Critical care Nursing PHARMACOLOGY

ASSIGMENT

CEPHALOSPORIN

AREEJ METANY ID:202212176

AYMAN ABU ZAINEH ID :202212119
ASHGAN ABUBAKER ID:202212124
HADEEL KITTANA ID:202212170
• Cephalosporin compounds were first isolated from cultures of Acremonium
strictum from a sewer in Sardinia in 1948 by Italian scientist Giuseppe
Brotzu.[42] He noticed these cultures produced substances that were
effective against Salmonella typhi, the cause of typhoid fever, which had β-
lactamase. Guy Newton and Edward Abraham at the
Sir William Dunn School of Pathology at the University of Oxford isolated
cephalosporin C. The cephalosporin nucleus, 7-aminocephalosporanic acid
(7-ACA), was derived from cephalosporin C and proved to be analogous to
the penicillin nucleus 6-aminopenicillanic acid (6-APA), but it was not
sufficiently potent for clinical use. Modification of the 7-ACA side chains
resulted in the development of useful antibiotic agents, and the first agent,
cefalotin (cephalothin), was launched by Eli Lilly and Company in 1964
Cephalosporins
• Cephalosporins are beta-lactam antimicrobials used to manage a wide
range of infections from gram-positive and gram-negative bacteria
• The five generations of cephalosporins are useful against skin
infection, resistant bacteria, meningitis, and other infections
• Cephalosporins are a type of antibiotic. Antibiotics are medications
that treat bacterial infections. There are many types, often called
classes, of antibiotics available. Cephalosporins are a type of beta-
lactam antibiotic.
• They can be taken orally or injected into a vein (intravenous injection),
depending on the infection.
• Read on to learn more about cephalosporins, including what they
treat and the side effects they can cause.
What do cephalosporins treat?

Healthcare providers use cephalosporins to treat a variety of bacterial infections,

especially for people who are allergic to penicillin, another common antibiotic.
• Some examples of infections that cephalosporins can treat include:
• skin or soft tissue infections
• urinary tract infections (UTIs)
• strep throat
• ear infections
• pneumonia
• sinus infections
• meningitis
• gonorrhea
• Oral cephalosporins are generally used for simple infections that are
easy to treat. For example, a routine case of strep throat might be
treated with a course of oral cephalosporins.
• Intravenous (IV) cephalosporins are used for more severe infections.
This is because IV antibiotics reach your tissues faster, which can
make a big difference if you have a serious infection, such as
meningitis.
 What are the different generations?

• Cephalosporins are grouped together based on the type of bacteria that

they’re most effective against. These groups are referred to as generations.
There are five generations of cephalosporins.
• To understand the differences between the generations, it’s important to
understand the difference between Gram-positive and Gram-negative bacteria.
• One of the main distinctions between the two is their cell wall structure:
• Gram-positive bacteria have thicker membranes that are easier to penetrate.
Think of their cell wall as a chunky, loose-knit sweater.
• Gram-negative bacteria have thinner membranes that are harder to penetrate,
making them more resistant to some antibiotics. Think of their wall as a piece
of fine chain mail.
Cephalosporins are antimicrobials grouped into five generations based
on their spectrum of coverage against gram-positive and gram-negative
bacteria and their temporal discovery :
• 1. First-generation cephalosporins have coverage against most gram-
positive cocci as well as some gram-negative bacteria,
e.g., Escherichia coli (E. coli), Proteus mirabilis, and Klebsiella
pneumoniae.
• 2. Second-generation cephalosporins have coverage
against Haemophilus influenzae (H. influenzae), Moraxella
catarrhalis, and Bacteroides spp.
• 3 Third-generation cephalosporins have less coverage against most
gram-positive organisms but have increased coverage against
Enterobacteriaceae, Neisseria spp., and H. influenzae.
• 4 Fourth-generation cephalosporins have similar coverage as third-
generation cephalosporins but with additional coverage against gram-
negative bacteria with antimicrobial resistance, e.g., beta-lactamase.

• 5 Fifth-generation cephalosporins have coverage against methicillin-

resistant staphylococci and penicillin-resistant pneumococci.
First-generation cephalosporins include:
• First-generation cephalosporins
• First-generation cephalosporins are very effective against Gram-positive bacteria.
But they’re only somewhat effective against Gram-negative bacteria.
• First-generation cephalosporins might be used to treat:
• skin and soft tissue infections
• UTIS
• strep throat
• ear infections
• pneumonia
• Some first-generation cephalosporins are used as prophylactic antibiotics for
surgery involving the chest, abdomen, or pelvis.
• Examples of first-generation cephalosporins include:
• Cefazolin
• cephalothin
• cephapirin
• cephradine
• cefadroxil
• cephalexin
Second-generation
• Second-generation cephalosporins also target some types of Gram-positive and
Gram-negative bacteria. But they’re less effective against certain Gram-positive
bacteria than first-generation cephalosporins are.
• They’re often used to treat respiratory infections, such as bronchitis or pneumonia.
• Other infections sometimes treated with second-generation cephalosporins include:
• ear infections
• sinus infections
• UTIs
• gonorrhea
• meningitis
• sepsis
Second-generation cephalosporins divide into
two subgroups:
• 1 the second-generation include :
• A)cefuroxime
• B)cefprozil

• the first subgroup, cefuroxime has increased coverage against H.

influenzae. Indications for cefuroxime also include Lyme disease in
pregnant women and children. The cephamycin subgroup has
increased coverage against Bacteroides species
• 2 cephamycin subgroup include :
• A)cefmetazole
• B)cefotetan
• C)cefoxitin

• The cephamycin subgroup has increased coverage

against Bacteroides species
• Second-generation cephalosporins have less activity against gram-
positive cocci than first-generation cephalosporins but have increased
activity against gram-negative bacilli.
Third-generation cephalosporins

• Third-generation cephalosporins are more effective against Gram-

negative bacteria compared to both the first and second generations.
They’re also more active against bacteria that may be resistant to
previous generations of cephalosporins.
• The third generation also tend to be less active than previous
generations against Gram-positive bacteria,
including Streptococcus and Staphylococcus species.
• One third-generation cephalosporin, ceftazidime (Fortaz), is often used to
treat pseudomonas infections, including hot tub folliculitis.
• Third-generation cephalosporins may also be used to treat:
• skin and soft tissue infections
• pneumonia
• UTIs
• gonorrhea
• menigitis
• Lyme disease
• sepsis
Third-generation cephalosporins include
• cefotaxime
• ceftazidime
• cefdinir,
• ceftriaxone
• cefpodoxime
• cefoperazone,
• cefixime
• This generation has extended gram-negative bacteria coverage often
used to treat gram-negative infections resistant to the first and
second-generation or other beta-lactam antimicrobials
 Fourth-generation cephalosporins

• Cefepime (Maxipime) is the only fourth-generation cephalosporin that’s

available in the United States. While effective against a variety of Gram-positive
and Gram-negative bacteria, it’s usually reserved for more severe infections.
• Cefepime can be used to treat the following types of infections:
• skin and soft tissue infections
• pneumonia
• UTIs
• abdominal infections
• meningitis
• sepsis
Fourth-generation cephalosporin includes :
• Cefepime .Cefepime can be administered intravenously or with an
intramuscular injection. It may also be given to people with a low white blood
cell count, which can increase the risk of developing a severe infection.

• Cefepime is a broad-spectrum antimicrobial that can penetrate the cerebral

spinal fluid. Cefepime has an additional quaternary ammonium group,
allowing it to penetrate the outer membrane of gram-negative bacteria
better. Similar to the activity of cefotaxime and ceftriaxone, cefepime can
cover Streptococcus pneumoniae and methicillin-sensitive Staphylococcus
aureus (MSSA). Similar to ceftazidime, cefepime, very importantly, can cover
for Pseudomonas aeruginosa
Fifth-generation cephalosporins

• You may hear fifth-generation cephalosporins referred to as

advanced- generation cephalosporins. There’s one fifth-generation
cephalosporin, ceftaroline (Teflaro), available in the United States.
• This cephalosporin can be used to treat bacteria, including
resistant Staphylococcus aureus (MRSA) and Streptococcus species,
that are resistant to penicillin antibiotics.
• Otherwise, ceftaroline’s activity is similar to that of third-generation
cephalosporins, although it isn’t effective against Pseudomonas
aeruginosa.
Fifth-generation cephalosporins include
• ceftaroline.
• Ceftaroline is also a broad-spectrum antimicrobial and thus can cover
susceptible gram-positive and gram-negative organisms.
Resistance
• Resistance to cephalosporin antibiotics can involve either reduced
affinity of existing PBP components or the acquisition of a
supplementary β-lactam-insensitive PBP. Compared to other β-lactam
antibiotics (such as penicillins), they are less susceptible to β-
lactamases. Currently, some Citrobacter freundii, Enterobacter
cloacae, Neisseria gonorrhoeae, and Escherichia coli strains are
resistant to cephalosporins. Some Morganella morganii,
Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa,
Serratia marcescens and Klebsiella pneumoniae strains have also
developed resistance to cephalosporins to varying degrees
Mechanism of Action

• Bacteria synthesize a cell wall that is strengthened by cross-linking

peptidoglycan units via penicillin-binding proteins (PBP, peptidoglycan
transpeptidase)
• Initially derived from the fungus Cephalosporium sp., cephalosporins
are a large group of bactericidal antimicrobials that work via their
beta-lactam rings
• The beta-lactam rings bind to the penicillin-binding protein and inhibit
its normal activity. Unable to synthesize a cell wall, the bacteria die.
• Staphylococcus aureus, which is initially susceptible to
cephalosporins, can develop resistance by changing the structure of
the penicillin-binding proteins
• S. aureus does this by having a gene that encodes a modified
penicillin-binding protein; this prevents the cephalosporin’s beta-
lactam rings from inactivating the protein
• The bacterium that develops this mechanism of resistance is called
methicillin-resistant Staphylococcus aureus (MRSA)
• As indicated above, out of the five generations of cephalosporin, only
the fifth generation ceftaroline has coverage against methicillin-
resistant Staphylococcus aureus. Another crucial resistance
mechanism is producing the enzyme beta-lactamase, which cleaves
the beta-lactam ring, preventing it from attaching to the penicillin-
binding proteins, e.g., peptidoglycan transpeptidase
• Beta-lactamase inhibitors can be co-formulated with cephalosporins
to increase their spectrum of activity, eg, ceftazidime/avibactam and
ceftolozane/tazobactam
Pharmacokinetic of the cephalosporins

• Most cephalosporins can only be administered parenterally. Among

agents that are absorbed from the gastrointestinal tract, those with
bioavailabilities of 85 to 90% include cefroxadine, cefadroxil,
cefsumide, cephalexin, cephradine, cephacetrile, and cefazaflur
• Most cephalosporins are eliminated rapidly, with serum half-lives
(t1/2s) of 1 to 2 hours. Exceptions are cefonicid with a t1/2 of 4.4
hours, cefpiramide with a t1/2 of 5.0 hours, and cefotetan with a t1/2
of 3.5 hours.
• The longest half-life is shown by ceftriaxone with a t1/2 of 8.5 hours.
• Cephalosporins are eliminated mostly by the kidneys, some with a
substantial contribution from active tubular secretion, which is
blocked by probenecid.
• The degree of metabolism varies. Only a few cephalosporins have a
high biliary elimination. For example, with intravenously administered
cefoperazone, about 70% appears in bile. High biliary elimination is
also observed with cefmenoxime, ceftriaxone, cefbuperazone, and
latamoxef (moxalactam). Because these are not appreciably absorbed
from the gastrointestinal tract, the consequence is high intraintestinal
concentrations of the drugs and a marked ensuing depression of the
normal microflora with simultaneous emergence of resistant bacteria.
The untoward ecological impact may even lead to Clostridium difficile-
associated enterocolitis.
Administration

• First-generation: Cefazolin, cephalothin, and cephapirin are

administered parenterally. The administration route for cefadroxil and
cephalexin is oral. Cephradine administration can be parenteral or
oral.
• Second-generation: Cefuroxime can be administered parenterally or
orally. Cefprozil administration is oral. Cefmetazole, cefotetan, and
cefoxitin are administered parenterally.
• Third-generation: Cefotaxime, ceftazidime, and ceftriaxone
administration is via the parenteral route. Cefdinir, cefixime, and
cefpodoxime are administered orally.

• Fourth-generation: Cefepime is administered parenterally.

• Fifth-generation: Ceftaroline is administered parenterally

Adverse Effects

• Cephalosporins have low toxicity and are generally safe. The most
common adverse reactions from cephalosporins are :
• nausea
• vomiting
• lack of appetite,
• abdominal pain.
The less common adverse reaction includes:
• Hypersensitivity Reaction
• A hypersensitivity reaction to cephalosporin is infrequent and is more
common in first and second-generation cephalosporins. Common allergic
reaction to cephalosporin includes rash, hives, and swelling
• Drug-induce Immune Hemolytic Anemia (DIIHA)
• The proposed mechanism of action of DIIHA is that the drug binds to the
red blood cell membrane; this causes no harm to the red blood cell itself or
the patient. However, if the patient starts making IgG antibodies against the
drug, the antibody will bind to the red blood cell. The immune system will
react with the abnormal red blood cells, resulting in hemolysis. Cefotetan
and ceftriaxone are the two cephalosporins most likely to cause DIIHA
• Disulfiram-like Reaction
• Cephalosporins containing a methyltetrazolethiol side chain can
inhibit the aldehyde dehydrogenase enzyme, resulting in the
accumulation of acetaldehyde. Cefamandole, cefoperazone, and
moxalactam are the most common cephalosporins to present with
this reaction
• Vitamin K Deficiency
• Certain cephalosporins can inhibit vitamin K epoxide reductase,
preventing the production of the reduced(active) vitamin K.
Therefore, there is a decreased synthesis of coagulation factors, and
the patient is predisposed to hypoprothrombinemia
• Increase Nephrotoxicity of Aminoglycosides
• There are reported cases of drug-induced nephrotoxicity when
patients take cephalosporin and aminoglycosides in combination, but
other factors often cloud the evidence. Therefore, the synergistic
nephrotoxicity of cephalosporin and aminoglycoside is not to be
completely understood
• Pseudomembranous Colitis
• Pseudomembranous colitis is often associated with the use of
clindamycin and ampicillin. Cephalosporin use is also a common cause
of pseudomembranous colitis, especially third-generation
cephalosporins
Contraindications

• One of the contraindications of cephalosporins is if patients are

allergic to them or have had an anaphylactic reaction to penicillin or
other beta-lactam antimicrobials
• Ceftriaxone is contraindicated in neonates with hyperbilirubinemia
because of reports that ceftriaxone displaces bilirubin from albumin,
increasing the free bilirubin concentrations and increasing the risk of
jaundice in neonates
• Ceftriaxone reacts to a calcium-containing solution, and it can
precipitate in the lungs and kidneys of infants less than 28 days old,
which could be life-threatening