Chapter 72 – Drugs that weaken the bacterial cell wall II: Other drugs
Inhibitors of cell wall synthesis disrupt the cell wall and produce bacterial lysis and
death
CEPHALOSPORINS
Cephalosporins are beta lactam antibiotics similar and structure and action to the
penicillins
they are bactericidal, often resistant to beta lactamases, and active against a broad
spectrum
toxicity is low
most widely used group of antibiotics
Chemistry
all cephalosporins are derived from the same nucleus which contains a B-lactam ring
(antibacterial) fused to a second ring
Mechanism of Action
Similar to PCNs, they bind to PBPs (penicillin binding proteins), disrupt cell wall
synthesis and activate autolysins (enzymes that cleave the cell wall)
As with PCNs, they are most effective against actively growing cells
Resistance
Cephalosporin resistance is mainly caused by the production of beta lactamases,
which are enzymes that cleave the beta lactam ring which inactivates the drug
Cephalosporinases aka beta lactamases that act on cephalosporins
Most first generation cephalosporins are destroyed by beta lactamases; second
generation are less sensitive to destruction; 3rd 4th and 5th generation are highly
resistant
Bacterial resistant can result from altered PBPs that have a low affinity for
cephalosporins
methicillin resistant staphylococci produce these PBPs and are resistant to most
cephalosporins
Ceftaroline is a fifth generation Cephalosporin active against MRSA
Classification and Antimicrobial Spectra
As we progress from 1st generation to 5th generation agents there is
o increased activity against gram negative bacteria and anaerobes
o increased resistance to destruction by beta lactamases
o Increased ability to reach the cerebrospinal fluid
Pharmacokinetics
Absorption
Many cephalosporins must be administered parenterally via IM or IV due to poor
absorption from the GI tract
in the US only 10 can be given by mouth; of these only one can be administered
orally and by injection – cefuroxime
, Distribution
Cephalosporins distribute well to most body fluids and tissues
therapeutic concentration is achieved in plural, pericardial, and peritoneal fluid;
however low concentrations in ocular fluid
1st and 2nd generation penetration to the CSF is unreliable so these should not be
given for bacterial meningitis
3rd 4th and 5th generations reach sufficient bactericidal effect in CSF
Elimination
Most are eliminated by the kidneys
excretion is by glomerular filtration and active tubular secretion
Probenecid can reduce tubular secretion in some cephalosporins thereby prolonging
effects
dose must be reduced to a prevent accumulation with renal insufficiency
Exception: Ceftriaxone is eliminated by the liver therefore dosage does not need to
be reduced with renal impairment
Adverse Effects
Generally well tolerated and one of the safest groups of antimicrobials
allergic reactions
hypersensitivity reactions are the most frequent
Most common is maculopapular rash several days after treatment started
Severe immediate reaction like bronchospasm or anaphylaxis is rare
should not be given to patients with a history of Cephalosporin allergy
because penicillins and cephalosporins are similar structurally, patients that are
allergic to one may cross react with the other, although rare. Patients with mild
penicillin allergy can use cephalosporins with little concern
but because of the potential for fatal anaphylaxis, cephalosporins should not be given
to patients with a history of severe reaction to penicillins
Drug interactions
Alcohol
Cefazolin and cefotetan Can induce a state of alcohol intolerance; patients taking
these who ingest alcohol have potential for disulfiram-like reaction; this reaction can
be dangerous and brought on by the accumulation of acetaldehyde secondary to
inhibition of aldehyde dehydrogenase; patients must avoid alcohol with these drugs
Drugs that promote bleeding
Cefotetan, cefazolin, ceftriaxone Can promote bleeding because they have a side
chain that interferes with vitamin K metabolism which can inhibit the formation of
clotting factors
Use caution if using these drugs with other drugs that promote bleeding like
anticoagulants, thrombolytics, NSAIDs, etc)
Therapeutic Uses
Inhibitors of cell wall synthesis disrupt the cell wall and produce bacterial lysis and
death
CEPHALOSPORINS
Cephalosporins are beta lactam antibiotics similar and structure and action to the
penicillins
they are bactericidal, often resistant to beta lactamases, and active against a broad
spectrum
toxicity is low
most widely used group of antibiotics
Chemistry
all cephalosporins are derived from the same nucleus which contains a B-lactam ring
(antibacterial) fused to a second ring
Mechanism of Action
Similar to PCNs, they bind to PBPs (penicillin binding proteins), disrupt cell wall
synthesis and activate autolysins (enzymes that cleave the cell wall)
As with PCNs, they are most effective against actively growing cells
Resistance
Cephalosporin resistance is mainly caused by the production of beta lactamases,
which are enzymes that cleave the beta lactam ring which inactivates the drug
Cephalosporinases aka beta lactamases that act on cephalosporins
Most first generation cephalosporins are destroyed by beta lactamases; second
generation are less sensitive to destruction; 3rd 4th and 5th generation are highly
resistant
Bacterial resistant can result from altered PBPs that have a low affinity for
cephalosporins
methicillin resistant staphylococci produce these PBPs and are resistant to most
cephalosporins
Ceftaroline is a fifth generation Cephalosporin active against MRSA
Classification and Antimicrobial Spectra
As we progress from 1st generation to 5th generation agents there is
o increased activity against gram negative bacteria and anaerobes
o increased resistance to destruction by beta lactamases
o Increased ability to reach the cerebrospinal fluid
Pharmacokinetics
Absorption
Many cephalosporins must be administered parenterally via IM or IV due to poor
absorption from the GI tract
in the US only 10 can be given by mouth; of these only one can be administered
orally and by injection – cefuroxime
, Distribution
Cephalosporins distribute well to most body fluids and tissues
therapeutic concentration is achieved in plural, pericardial, and peritoneal fluid;
however low concentrations in ocular fluid
1st and 2nd generation penetration to the CSF is unreliable so these should not be
given for bacterial meningitis
3rd 4th and 5th generations reach sufficient bactericidal effect in CSF
Elimination
Most are eliminated by the kidneys
excretion is by glomerular filtration and active tubular secretion
Probenecid can reduce tubular secretion in some cephalosporins thereby prolonging
effects
dose must be reduced to a prevent accumulation with renal insufficiency
Exception: Ceftriaxone is eliminated by the liver therefore dosage does not need to
be reduced with renal impairment
Adverse Effects
Generally well tolerated and one of the safest groups of antimicrobials
allergic reactions
hypersensitivity reactions are the most frequent
Most common is maculopapular rash several days after treatment started
Severe immediate reaction like bronchospasm or anaphylaxis is rare
should not be given to patients with a history of Cephalosporin allergy
because penicillins and cephalosporins are similar structurally, patients that are
allergic to one may cross react with the other, although rare. Patients with mild
penicillin allergy can use cephalosporins with little concern
but because of the potential for fatal anaphylaxis, cephalosporins should not be given
to patients with a history of severe reaction to penicillins
Drug interactions
Alcohol
Cefazolin and cefotetan Can induce a state of alcohol intolerance; patients taking
these who ingest alcohol have potential for disulfiram-like reaction; this reaction can
be dangerous and brought on by the accumulation of acetaldehyde secondary to
inhibition of aldehyde dehydrogenase; patients must avoid alcohol with these drugs
Drugs that promote bleeding
Cefotetan, cefazolin, ceftriaxone Can promote bleeding because they have a side
chain that interferes with vitamin K metabolism which can inhibit the formation of
clotting factors
Use caution if using these drugs with other drugs that promote bleeding like
anticoagulants, thrombolytics, NSAIDs, etc)
Therapeutic Uses
