Cephalosporins & other β-

Lactam Antibiotics.

β- Lactam Antibiotics

β-lactam antibiotics, inhibit bacterial growth

by interfering with bacterial cell wall

synthesis.

The β-lactam antibiotics may be further sub-

divided into two categories:

Penicillin

Cephalosporin

Cephalosporins

Cephalosporins are similar to Penicillins,

but more stable to bacterial β lactamases

and therefore have a broader spectrum of

activity.

History

The 1st source of Cephalosporins,

Cephalosporium acremonium(Fungus), was

isolated in 1948 by Giuseppe from the sea

near a sewer outlet of the Sardinian Coast.

The crude filtrates from this fungus were

found to inhibit the in vitro growth of β-

lactamase producing S. aureus and to cure

the Staphylococcal infections and typhoid

fever in humans.

Subsequently, Abraham and his colleagues

identified three distinct antibiotics from the

culture fluid of fungus.

These antibiotics were named

Cephalosporin N and C (which were

chemically related to penicillin) and

Cephalosporin P, a steroid antibiotic that

resembles Fusidic Acid.

Chemistry

The nucleus of Cephalosporins, 7-aminocephalosporanic acid bears a closeresemblance to 6-aminopencillanic acid.

The core of the basic cephalosporin moleculeconsists of a two ring system which includesa β-lactam ring condensed withdihydrothiazine ring. The core itself canalso be referred to as 7-aminocephalosporanic acid which can bederived by hydrolysis from the naturalcompound Cephalosporin C.

Chemical compounds

containing this core

are relatively stable to

acid hydrolysis and

tolerance to β-

lactamases.

Cephalosporin C ring

structure contains a

side-chain.

Modification of side

chains on the relevant

positions has been used

to create a whole new

class of cephalosporin

antibiotics.

Modification of side-chains at position 7 of the

lactam ring seems to affect the antibacterial

activity while position 3 of the dihydrothiazine

ring alters pharmacokinetic properties and

receptor binding affinity.

Mechanism of Action

Cephalosporins exert bactericidal effect in

manner similar to that of Penicillins.

Binding to specific PBPs

Inhibition of cell wall synthesis by

inhibiting transpeptidation of

Peptidoglycan

Activation of Autolytic enzymes Autolysins

or Murein Hydrolases

Classification

Cephalosporins can be classified into four

major groups or generations, depending

mainly on the spectrum of antimicrobial

activity.

Recently, Fifth generation cephalosporins were

developed in the lab to specifically target

against resistant strains of bacteria

particularly Methicillin Resistance

Staphlococcus Aureus (MRSA).

1st Generation Cephalosporins

The agents included in this group have good

activity against gram-positive cocci, such

as pneumococci, streptococci and

staphylococci but not active against

methicillin resistant strains of

staphylococci, and relatively modest

activity against gram-negative

microorganisms (E.Coli and Klebsiella

pnumoniae).

1st generation Cephalosporins include:

Cefazolin (IV/IM)

Cefadroxil (PO)

Cephalexin (PO)

Cephalothin (IV/IM)

Cephapirin (IV/IM)

Cephradine (PO)

2nd Generation Cephalosporins

These compounds show modest activity

against gram-positive bacteria (less active

than 1st generation drugs) and display

greater activity against gram-negative

microorganisms including Haemophilus

influenza, some Enterobacter and Neisseria

Species.

In comparison to 1st generation, they have

some what increased activity against gram-

negative bacteria but this activity is much

less than the activity of 3rd generation

compounds.

The drugs included in this class are:

Cefaclor (PO)

Cefamandole (IV/IM)

Cefonicid (IM/IV)

Cefuroxime (IV/IM/PO)

Cefprozil (PO)

Loracarbef (PO)

Ceforanide (IM/IV)

3rd Generation Cephalosporins

Though greatly inferior to 1st generation

cephalosporins in regard to their activity

against gram-positive cocci, the 3rd

generation cephalosporins exhibit much

more activity against gram-negative bacilli,

most other enteric organisms and β-

lactamase producing strains of

Haemophilus and Neisseria.

Drugs of this group have superiority over the

other two generation in having ability to

reach CNS (cross BBB). They include:

Cefoperazone (IV/IM)

Cefotaxime (IV/IM)

Ceftriaxone (IV/IM)

Cefixime (PO)

Ceftazidime (IV/IM)

Moxalactam (IM/IV)

4th Generation Cephalosporins

They have an extended spectrum of activity

as compared to the 3rd generation and have

increased stability from hydrolysis by β-

lactamases.

Aerobic gram-negative bacilli resistant to 3rd

generation cephalosporins can be

successfully treated with 4th generation

drugs.

Drugs included in this class are:

Cefepime (IV)

Cefpirome (IV)

Cefozopran (IV)

5th Generation Cephalosporins

These 5th generation cephalosporins are

active against Methicillin resistant

staphylococci.

Agents under this class include:

Ceftaroline Fosamil (IV)

Ceftobiprole (IV)

Ceftolozane

FDA has approved Ceftaroline under the

trade name Teflaro which was developed

by modifying the structure of 4th generation

cephalosporin Cefozopran.

Ceftobiprole has powerful antipseudomonal

characteristics and appears to be less

susceptible to development of resistance

and are now on the FDA fast-track.

Currently, ceftaroline and ceftobiprole are on

an unnamed subclass of cephalosporins by

the Clinical and Laboratory Standards

Institute (CLSI) but generally classified

under the category of 5th generation

cephalosporins.

Others

Cefaloram

Cefaparole

Cefcanel

Cefedrolor

Cefmatilen

Cefmepidium

Cefrotil

Cefsumide

Nitrocefin

Nitrocefin isa chromogenic cephalosporinsubstrate routinely used to detect thepresence of beta-lactamase enzymesproduced by various microbes. Asa cephalosporin, nitrocefin contains a beta-lactam ring which is susceptible to betalactamase mediated hydrolysis. Oncehydrolyzed, the degraded nitrocefincompound rapidly changes color fromyellow to red. Although nitrocefin isconsidered a cephalosporin, it does notappear to have antimicrobial properties.

Resistance to Cephalosporins

Resistance to cephalosporins can be due to

following mechanisms:

Poor penetration of drug into bacteria

Lack of specific PBPS for a particular

agent

Degradation of the drug by β-lactamases

Failure of activation of Autolytic enzymes

in the bacterial cell wall.

Therapeutic Uses

Cephalosporins are widely used antibiotics.

Unfortunately, overuse of these agents in

situations where drugs with less broad

spectrum activity would be more

appropriate has led to the emergence of wide

array of cephalosporin resistant bacteria.

Cephalosporins are effective as both

Prophylactically & Therapeutically.

Chemoprophylaxis

Single dose of Cefazoline (1-2 g IV/IM ≤60

minutes before procedure) just before

surgery is preferred prophylaxis for

procedures in which skin flora are likely to

be pathogenic.

Alternative to Penicillins

Cephalosporins are still useful alternatives to

Penicillins for a variety of infections in

patients who cannot tolerate penicillins.

Infections

Cefotaxime and ceftriaxone are approved for

use in essentially all pediatric bacterial

infections, including sepsis, meningitis,

pneumonia, those of the skin and soft

tissues, septic arthritis, osteomyelitis, intra-

abdominal, and infections of the

genitourinary tract.

Ceftazidime is the most active third-generation cephalosporin against Paeruginosa. It exhibits excellentpenetration to the CSF and is effective inthe treatment of meningitis caused by Paeruginosa. Ceftazidime commonly iscombined with an aminoglycoside for thetreatment of acute exacerbations ofbronchopulmonary infections in patientswho have cystic fibrosis.

Ceftolozane is combined with the β-

lactamase inhibitor tazobactam, as multi-

drug resistant bacterial infections will

generally show resistance to all β-lactam

antibiotics unless this enzyme is inhibited.

Treatment of Gonorrhoea

Ceftriaxone (as a single dose 125mg by

injection) and Cefixime (400mg oral dose)

are drugs of 1st choice for the treatment of

all forms of gonorrhoea.

Treatment of Typhoid

Cefoperazone and Ceftriaxone (1-2g BD,

IV/IM for 7-10 days) have been used

effectively for the treatment of typhoid fever.

Meningitis

Ceftriaxone and Cefotaxime, currently are

the drug of choice for empirical treatment

of meningitis in non immunocompromised

adults and children older than 3 months.

They are proven effective for the treatment

of meningitis caused by Haemophilus

influenzae, Neisseria meningitidis.

Treatment of Lyme Disease

Lyme is an inflammatory disease spread

by infected Tics bite by Borrelia specie.

Ceftriaxone (2 g once daily

iv for 14–28 days) or

Cefotaxime (2 g iv

every 8 h) is the treatment

of choice for severe forms of Late Lyme

Disease.

Adverse Effects

Allergic Reactions (Rare)

Nephrotoxicity

Diarrhoea (cefixime, cefoperazone)

Disulfiram like Reaction (cefoperazone and cefamandole)

Hypoprothrobinemia (common with cefoperazone and cefamandole)

Phlebitis, pain on IM Injection (cefotaxime, cefalothin)

Other β-Lactam Antibiotics

& Cell Wall Destructor

Other β-Lactam Antibiotics

β-Lactamase Inhibitors

Clavulanic Acid

Salbactum

Tazobactum

Monobactams

Aztreonam

Carbapenems

Doripenem

Imipenem

Ertapenem

Meropenem

β-Lactamase Inhibitors

β-lactamase inhibitors are used in

conjunction with a β-Lactam antibiotic to

extend its spectrum of activity.

Although β-lactamase inhibitors have little

antibiotic activity of their own, they instead

inhibit the activity of β-lactamases, (a

family of enzymes that break the beta-

lactam ring) that allows penicillin-like

antibiotics to work, thereby conferring

bacterial resistance.

Hence β-lactamase inhibitors are often given

in combination with penicillins to tackle the

problem of the resistance caused by the

presence of β-lactamases from bacterial

cells.

An example is Co-Amoxiclav [Augmentin],

which is a combination of amoxicillin and

clavulanic acid. Salbactum usually combined

with Ampicillin (Unasyn) and Tazobactum

with Piperacillin (Zosyn).

Monobactams

Monobactams are drugs with a monocyclic

β- lactam ring.

They are resistant to β-lactamases and

active against gram-negative rods.

They have no activity against gram-positive

bacteria or anaerobes.

Penicillin-allergic patients tolerate

aztreonam without reaction.

Carbapenems

Imipenem has good activity against gram-

negative, gram-positive and anaerobic

organisms.

Imipenem is inactivated by

dehydropeptidases in renal tubules.

It is administered with an inhibitor of renal

dehydropeptidase, cilastatin, for clinical use.

Meropenem and ertapenem are not degraded

by renal dehydropeptidase.

Cell Wall Destructor

Vancomycin

Fosfomycin

Polymyxin

Cycloserine

Vancomycin

Vancomycin is active against gram-positive

bacteria, particularly staphylococci.

Machanism: Inhibits cell wall synthesis by

binding to the D-Ala-D-Ala terminus of

peptidoglycan pentapeptide, preventing

peptidoglycan elongation and cross-linking.

β-lactamase producing staphylococci and

those resistant to nafcillin and methicillin

are killed by vancomycin.

Vancomycin is poorly absorbed from the GI

tract.

It is used orally only for antibiotic-

associated enterocolitis caused by C.

difficile.

Metronidazole is preferred as initial therapy

and vancomycin is reserved for refractory

cases.

Parenteral vancomycin is used in sepsis

caused by methicillin-resistant

staphylococci.

Vancomycin is irritating to tissue, resulting

in phlebitis at the site of injection.

A common reaction is "red man" or "red

neck" syndrome (infusion related flushing).

It can be largely prevented by prolonging

the infusion period to 1-2 hours or

increasing the dosing interval.

Fosfomycin

It inhibits bacterial cell wall biogenesis by

inactivating the cytoplasmic enzyme,

enolpyruvate transferase.

Fosfomycin is active against both gram-

positive and gram-negative organisms.

Fosfomycin is used for treatment of

uncomplicated urinary tract infections.

Polymyxins

Polymyxins antibiotic primarily used for

resistant Gram-negative infections.

Alters bacterial outer membrane permeability

by binding to a lipopolysaccharide layer

resulting in disruption of membrane

integrity.

Polymyxin is applied topically to treat

infections such as those of the eye, ear,

and skin.

Because polymyxins also react with the

membranes of human cells, they can

cause kidney damage and neurotoxicity. The

availability of better antibiotics limits the use

of polymixins.

Cycloserine

Cycloserine is used only to treat

tuberculosis resistant to first-line agents.

Cycloserine causes serious CNS toxicity

with headaches, tremors, acute psychosis,

and convulsions.

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