Cell Wall Synthesis Inhibitors-Lecture 1
Cell Wall Synthesis Inhibitors-Lecture 1
Cell Wall Synthesis Inhibitors-Lecture 1
THERAPY
N Ngcobo
• Antibiotics are designed to advantage of the biochemical
differences that exist between microorganisms and human
beings.
• Antimicrobial drugs are effective in the treatment of
infections because of their selective toxicity.
• They have the ability to injure or kill an invading
microorganism without harming the cells of the host.
How do we select the correct antimicrobe?
• Identity of the organism
• Identify the susceptibility of the organism to a particular agent/s
• Identify the site of the infection
• Look at patient factors
• Consider the safety and efficacy of the agent
• Depending on the setting, one may need to look the cost of therapy
• However, most patients require empiric therapy (immediate administration of drug(s) prior to
bacterial identification and susceptibility testing.
• Drug of choice in such instances (empirical therapy) is influenced by the site of infection, the
patient history (for example, previous infections, age, recent travel history, recent antimicrobial
therapy, immune status, whether the infection was hospital- or community-acquired), and local
susceptibility data.
BACTERIOSTATIC VERSUS BACTERICIDAL
DRUGS
Bacteriostatic drugs
• Temporarily inhibit growth of the microorganism
• Require the host defence mechanisms to eradicate the infection as they do not kill the
organism.
• These include protein synthesis inhibitors
Bactericidal drugs
• They cause the death of the microorganism
• They eradicate the infection in the absence of the host defence mechanisms
• These include cell wall , DNA synthesis inhibitors and aminoglycosides.
ANTIBIOTIC RESISTANCE
Intrinsic Resistance
• The natural ability of a bacteria to resist activity from certain antibacterial agents.
• May occur due to different functional or structural features such as the production of enzymes
that metabolise the drug or the inability of the drug to enter/penetrate the bacterial.
Acquired Resistance
• Occurs when bacteria develop the ability to resist activity from certain antimicrobial agent/s.
• May occur due to spontaneous chromosomal mutations which lead to changes in the structural
receptor for an antibiotic or a protein involved in drug transport.
CLASSIFICATION OF ANTIMICROBIALS
1. Chemical structure
2. Spectrum
• Narrow spectrum: acting only on a single or a limited group of microorganisms e.g. isoniazid (TB)
• Extended spectrum: modified to be effective against gram-positive organisms and also against a
significant number of gram-negative bacteria e.g. ampicillin
• Selectively interfere with synthesis of the bacterial cell wall resulting in weakened cell wall and
ultimately cell death.
• The interference with the enzymes results in the formation of porins in the cell wall leading to cell death..
• Interfere with the last step of bacterial cell wall synthesis, which is the cross-linking of adjacent
peptidoglycan strands by a process known as transpeptidation.
• Compete for and bind to enzymes called penicillin-binding proteins (PBPs), which catalyze
transpeptidase and facilitate cross-linking of the cell wall.
• Gram-positive microorganisms have cell walls that are easily traversed by penicillins, and,
therefore, in the absence of resistance, they are susceptible to these drugs.
• Penicillins have a beta-lactam ring; the integrity of the beta-lactam ring is required for
antibacterial activity
• Penicillins are absorbed rapidly after oral administration and parenteral administration
• GI absorption may be decreased in the presence of food
• Penicillins do not cross the BBB, except in meningitis; Meningitis increases the permeability
of the BBB, but even then very high doses of penicillin must be administered
• Some bacteria, such as staphylococci, become resistant to penicillins as they produce the beta-
lactamase enzyme, penicillinase, which inactivates the penicillins
• Bactericidal
PENICILLINS
ADVERSE EFFECTS
• Hypersensitivity
• Diarrhoea
• Nephritis
• Neurotoxicity
• Hematologic hepatoxicities
THERAPEUTIC INDICATIONS
• Respiratory infections
• UTIs
• Endocarditis
• Otitis media
• Pneumonia
• Hospital-acquired infections
PENICILLINS
CLINICAL CONSIDERATIONS
• Dose reductions are necessary in cases of renal impairment as penicillins excreted by
kidney.
• Avoid where there is a history of penicillin allergy (if a patient is allergic to one
penicillin, will be allergic to ALL penicillins – CROSS allergy).
• Penicillins reduce the elimination of methotrexate (used in cancer treatment)
Broad spectrum drugs increase C difficile infection risk
C difficile – anaerobic bacteria C difficile colonize the human colon without
symptom; antibiotic treatment can produce overgrowth
Produce diarrhoea and inflammation
Antibiotic treatment is difficult due to antibiotic resistance and physiological factors
of the bacteria (spore formation, protective effects of the pseudomembrane)
Except for oral amoxicillin, penicillins should be given 1-2 hrs before or after a meal; they
should not be given with food to minimize binding to food proteins and acid inactivation
Penicillins • 4) efflux (bacterial cell pumps antibiotic out, so antibiotic cannot reach PBP)
MOA PK AE
All living cells are surrounded by a Oral absorption of the penicillins is Most important adverse effect of
cell membrane, but bacterial cells poor, but there are exceptions penicillins as a group is the
are also surrounded by a firm cell hypersensitivity reaction
wall essential for their normal Assume complete cross-allergy
growth and development Most of the penicillins only cross the between individual penicillins
BBB if it is inflamed
Β-lactams inhibits cell wall synthesis
by binding to penicillin binding GI distress such as nausea and
protein (PBP) preventing cross- Penicillins are, for the most part, diarrhea (especially ampicillin)
linking of peptidoglycan excreted by tubular secretion; dose
Lysis of the bacterial cells takes reduction only needed in major
place after exposure to penicillins renal dysfunction Cholestatic jaundice (rare – most
linked to co-amoxiclav)
CEPHALOSPORINS
• Have the same mode of action as penicillins, and they are affected by the same resistance
mechanisms. However, they tend to be more resistant than the penicillins to certain β-lactamases.
• Classified as first, second, third, fourth, and advanced generation, based largely on their bacterial
susceptibility patterns and resistance to β-lactamases
• First generation has a narrow spectrum. The 2 nd, 3rd and 4th generations have a wider spectrum.
• Cephalosporins are classified into generations – first generation mainly effective against gram-
positive cocci; second generation more gram-negative coverage incl. anaerobes; 3 rd generation
both gram-positive and gram-negative coverage; fourth generation wider spectrum than 3 rd
• Cephalosporins are widely distributed in body fluids;
selected agents (cefuroxime, cefotaxime, ceftizoxime)
penetrate the CSF
• Orally administered cephalosporins are second- and third-
line in the treatment of respiratory and urinary tract
infections
THERAPEUTIC
• IV administered cephalosporins are used in the treatment
of more severe infections, including antibiotic-resistant INDICATIONS
infections
• Earlier cephalosporin generations have greater activity
against Gram-positive organisms; their Gram-negative
activity can be summarized by the mnemonic PEcK –
Proteus mirabilis, some E coli and Klebsiella pneumoniae
• As cephalosporin generations progress, they become more
and more active against Gram-negative organisms
• Second generation have less activity against Gram-positive
organisms, however, they have greater Gram-negative
activity: HEN – Haemophilus influenza, Enterobacter, and THERAPEUTIC
some Neisseria (in addition to PEcK)
INDICATIONS
• Each newer generation is increasingly resistant to
penicillinases
• Third generation cephalosporins are sensitive to the
cephalosporinases
ADVERSE EFFECTS
• Generally well tolerated.
• Allergic reactions are a concern
• Patients who have had an anaphylactic response, Stevens-Johnson
syndrome, or toxic epidermal necrolysis to penicillins should not
receive cephalosporins.
• Should be avoided or used with caution in individuals with
penicillin allergy.
Cephalosporin generations
(spectrum increases with newer generations)
First generation Second generation Third generation Fourth-generation
cephalosporins cephalosporins cephalosporins cephalosporins
• Cefadroxil / Cephalexin (PO) • Cefuroxime / Cefoxitin / • Ceftriaxone / Cefotaxime / • Cefepime / Cefpirome (IV /
• Cefazolin (IV) Cefamandole Ceftazidime (IM / IV) IM)
• Cefaclor / Cefprozil (PO) • Cefixime / Cefpodoxime
• Have good activity against (PO) • Coverage against
some gram-positive and • Have somewhat broader Pseudomonas as well as
some gram-negative spectrum than first- • Enhanced activity against other gram-negative
organisms generation gram-negative organisms bacteria
• Used mainly for Klebsiella • Used in the treatment of • These agents penetrate the
and penicillin- and streptococcal infections CSF
sulfonamide-resistant UTI • Active against most • Most are excreted by the
• Used prophylactically in anaerobes kidney except cefoperazone
surgical procedures • Used primarily in UTI, RTI, and ceftriaxone which are
• Do not penetrate the CSF bone and soft tissues excreted through the biliary
infections and surgical tract
prophylaxis
• With exception of
cefuroxime, these agents do
not penetrate CSF
• Used for Staph and Strep infections, respiratory
tract infections (RTIs), meningitis, pneumonia
• Organisms not covered by cephalosporins = LAME
AE
• Some cephalosporins can cause disulfiram-like
reactions because they block alcohol oxidation
causing acetaldehyde to accumulate
• Some cephalosporins have anti-vit K effects (may
result in increased bleeding)
Include
• Imipenem / Meropenem / Ertapenem / Doripenem
MOA
• similar to other beta-lactams carbapenems inhibit bacterial cell wall synthesis by binding to PBP
• carbapenems are relatively resistant to beta-lactamases and do not demonstrate cross-resistance
with other antibiotics
PK
• Important agents in hospital for empiric treatment in life-threatening conditions
• Imipenem is formulated with an equal amount of cilastatin, a specific enzyme inhibitor that blocks
renal metabolism of imipenem and enhances its urinary concentration; cilastatin has no
CARBAPENE
antibacterial action
• Imipenem is not suitable for treating meningitis as seizures may occur with higher doses
• Meropenem: more stable to renal inactivation than imipenem and thus given without cilastatin.
MS • Imipenem, meropenem, and doripenem are administered IV and penetrate well into body tissues and
fluids, including the CSF when the meninges are inflamed.
• Meropenem is known to reach therapeutic levels in bacterial meningitis even without inflammation.
T/I
• infections caused by penicillinase-producing S aureus, E coli, Klebsiella, Enterobacter
• Also used for Pseudomonas (except ertapenem)
AE
• Hypersensitivity reactions; Penicillin cross-allergy
• Excessive levels of imipenem may result in seizures in patients with renal failure
• GI distress
• Potential to cause CNS effects including seizures (high risk with imipenem)
MONOBACTAMS
E.g. Aztreonam
• IM / IV
• Mainly used against gram - rods
Spectrum
MOA
• Although azatreonam has a monobactam ring, the MOA is the same as penicillins and cephalosporins – inhibit bacterial cell wall
synthesis by binding to PBP
• Resistant to beta-lactamases
A/E
MOA
• Bind to the terminal end of the growing peptidoglycan; prevent further elongation and cross-linking due to inhibition of transglycosylase
• This results in decreased cell membrane activity and increased cell lysis
Bactericidal
• Commonly used in patients with skin and soft tissue infections, infective endocarditis, and nosocomial pneumonia.
• Vancomycin is only active against gram-positive organisms, incl MRSA
• Oral vancomycin is used to treat C difficile colitis
• Televancin, dalbavancin and oritavancin are used to treat skin and skin-structure infections
A/E
• Rapid infusion of vancomycin cause red-man syndrome, which is an infusion-related reaction caused by the release of histamine; it is not considered a drug allergy – prolonging the
infusion to 1-2hrs will prevent this reaction
• High levels of vancomycin may cause nephrotoxicity and ototoxicity
• Televancin and dalbavancin are potentially teratogenic
LIPOPEPTIDE
Daptomycin
MOA
• Daptomycin binds to the cell membrane via calcium-dependent insertion of its lipid tail
• This results in depolarization of the cell membrane with potassium efflux and rapid cell death
A/E
• May cause myopathy
• May result in eosinophilic pneumonia
OTHER CELL WALL SYNTHESIS INHIBITORS
Fosfomycin
• Inactivates pyruvyl transferase, an enzyme that is critical in the synthesis of bacterial cell wall
• Active against both gram-positive and gram-negative infections
• Treatment of uncomplicated UTIs
• A/E may include headache and GI distress
Bacitracin
Colistin (polymixin)
• This unlicensed drug has become important as the only treatment available for highly resistant
Acinetobacter infections;
• Not registered in SA, but can be obtained from the company on a named-patient basis after MCC
approval
• Nephrotoxicity / Neurotoxicity
Summary of important points
Beta-lactamase inhibitors
The beta-lactam antibiotics
Beta-lactam antibiotics, (clavulanic acid, sulbactam,
inhibit the transpeptidase Narrow-spectrum penicillins are
vancomycin, bacitracin, and tazobactam) are administered in
reaction that cross-links the primarily active against gram-
fosfomycin are drugs that inhibit combination with a beta-lactam
peptidoglycan component of the positive cocci and spirocheted
bacterial cell wall synthesis antibiotic to prevent degradation
cell wall
of the antibiotic by bacteria
Aztreonam is a monobactam
antibiotic that is active against Vancomycin is active against Bacitracin is used topically for Fosfomycin is administered as a
aerobic gram-negative bacilli; it gram-positive organisms incl infections caused by gram- single dose for uncomplicated
does not show cross-sensitivity MRSA and Clostridium difficule positive cocci UTI’s case by E coli or enterococci
with other beta-lactam antibiotics