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PHL 424
Antimicrobials
4th Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Cephalosporins,
Overview
 Cephalosporins were first obtained from a filamentous fungus
“Cephalosporium”
 Cephalosporins are similar to penicillins chemically, in mechanism of
action and in toxicity
 The intrinsic antimicrobial activity of natural cephalosporins is low, but the
attachment of various R1 and R2 groups (see classification) has yielded
drugs of good therapeutic activity and low toxicity
 Cephalosporins are affected by the same resistance mechanisms as
penicillins. However, they tend to be more resistant than the penicillins to
bacterial b-lactamases, and therefore usually have a broader spectrum of
activity
 Methicillin-resistant Staphylococcus aureus (MRSA) should be considered
resistant to all cephalosporins
Resistance to Cephalosporins
I. Production of b-lactamases
 Bacteria can destroy b-lactam antibiotics enzymatically by a group of
enzymes called b- lactamases
 The production of b-lactamases is considered the principal cause of bacterial
resistance to b-lactam antibiotics
 The introduction of new classes of b-lactams has invariably been followed by
the emergence of new b-lactamases capable of degrading them, as an
example of rapid bacterial evolution under a rapidly changing environment
 Some b-lactamases are relatively substrate specific, and these are described
as either penicillinases or cephalosporinases
 Other "extended spectrum" enzymes are less discriminant and can hydrolyze
a variety of b-lactam antibiotics
Resistance to Cephalosporins,
I. Production of b-lactamases, contd.
 b-Lactamases are grouped into four classes:
Class A b-lactamases include the extended-spectrum b-lactamases,
which degrade penicillins, some cephalosporins and carbapenems
Class B b-lactamases are Zn2+-dependent enzymes that destroy almost
all b-lactams
Class C b-lactamases are active against cephalosporins
Class D includes cloxacillin-degrading enzymes. They also are active
against some cephalosporins
 Class A and D enzymes are inhibited by the commercially available blactamase inhibitors, such as clavulanate and sulbactam
 Examples of bacteria that produce b-lactamases are staphylococcus
aureus and many strains of H. influenzae, Neisseria and Pseudomonas
Resistance to Cephalosporins
II. The occurrence of PBPs with low affinity to cephalosporins
 The microorganism may be intrinsically resistant because of structural
differences in the PBPs that are the targets of these drugs
 A sensitive strain may acquire resistance of this type by the development of
high-molecular-weight PBPs that have decreased affinity for cephalosporins
and penicillins, requiring clinically unattainable concentrations of the drug to
effect its bactericidal activity
 Example 1: Methicillin-resistant S. aureus are resistant via acquisition of an
additional high-molecular-weight PBP with a very low affinity for all b-lactam
antibiotics
 Example 2: Cephalosporin resistance in Streptococcus pneumoniae is
caused by altered PBPs (2 of the 5 high molecular weight PBPs)
Resistance to Cephalosporins
III. Decreased permeability to the drug
 Decreased penetration through the outer membrane prevents the drug from
reaching the target PBP
 In G+ve bacteria, the peptidoglycan polymer is very near the cell surface, thus
the small b-lactam antibiotic molecules can penetrate easily to the PBPs,
where the final stages of the synthesis of the peptidoglycan take place
 G-ve organisms have an outer membrane that limits penetration of b-lactam
antibiotics
 Some small hydrophilic antibiotics can diffuse through aqueous channels in
the outer membrane that are formed by proteins called porins
 An extreme example is P. aeruginosa, which is intrinsically resistant to a wide
variety of antibiotics because it lacks the classical high-permeability porins
 Active efflux pumps serve as another mechanism of resistance, removing the
antibiotic from its site of action before it can act
 This is an important mechanism of b-lactam resistance in P. aeruginosa, E. coli and
Neisseria gonorrhoeae
Cephalosporins, Classification
 Cephalosporins are divided into four generations with
original agents being referred to as first-generation
cephalosporins, and the most recent agents as fourthgeneration cephalosporins
 In general, the spectrum of activity of cephalosporins
increases with each generation because of
decreasing susceptibility to bacterial b-lactamases
 First-Generation Cephalosporins
 Examples: cephradine, cephalexin (there are "longacting" agents, such as cefadroxil)
 They are active against most staphylococci,
pneumococci, and all streptococci, with the important
exception of enterococci
 Their activity against aerobic G-ve bacteria and
against anaerobes is limited
 They act as penicillin G substitutes. They are resistant
to b-lactamase
 They distribute widely throughout the body, but do not
penetrate well into the CSF (not used for meningitis)
 Their t1/2 ranges from 30 minutes to 1.5 hours, and
they are eliminated unchanged in the urine
 They should not be given to patients with a history of
immediate-type hypersensitivity reactions to penicillins
Cephalosporins, Classification
 Second-Generation Cephalosporins
 They have a broader bacteriologic spectrum than
do the first-generation agents
 They are more resistant to b-lactamase than the
first-generation drugs
 For example, cefamandole, cefuroxime, and
cefaclor not only are more active against G-ve
enteric bacteria but are active against both blactamase-negative and -positive strains of H.
influenzae
 Their half-lives are similar to those of the firstgeneration agents
 Excretion is primarily renal, and they distribute
widely. However, they do not attain sufficient
concentrations in the CSF to warrant their use in
the treatment of bacterial meningitis
Cephalosporins, Classification
 Third-Generation Cephalosporins
 These agents retain much of the G+ve activity of the
first two generations, although their antistaphylococcal activity is reduced. They are
remarkably active against most G-ve enteric isolates
 Some third-generation cephalosporins (e.g.,
ceftazidime and cefoperazone) also are active against
most isolates of P. aeruginosa
 In healthy subjects, their half-lives range from 1 hour
(cefotaxime) to between 6 and 8 hours (ceftriaxone)
 These antibiotics diffuse well into most tissues (e.g.,
cefotaxime and ceftriaxone
 Excretion is primarily renal
 Indications include suspected bacterial meningitis and
treatment of hospital-acquired multiple-resistant G-ve
aerobic infections and suspected infections in certain
compromised hosts
 Ceftriaxone is the drug of choice in treating infections
caused by N. gonorrhoeae in geographic areas with a
high incidence of penicillin-resistant isolates
Cephalosporins, Classification
 Fourth-Generation Cephalosporins
 This generation of cephalosporins (such as cefepime, cefpirome) combines the antistaphylococcal activity (but only those that are methicillin-susceptible) of firstgeneration agents with the G-ve spectrum (including Pseudomonas) of thirdgeneration cephalosporins
 This class of cephalosporins have increased stability against hydrolysis by blactamases
 These drugs are usually administrated parenterally
 They demonstrated good penetration into CSF compared to cefotaxime
 They are highly active against common pediatric meningeal pathogens, including
Streptococcus pneumoniae. Their vitro activity against penicillin-resistant
pneumococci is generally twice that of cefotaxime or ceftriaxone
 Fourth-generation agents are particularly useful for the empirical treatment of serious
infections in hospitalized patients when gram-positive microorganisms,
Enterobacteriaceae, and Pseudomonas all are potential etiologies
Cephalosporins, Classification
 Fifth-Generation Cephalosporins
 These are novel cephalosporins with activity against MRSA
 Example: Ceftaroline
 Ceftaroline, the active metabolite of a N-phosphono prodrug, ceftaroline fosamil,
has been recently approved by the US FDA for the treatment of acute bacterial
skin and skin structure infections and community-acquired bacterial pneumonia
 This antimicrobial agent binds to penicillin binding proteins (PBP) inhibiting cell
wall synthesis and has a high affinity for PBP2a, which is associated with
methicillin resistance
 Ceftaroline is consistently active against multidrug-resistant Streptococcus
pneumoniae and Staphylococcus aureus, including methicillin-resistant strains
 The drug is usually administrated intravenously at 600 mg every 12 h
 Ceftaroline has low protein binding and is excreted by the kidneys and thus
requires dose adjustments in individuals with renal failure
Cephalosporins,
Side Effects
 Serious, adverse reactions to the cephalosporins are uncommon. As with most
antibiotics, the full spectrum of hypersensitivity reactions may occur, including
rashes, fever, eosinophilia, serum sickness and anaphylaxis
 The incidence of immediate-type allergic reactions to the cephalosporins is increased
among patients known to be allergic to penicillins
 Adverse reactions attributable to irritation at the site of administration are common.
These reactions include local pain after i.m. injection, phlebitis after i.v. administration
and minor GI complaints after oral administration
 Third-generation drugs may cause transient elevations of liver function test results
and blood urea nitrogen concentrations. They also have a profound inhibitory effect
on the vitamin K-synthesizing bacterial flora of the GIT. In addition, some agents,
such as cefoperazone, can cause hypoprothombinemia and bleeding