cefuroxime axetil, and cefuroxime
sodium.
Third -generation cephalosporins include cefdinir, cefixime, cefotaxime sodium, cefpodoxime proxetil,
ceftazidime, ceftibuten, and ceftriaxone sodium.
Fourth -generation cephalosporins include cefepime hydrochloride.
Sensitivity
Because penicillins and cephalosporins are chemically similar (they have what’s called a beta-lactam
molecular structure ), cross-sensitivity occurs in 10% to 15% of patients. This means that someone who
has had a reaction to penicillin is also at risk for a reaction to cephalosporins.
B. Pharmacokinetics
Many cephalosporins are administered parenterally because they aren’t absorbed from the GI tract. Some
cephalosporins are absorbed from the GI tract and can be administered orally, but food usually decreases
the absorption rate of these oral cephalosporins, though not the amount absorbed. Two cephalosporins
(oral cefuroxime and cefpodoxime) actually have increased absorption when given with food.
1. Administration: Many of the cephalosporins must be administered IV or IM because of their poor
oral absorption.
2. Distribution: All cephalosporins distribute very well into body fluids. However, adequate therapeutic
levels in the CSF, regardless of inflammation, are achieved only with select a few cephalosporins.
> For example, ceftriaxone or cefotaxime is effective in the treatment of neonatal and childhood
meningitis caused by H. influenzae.
> Cefazolin finds application as a single prophylaxis dose prior to surgery because of its 1.8-hour half-life
and its activity against penicillinase-producing S. aureus. However, additional intraoperative cefazolin
doses may be required if the surgical procedure lasts longer than 3 hours.
> Cefazolin is effective for most surgical procedures, including orthopedic surgery because of its ability to
penetrate bone.
> All cephalosporins cross the placenta.
3. Metabolism
Many cephalosporins aren’t metabolized at all. To a small extent, ceftriaxone is metabolized in the
intestines to inactive metabolites, which are excreted via the biliary system.
4. Elimination: Elimination occurs through tubular secretion and/or glomerular filtration. Therefore
doses must be adjusted in cases of severe renal failure to guard against accumulation and toxicity. An
exception is ceftriaxone which is excreted through the bile into the feces and, therefore, is frequently
employed in patients with renal insufficiency.
Generational divide
Cefuroxime (second -generation) and the third -generation drugs cefotaxime, ceftriaxone, and
ceftazidime cross the blood -brain barrier after I.V. or I.M. administration. Cefepime (fourth -generation)
also crosses the blood -brain barrier, but to what extent isn’t known.
C. Pharmacodynamics
Like penicillins, cephalosporins inhibit cell -wall synthesis by binding to the bacterial enzymes known as
PBPs, located on the cell membrane. After the drug damages the cell wall by binding with the PBPs, the
body’s natural defense mechanisms destroy the bacteria.
D. Adverse Reactions to Cephalosporins
Adverse reactions to cephalosporins include:
Confusion, seizures, bleeding, nausea, vomiting, diarrhea.
Ceftriaxone may be associated with a decrease in prothrombin activity (prothrombin time and partial
thromboplastin time), leading to an increased risk of bleeding. Patients at risk include those with renal
impairment, liver disease, or impaired vitamin K synthesis or storage.
Hypersensitivity reactions are the most common systemic adverse reactions to cephalosporins. They
include: hives, itching, measles -type rash, serum sickness (reaction after injection of a foreign serum
characterized by edema, fever, hives, and inflammation of the blood vessels and joints) anaphylaxis (in
rare cases).
E. Drug interactions
The patient receiving cephalosporins who drinks alcoholic beverages with or up to 72 hours after taking a
dose may experience acute alcohol intolerance, with such signs and symptoms as headache, flushing,
dizziness, nausea, vomiting, or abdominal cramps within 30 minutes of alcohol ingestion. This reaction
can occur up to 3 days after discontinuing the antibiotic.
Other Drug Interaction
1. Uricosurics (drugs to relieve gout), such as probenecid and sulfinpyrazone, can reduce kidney
excretion of some cephalosporins. Probenecid is used therapeutically to increase and prolong
plasma cephalosporin concentrations.
2. Cephalosporins may also decrease estrogen absorption, leading to decreased efficacy of oral
contraceptives containing estrogen and progesterone.
Therapeutic Application of Cephalosporins
st
1 Generation Cephalosporins
3rd Generation Cephalosporins
Gram (+) cocci
Gram (+) cocci
Staphylococcus aureus*_
Staphylococcus epidermidis
Streptococcus pneumoniae
Streptococcus pyogenes
Anaerobic streptococci
Streptococcus pneumoniae
Streptococcus pyogenes
Anaerobic streptococci
Gram (-) rods
Neisseria gonorrhoeae
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
*Methicillin-resistant staphylococci are resistant
2nd Generation Cephalosporins
Gram (+) cocci
Staphylococcus aureus_
Streptococcus pneumoniae
Streptococcus pyogenes
Anaerobic streptococci
Gram (-) cocci
Neisseria gonorrhoeae
Gram (-) rods
Enterobacter aerogenes
Escherichia coli
Haemophilus in_uenzae
Klebsiella pneumoniae
Proteus mirabilis
Anaerobic organisms**
**Cefoxitin and cefotetan have anaerobic coverage
Gram (-) cocci
Gram (-) rods
Enterobacter aerogenes
Escherichia coli
Haemophilus in_uenzae
Klebsiella pneumoniae
Proteus mirabilis
Pseudomonas aeruginosa