word antibiotics come from the word - antibiosis which means against life.
are one of the most commonly used antibiotics in clinical practice.
different types of cephalosporins have been developed since its first
In cephalosporins, the β-lactam ring is bonded to
a six-membered dihydrothiazine ring, or cepham.
First generation cephalosporins were created by
modifying the R1 site of the cephalosporin structure. The succeeding
generations of cephalosporins have been synthetically produced with
modifications at the R1 and R2 sites. These changes in the R site also
differentiate the spectrum of activity amongst the cephalosporins.
Mechanism of action of
Since the cephalosporin also has the same beta
lactam ring like penicillin – it acts by inhibiting the transpeptidation
reaction. This impairs the peptidoglycan synthesis which plays an important
role in maintaining the cellular integrity.
replication, a bacterium removes “tiles” circumferentially to allow cell division
via a pinching-like action, while quickly placing new “tiles” at the ends of
what have become two bacteria. This process requires enzyme – This process
requires enzymes to interlock replacement tiles. Such enzymes are the targets
of beta-lactam antibiotics and are called penicillin-binding proteins (PBPs).
Antibiotic action requires binding to PBPs, preventing them from closing the
vulnerable ends on dividing bacteria and causing the natural intrabacterial
hyperosmotic pressure to rupture the bacteria. Thus, beta-lactam antibiotics
of the available cephalosporins are semi-synthetic derivatives of cephalosporin
C, a compound with antibacterial activity produced by the fungus
Cephalosporium. The closely related cephamycin compounds (derived from
Streptomyces spp) are regarded as members of the cephalosporin class.
clinical practice, these antibiotics are grouped into five
"generations" based upon their spectrum of activity against aerobic
and facultative gram-negative bacilli and gram-positive bacteria.
general, lower-generation cephalosporins have more gram-positive activity and
higher-generation cephalosporins more gram-negative activity. The
fourth-generation drug cefepime is the exception, with gram-positive activity
equivalent to first-generation and gram-negative activity equivalent to
advanced cephalosporins include a siderophore cephalosporin (cefiderocol) and cephalosporin combinations with
First generation of
All the cephalosporin drugs that have FA/PHA/PHRA belong to 1st
generation except – cefaclor which belongs to 2nd generation.
drugs in 1st generation are –
Spectrum of activity of 1st generation
Gram Positive organisms
Gram negative organisms
Active against – Streptococci and MSSA
Inactive against -MRSA,
Penicillin resistant pneumococcus and Listeria.
Active against –
Gm-ve rods like E.
coli, Klebsiella, Proteus but not against Serratia, Indole positive Proteus,
Inactive against Gm
-ve cocci like Meningococcus, Gonococcus, Hemophilus
common anaerobes but inactive against Bacteroides.
Never prescribe 1st generation cephalosporins for
CNS infection as they cannot penetrate the meninges even when inflamed.
first-generation cephalosporins, including cephalexin, cefadroxil, and Cephradine,
are well absorbed. Therapeutic concentrations occur in most tissues, including
pleura, synovial fluids, and bone, but not middle ear fluid. Cefadroxil has a
half-life of more than 1 hour and is administered every 12 hours versus every 6
to 8 hours for cephalexin.
used for MSSA and penicillin sensitive streptococci but rarely used as first
In fact, cefazolin is the cephalosporin of choice for surgical prophylaxis. Cefazolin with high biliary concentrations is still used for surgical prophylaxis and for treatment of abdominal infections. One of the non-FDA approved indication is to use first-generation cephalosporins for endocarditis prophylaxis for those who are susceptible and undergoing a dental or respiratory procedure.
Second generation of
Drugs are –
Second generation cephalosporins are broken up into two
groups: true second generation cephalosporins and the cephamycins. The true
second generation cephalosporins include cefuroxime and cefprozil, while the
cephamycins include cefoxitin, cefotetan, and cefmetazole.
Spectrum of activity of second generation:
of greater stability against beta-lactamases of gram-negative bacteria,
enhanced activity occurs among second-generation cephalosporins against many
Enterobacteriaceae, H influenzae, and Moraxella catarrhalis, but they have less
gram-negative activity than do third generation cephalosporins.
cephalosporins retain good activity against gram-positive organisms, including
some strains of PNSP, but have less S aureus activity compared with their
has no PNSP activity.
the first subgroup, cefuroxime is available parenterally and orally, and is
more active than cefazolin in vitro against strains of Enterobacter and
a cephamycin, is classified with second-generation cephalosporins but
demonstrates more anaerobic activity, especially for Bacteroides fragilis.
also offers activity against rapidly growing nontuberculous mycobacteria and
often is included in multiple-drug combination regimens to treat serious nontuberculous
Pharmacokinetics of some drugs:
with cefaclor and Cefprozil, which are well absorbed orally, the
bioavailability of cefuroxime axetil is less than 50% but is enhanced when
taken with food.
axetil suspension is less bioavailable than the tablet form, and dosage
adjustments are necessary between these two forms.
axetil is hydrolyzed rapidly in the GI tract and in serum to its active parent compound,
Use of second generation in CNS infections?
concentrations of second-generation cephalosporins are achieved in most
tissues, including pleural and synovial fluids and bone. Of parenteral
second-generation cephalosporins, cefuroxime penetrates CSF but is not recommended
for treating meningitis due to its potential for delayed CSF sterilization,
therapeutic failures, and more frequent hearing loss compared with ceftriaxone.
to first generation and they are not always the first choice.
media, pharyngitis, sinusitis –
of the anaerobic coverage, cefoxitin is used prophylactically in multiple
surgeries, including cardiac, biliary, appendectomy, small intestine,
colorectal, head and neck, hysterectomy, and urologic.
can also be prescribed for use in treating pelvic inflammatory disease (PID),
moderate severity DFIs, human and animal bites, early localized or early
disseminated Lyme or Lyme-induced arthritis, and mild-to-moderate severity IAIs.
Drugs of 3rd generation are –
cephalosporins are the most prescribed cephalosporins and are the first
generation to be considered an extended-spectrum cephalosporin or broad
Drugs with -ime or
-ten or -one at the end are 3rd generations with the exception of
cefuroxime which belongs to 2nd generation.
cefdinir do not follow this rule but belong to 3rd generation.
They are effective
against both gram-positive and gram-negative organisms, but their optimum
activity is mostly against gram-negative organisms.
Spectrum of activity:
stability to the common beta-lactamases of gram-negative bacilli, and these
compounds are highly active against Enterobacteriaceae (E. coli, Proteus
mirabilis, indole-positive Proteus, Klebsiella, Enterobacter, Serratia, Citrobacter), Neisseria,
and H. influenzae. They are the therapy of choice for gram-negative
meningitis due to susceptible Enterobacteriaceae.
third-generation cephalosporins are less active against most gram-positive
organisms than the first-generation cephalosporins and are inactive against
enterococci, Listeria, methicillin-resistant staphylococci,
Cefotaxime and ceftriaxone are usually active against
pneumococci with intermediate susceptibility to penicillin, but strains fully
resistant to penicillin are often resistant to the third-generation
cephalosporins as well.
Based on the activity against
pseudomonas 3rd gen are sometimes grouped as
active against Pseudomonas:
bactericidal for gram negative pathogens, specifically all H influenzae
(including beta-lactamase-producing strains);
most E coli,
Neisseria, Proteus, and Enterobacter sp; Serratia marcescens;
It also is active
against all group A and group B streptococci and nearly all S pneumoniae,
including PNSP outside the CSF.
MSSA, S epidermidis,
other coagulase negative staphylococci, MRSA, and all enterococci are considered
minimal anaerobic activity.
cephalosporins, ceftriaxone is highly protein-bound. This effect prolongs its
half-life (5.5 to 8.7 hours beyond the neonatal period and 9.0 to 15.5 hours in
the neonate), allowing once- or twice-daily dosing.
bone, joint, muscle, skin, and middle ear, with approximately 10% reaching the
CSF through inflamed meninges.
Up to 70% is
excreted unchanged in urine, with the rest excreted unchanged into bile (stool
has very high concentrations).
Side effects of Ceftriaxone:
superinfection like diaper dermatitis
infants because of Biliary sludging and pseudolithiasis. Also they tend to
displace bilirubin bound to albumin.
Rare but serious
side effects is hemolysis which is often life threatening and occur in patients
with no prior h/o cephalosporin allergy.
due to calcium-ceftriaxone precipitates in the lungs and kidneys of neonates
have been reported. Ceftriaxone should not be reconstituted or mixed
with a calcium-containing product (eg, Ringer's or Hartmann's solution or
parenteral nutrition). In addition, ceftriaxone should be avoided in infants
aged ≤28 days if they are receiving or expected to receive intravenous
calcium-containing products. However, ceftriaxone and calcium-containing
products may be used concomitantly in patients aged >28 days, provided that
the infusion lines are thoroughly flushed between infusions.
ceftriaxone are used in similar clinical scenarios because of similar spectra.
Advantages of cefotaxime over ceftriaxone include no bilirubin displacement
from albumin (preferred neonatal drug), better in vivo activity against MSSA,
and no sludging in the gallbladder.
dosing of 6-8 hourly as they have shorter half life.
Side effects –
activity against most community acquired gram-negative pathogens and P
aeruginosa. It has been effective in treating P aeruginosa meningitis.
Ceftazidime is the
only cephalosporin with a Food and Drug Administration (FDA)-approved
indication for the inpatient treatment of febrile neutropenia, however, its use
is not recommended due poor pneumococcal and MSSA activity and no activity
against MRSA, methicillin resistant S epidermidis, or enterococci. Further, the
drug can induce the production of high-level cephalosporinases among mostly
nosocomial gram-negative pathogens, including Serratia, Pseudomonas,
Acinetobacter, Citrobacter, and Enterobacter (SPACE) species. Thus, should be
should be reserved for use in infections proven or highly suspected to be due
to P. aeruginosa.
Oral 3rd generation
cefpodoxime have balanced gram-positive and gram-negative spectra. Cefdinir is
very palatable; cefpodoxime is bitter. Both are active against MSSA and some
cefdinir are used primarily for treating acute otitis media, acute bacterial
sinusitis, and as once or twice-daily regimens for penicillin-allergic patients
who have group A streptococcal pharyngitis.
ceftibuten are similar in spectra, dose, and dosing schedules, but cefixime has
slightly more gram-positive activity. Ceftibuten is less active against M
catarrhalis. Both have excellent activity against coliform bacteria and are
more stable to beta-lactamases than other oral cephalosporins.
cefixime are excellent for treating urinary tract infections or respiratory
infections due to beta-lactamase-producing ntHi.
produce a “bloodlike” appearance in stools when infants consume iron-containing
foods. Both cefdinir and cefpodoxime are associated with about an 8% diarrhea
rate, with cefpodoxime associated with higher emesis rate.
Drugs with PI in
the name like
in vitro activity resembles that of cefazolin combined with ceftazidime, with
effectiveness against MSSA, S pyogenes, S pneumoniae (PNSP outside CSF), E
coli, H influenzae, M catarrhalis, N gonorrhoeae, P aeruginosa, Morganella
morganii, Proteus mirabilis, Citrobacter, Enterobacter, Klebsiella,
Providencia, and Serratia sp. It has no activity against MRSA, enterococci,
ESBL- or Amp-C beta-lactamase-producing gram-negative organisms, or
multidrug-resistant Acinetobacter sp.
It has a positively
charged quaternary ammonium attached to the dihydrothiazone ring, which results
in better penetration through the outer membrane of gram-negative bacteria and
a lower affinity than the third-generation cephalosporins for certain
chromosomal beta-lactamases of gram-negative bacilli.
Cefepime is as active as ceftazidime for P. aeruginosa, and is
active against some ceftazidime-resistant isolates. As with the
anti-pseudomonal penicillins, cefepime should generally be given in combination
with an aminoglycoside for treatment of serious P. aeruginosa infection
when susceptibilities are unknown.
At high doses in
renal insufficiency can cause seizures (nonconvulsive status epilepticus).
generation cephalosporins, otherwise known as anti-methicillin-resistant S.
aureus (MRSA) cephalosporins, include ceftaroline and ceftibiprole
ceftaroline has higher affinity for PBP2a in methicillin-resistant staphylococci,
and has activity against MRSA, as well as vancomycin-intermediate Staphylococcus
aureus (VISA) and hetero-VISA. In addition, ceftaroline has
activity for Streptococcus pneumoniae that is intermediate or
resistant to penicillin or ceftriaxone.
Ceftaroline is not
active for enterococci nor against AmpC-overproducing or ESBL-producing
Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter
baumannii, or Bacteroides fragilis.
Ceftobiprole is a cephalosporin available in
Canada and some European countries (but not the United States) that is also
capable of binding to penicillin binding protein 2a, the protein
conferring S. aureus resistance to beta-lactam antibiotics .
It can also bind
penicillin binding protein 2x in penicillin-resistant S. pneumoniae.
It has in vitro activity similar to that of ceftazidime or cefepime against Enterobacteriaceae; it also has activity against
enterococci. In addition, ceftobiprole appears to have a low potential for
selection of resistance.
cephalosporin has activity against multidrug-resistant gram-negative bacteria,
including extended-spectrum beta-lactamase- or carbapenemase-producing
organisms and multidrug-resistant P. aeruginosa, A.
baumannii, Stenotrophomonas maltophilia, and Burkholderia
In addition to
enhanced stability against beta-lactamases, it has a novel mechanism for
transport across the outer membrane that can overcome the effect of membrane
permeability mutations, as seen in P. aeruginosa. Cefiderocol is
thought to have poor gram-positive and anaerobic activity.
In the United
States, cefiderocol has been approved by the Food and
Drug Administration for use in adults with complicated urinary tract infections
(UTIs) and/or pyelonephritis due to highly resistant gram-negative organisms
when there are no alternative treatment regimen.
All of the
cephalosporins except ceftriaxone require dose modification in the presence of
severe renal failure.
resistance of Cephalosporins.
2. Outer membrane