Newer Cephalosporins

Newer cephalosporins currently undergo clinical trials or recently being marketed in the United States
which falls into two categories: (a) orally active beta-lactamase–resistant cephalosporins and (b)
parenteral beta-lactamase–resistant antipseudomonal cephalosporins.

These compounds undergo extensive research and clinical evaluations to further develop and improve
their efficacy. So these newer cephalosporins have broader spectrum of action compared to the older
generation of cephalosporins.

Ceftibuten belongs to the third-generation cephalosporins

Generic Name: Ceftibuten

Brand Name: Cedax
Chemical Name: (6R, 7R)-7-([Z)-2(2- Amino-1,3-thiazol-4-yl)-5-hydroxy-5-oxopent-2-enoyl]
amino)-8-oxo-5-thia-1-azabicyclo-oct-2-ene-2-carboxylic acid
Modification: chemically novel analog of the oximino cephalosporins (such as cefotaxime and
ceftazidime include an oxymino side chain at C7 position) in which an olefinic methylene group
(CBCHCH -) with Z stereochemistry has replaced the syn oximino (CBNO-) group.

This isosteric replacement yields a compound that retains resistance to hydrolysis catalyzed by many
-lactamases, has enhanced chemical stability, and is orally active.

Showed excellent potency against most members of enterobacteriacea.

For the Property/-ies of Ceftubuten

Its oral absorption is rapid and nearly complete.
And take note that it has the highest oral bioavailability of the third-generation cephalosporins
Hence, it is excreted largely unchanged in the urine and has a half-life of about 2.5 hours

Plasma protein binding of this cephalosporin is estimated to be 63%.

It possesses excellent potency against most members of the Enterobacteriaceae family,

Haemophilus influenzae, Neisseria species., and Moraxella catarrhalis

It is not active against Staphylococcus aureus or Pseudomona aeruginosa

Exhibits modest antistreptococcal activity

 Clinical Application: Ceftibuten is recommended in the management of community-acquired
respiratory tract, urinary tract, and gynecological infections.

Pharmacist’s notes

Ceftibuten may decrease the excretion rate of Acetaminophen which could result in a higher serum
level.
Overdosage of cephalosporins can cause cerebral irritation leading to convulsions.

Cefpirome

(fourth generation cephalosporins)

Generic Name: Cefpirome

Brand Name: Cefrom

Chemical Name: (6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]

amino]-3-(6,7-dihydro-5H-cyclopenta[b]pyridin-1-ium-1-ylmethyl)-8-oxo-5-thia-1-
azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Modification: Is a newer parenteral, β -lactamase– resistant cephalosporin with a quaternary

ammonium group at the 3-position of the cephem nucleus (β-lactam ring fused to a six-member sulfur-
containing dihydrothiazine ring)

C3 is substituted with ammonium group provided greater activity toward gram positive and gram
negative bacteria than first, second, and third generation.

Property/-ies:
• Potent against Gram-positive and Gram-negative bacteria

Because its potency against Gram-positive and Gram-negative bacteria rivals that of the first-
generation and third-generation cephalosporins, respectively, cefpirome is being touted as the first
fourth generation cephalosporin
 Its broad spectrum includes methicillin-sensitive staphylococci, penicillin-resistant pneumococci,
and -lactamase–producing strains of E. coli, Enterobacter, Citrobacter, and Serratia spp.

Its efficacy against P. aeruginosa is comparable with that of ceftazidime. Cefpirome is excreted
largely unchanged in the urine with a half-life of 2 hours.

Clinical Application:
It is approved for the treatment of serious or life threatening infections. It can be given for septicemia,
infections of the lower respiratory tract, skin and soft tissues and complicated infections of the urinary
tract. Cefpirome can also be used to treat infections in neutropenic patients. (low level of neutrophils
which fight infections)
Pharmacist’s notes:
Clearance is mainly renal so a lower dose is given if creatinine clearance is reduced. The
half life is 2 hours, but cefpirome can usually be given twice a day.
Adverse reactions can range from pain at the injection site to pseudomembranous colitis and jaundice.
Renal function should be monitored if cefpirome is given with an aminoglycoside or a loop diuretic.

Cefepime (fourth generation cephalosporin)

Generic Name: Cefepime

Brand Name: (Maxipime, Axepin)

Chemical Name: (6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-

3-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylate

Modification:

C3 substituted with ammonium group and C-alpha substituted with oxime ether and 2-amino
thiazole similar to that of cefpirome

is a parenteral, b- lactamase–resistant cephalosporin that is chemically and microbiologically similar

to cefpirome

Property/-ies: It has a broad antibacterial spectrum, with significant activity against both Gram-
positive and Gram-negative bacteria, including streptococci, staphylococci, Pseudomonas spp., and the
Enterobacteriaceae
 It is active against some bacterial isolates that are resistant to ceftazidime
It is excreted in the urine with a half-life of 2.1 hours.
It is bound minimally to plasma proteins.

Clinical Application: The efficacy of cefepime has been demonstrated in the treatment of urinary
tract infections, lower respiratory tract infections, skin and soft tissue infections, chronic osteomyelitis,
and intra-abdominal and biliary infections.

Pharmacist’s notes:

This product may contain inactive ingredients, which can cause allergic reactions or other problems.

Cefepime may cause live bacterial vaccines (such as typhoid vaccine) to not work as well. The
pharmacist should advise the patient to not have any immunizations/vaccinations while using this
medication.

Future Developments in Cephalosporin Design

Recent research efforts in the cephalosporin field have focused primarily on two desired antibiotic
properties:

(a) increased permeability into Gram-negative bacilli, leading to enhanced efficacy against
permeability-resistant strains of Enterobacteriaceae and P. aeruginosa,

(b) increased affinity for altered Penicillin Binding Proteins, in particular the PBP 2a (or PBP 2) of
MRSA Methicillin-resistant staphy aureus .

The observation that certain catechol-substituted cephalosporins exhibit marked broad-spectrum

antibacterial activity led to the discovery that such compounds and other analogs capable of
chelating iron could mimic natural siderophores (iron-chelating peptides) and thus be actively
transported into bacterial cells via the tonB-dependent irontransport system. This provides a means
of attacking bacterial strains that resist cellular penetration of cephalosporins.

GR-69153- A catechol-containing cephalosporin that exhibits excellent in vitro antibacterial activity

against clinical isolates and promising pharmacokinetic properties

-is a parenteral -lactamase–resistant cephalosporin with a broad spectrum of activity against Gram-
positive and Gram-negative bacteria.

The antibacterial spectrum of GR-69153 includes most members of the Enterobacteriaceae family,
P. aeruginosa, H. influenzae, Neisseria gonorrhoeae, M. catarrhalis, staphylococci, streptococci, and
Acinetobacter spp.

It was not active against enterococci, B. fragilis, or MRSA (Methicillin-resistant Staphylococcus

aureus )

Half-life: in human volunteers was determined to be 3.5 hours, (suggesting that metabolism by
catechol-O-methyltransferase may not be an important factor. The relatively long half-life would
permit once-a-day parenteral dosing for the treatment of many serious bacterial infections).
Another experimental cephalosporin that has exhibited considerable promise against MRSA in
preclinical evaluations is TOC-039.

TOC-039 is a parenteral, -lactamase–resistant, hydroxyimino cephalosporin with a vinylthiopyridyl

side chain attached to the 3-position of the cephem nucleus.

It is a broad-spectrum agent that exhibits good activity against most aerobic Gram-positive and
Gram-negative bacteria, including staphylococci, streptococci, enterococci, H. influenzae, M.
catarrhalis, and most of the Enterobacteriaceae family. A few strains of P. vulgaris, S. marcescens,
and Citrobacter freundii are resistant

TOC-039 is inactive against P. aeruginosa.

Although the minimum inhibiting concentration (MIC) of TOC-039 against MRSA (Methicillin-
resistant Staphylococcus aureus) is slightly less than that of vancomycin, it is more rapidly
bacteriocidal.

to be approved for the treatment of infections in humans, future clinical evaluations will determine
if TOC-039 has the appropriate pharmacokinetic and antibacterial properties in vivo treatment of
bacterial infections in humans.

MONOBACTAMS

The development of useful monobactam antibiotics began with the independent isolation of
sulfazecin (SQ 26,445) and other monocyclic -lactam antibiotics from saprophytic soil bacteria in
Japan and the United States.

Sulfazecin was found to be weakly active as an antibacterial agent but highly resistant to beta
-lactamases.
 Extensive SAR studies eventually led to the development of aztreonam w/c we’ll discuss later, has
useful properties as an antibacterial agent. Early work established that the 3-methoxy group, which
was in part responsible for -lactamase stability in the series, contributed to the low antibacterial
potency and poor chemical stability of these antibiotics.

A 4-methyl group, however, increases stability to -lactamases and activity against Gram-negative
bacteria at the same time. Unfortunately, potency against Gram-positive bacteria decreases.

4,4-Gem-dimethyl substitution slightly decreases antibacterial potency after oral administration.

Aztreonam Disodium- a monobactam prepared by total synthesis. It binds with high affinity to PBP 3 in
Gramnegative bacteria only

Generic Name: Aztreonam

Brand Name: Azactam

Chemical Name: 2-[(Z)-[1-(2-amino-1,3-thiazol-4-yl)-2-[[(2S,3S)-2-methyl-4-oxo-1-

sulfoazetidin-3-yl]amino]-2-oxoethylidene]amino]oxy-2-methylpropanoic acid

Modification: Monocyclic lactam with electron withdrawing group at the nitrogen atom (Sulfonic
acid) to facilitate ring opening of the lactam ring.
The C-alpha normally present in penicillins was converted to oxime derivative (isobutyric acid
oximinoacyl group)

Property/-ies:
 Highly stable to B-lactamase (resistance to B-lactamase) Lactamase resistance is like that of
ceftazidime, which has the same isobutyric acid oximinoacyl group

Highly active against gram-negative bacteria

It is inactive against Gram-positive bacteria and anaerobes.

Poor oral activity

does not induce chromosomally mediated -lactamases.

Aztreonam is particularly active against aerobic Gramnegative bacilli, including E. coli, K.
pneumoniae, Klebsiella oxytoca, P. mirabilis, S. marcescens, Citrobacter spp., and P. aeruginosa.

Clinical Application: It is used to treat urinary and lower respiratory tract infections, intra-
abdominal infections, and gynecological infections, as well as septicemias caused by these organisms.

also effective against, but is not currently used to treat, infections caused by Haemophilus,

* Urinary excretion is about 70% of the administered dose. Some is excreted through the bile.
Serum half-life is 1.7 hours, which allows aztreonam to be administered 2 or 3 times daily,
depending on the severity of the infection. Less than 1% of an orally administered dose of aztreonam is
absorbed, prompting the suggestion that this -lactam could be used to treat intestinal infections.
Pharmacist’s notes:
(The disodium salt of aztreonam is very soluble in water. Solutions for parenteral administration
containing 2% or less are stable for 48 hours at room temperature. Refrigerated solutions retain full
potency for 1 week.)
If aminoglycoside is used concurrently, especially if high dosages of former are used or if therapy is
prolonged, renal function should be monitored because of potential nephrotoxicity and ototoxicity of
aminoglycoside antibiotics

Tigemonam- is a newer monobactam that is orally active. It is highly resistant to -lactamases.

Generic Name: Tigemonam

Brand Name: Tigemen

 Chemical Name: 2-[[1-(2-Amino-1,3-thiazol-4-yl)- 2-[[(3S)-2,2-dimethyl-4-oxo-1-
sulfooxyazetidin-3-yl]amino]-2- oxoethylidene]amino]oxyacetic acid
Modification: Investigational monobactam, with similar spectrum of activity of aztreonam
Property/-ies:
It is highly resistant to -lactamases (The antibacterial spectrum of activity resembles that of
aztreonam.
It is very active against the Enterobacteriaceae, including E. coli, Klebsiella, Proteus, Citrobacter,
Serratia, and Enterobacter spp. It also exhibits good potency against H. influenzae and N. gonorrhoeae)
Tigemonam is not particularly active against Gram-positive or anaerobic bacteria and is inactive
against P. aeruginosa.
In contrast to the poor oral bioavailability of aztreonam, the oral absorption of tigemonam is
excellent.

Clinical Application: It could become a valuable agent for the oral treatment of urinary tract
infections and other non–life-threatening infections caused by -lactamase–producing Gram-negative
bacteria.

Pharmacist’s notes:
Tigemonam decreases effects of BCG and Typhoid vaccine by pharmacodynamics antagonism

The dose of Tigemonam is reduced to patients with renal failure.