1. β- Lactam Antibiotics Renaissance
Wenling Qin ,Mauro Panunzio and Stefano Biondi
Antibiotics 2014, 3, 193-215
Presented by
Neeraj Chauhan
M.Sc 2nd year
DMBT
2. Antibiotics
An antibiotic is an agent that either kills or inhibits the growth of
a microorganism
Classification of Antibiotics
Based on
mode of
Action
Cell Wall
Synthesis
Protein
Synthesis
DNA Synthesis RNA synthesis
Based on their
spectrum of
action
Broad-spectrum
Narrow
Spectrum
4. β-lactam antibiotics
Contain β-lactam ring
β-lactam (beta-lactam) ring is a four-membered lactam
Active against both Gram positive and Gram negative pathogens
Includes penicillin derivatives
(penams), cephalosporins (cephems), monobactams, and carbapenems
β-lactam
ring
5. Adverse effects
Adverse drug reactions
diarrhea, nausea, rash, urticaria, superinfection (including candidiasis)
fever, vomiting, erythema, dermatitis, angioedema
Pain and inflammation at the injection site also common
Allergy/hypersensitivity
urticaria, anaphylaxis, interstitial nephritis
6. Mode of action:
β-lactams disrupt the synthesis of bacterial cell wall
mimic the structure of D-Ala-D-Ala link
bind to the active site of PBPs
PBP recognise the D-Ala-D-Ala sequence of the NAMA peptide side chain
disrupt the cross-linking process.
7. Mechanism of β-Lactam Drugs
The PBP is now covalently bound by the drug
and cannot perform the cross linking action
The tetrahedral intermediate collapses, the amide
bond is broken, and the nitrogen is reduced
The hydroxyl attacks the amide and
forms a tetrahedral intermediate
9. β-Lactamases
Provide resistance to β-lactam antibiotics
Hydrolyze β-lactam ring
deactivate drug
Especially prevalent in Gram (-) bacteria.
10.
11. To counter bacterial resistance, there is a need of development of new
antibiotics
In particular, two types of strains have led to the need for developing
new drugs:
multidrug-resistant strains (MDR)
extremely drug-resistant strains (XDR)
In antibiotic development ,novel β-lactam antibiotics or β-lactamase
inhibitors play a significant role
Avenues:
Identify novel β-lactams
Identify novel β-lactamase inhibitors
12. β-Lactamase Inhibitors
Used in conjunction with β-Lactam antibiotics
Examples:
Clavulanic acid+ amoxicillin or ticarcillin
Sulbactam + ampicillin or cefoperazone
Tazobactam + piperacillin
Efficacy against β-lactamases
class A β-lactamases- effective
class C enzymes- less effective
class B and most class D enzymes- inactive
Avibactam, MK-7655, MK-8712, and RPX7009
Able to inhibit class A and C β-lactamases, such.
Among these, only avibactam and MK-7655 are under development
Sulbactam
13. Combinations of β-lactam antibiotics and β-
lactamase inhibitors Commercially available
(i) Amoxicillin-clavulanate.
first β-lactam-β-lactamase inhibitor combination
introduced in 1981 in the United Kingdom and in 1984 in the United
States, and
only combination available for oral use.
Amoxicillin active against streptococci, enterococci, E. coli, and Listeria
spp
Addition of clavulanate expands amoxicillin's spectrum
penicillinase-producing S. aureus, H. influenzae, Moraxella
catarrhalis, Bacteroides spp., N. gonorrhoeae, E. coli, Klebsiella
spp., and P. mirabilis
an oral equivalent of ampicillin-sulbactam or ticarcillin-clavulanate in
the treatment of skin, soft tissue, abdominal infections.
Intravenous formulations of amoxicillin-clavulanate available in Europe
14. (ii) Ticarcillin-clavulanate
Introduced in 1985
first combination for parenteral administration.
ticarcillin effective against non-β-lactamase-producing
Haemophilus spp., E. coli, Proteus spp., Enterobacter spp., Morganella spp.,
Providencia spp., and P. aeruginosa.
ticarcillin + clavulanate increase activity against
β-lactamase-producing staphylococci, E. coli, H. influenzae, Klebsiella spp.,
Proteus spp., Pseudomonas spp., Providencia spp., N. gonorrhoeae, Moraxella
catarrhalis, and Bacteroides spp
Exhibits activity against multidrug-resistant
15. (iii) Ampicillin-sulbactam.
Ampicillin activity against
Streptococci, Enterococci, Listeria spp., and strains of S. aureus, H.
influenzae, E. coli, P. mirabilis, Salmonella spp., and Shigella spp. that
are devoid of β-lactamases
In combination with sulbactam, the activity extends to β-lactamase-
containing S. aureus, H. influenzae, M. catarrhalis, E. coli, Proteus
spp., Klebsiella spp., and anaerobes
combination of ampicillin at 2.0 g + sulbactam at 1.0 g
ideal therapy for polymicrobial infections such as abdominal and
gynecological surgical infections, aspiration pneumonia, odontogenic
abscesses, and diabetic foot infections.
Unfortunately, the resistance to ampicillin-sulbactam among clinical
isolates of E. coli is increasing
16. (iv) Piperacillin-tazobactam.
Introduced in United States in 1993
Piperacillin broad-spectrum penicillin that is bactericidal against many Gram-
positive and Gram-negative aerobes and anaerobes
Piperacillin demonstrates activity against P. aeruginosa, pneumococci, streptococci,
anaerobes, and Enterococcus faecalis, and this activity is retained in combination
with tazobactam .
Tazobactam extend piperacillin's activity
β-lactamase producing strains of Enterobacteriaceae, H. influenzae, N.
gonorrhoeae, and M. catarrhalis and has the potential to lower MICs against
these strains expressing ESBLs
17. CXA-101 (Zerbaxa)
ceftolozane + tazobactam
Ceftolozane- cephalosporin
Active against MDR P. aeruginosa
Have enhanced affinity for the PBPs
Stable to β-lactamase AmpCs
Tazobactam- sulfone penam β-lactamase inhibitor
Restore susceptibility of
93% of ESBL producers
95% of the AmpC producer
Used to treat cUTI, including kidney infection (pyelonephritis).
Used with metronidazole to treat cIAI
Dosage-
1.5 g (1 g/0.5 g) every 8 hours
intravenous
in patients 18 years or older .
18. CAZ104 (AVYCAZ)
Ceftazidime + avibactam
Ceftazidime
third-generation cephalosporin
good activity against Gram-negative pathogens
Avibactam
Inhibits class A β-lactamases;including ESBLs and KPCs
less active against AmpCs
Inactive towards metallo-β-lactamases
For treatment of cUTI including pyelonephritis caused by:
Escherichia coli, Klebsiella pneumoniae, Citrobacter koseri, Enterobacter aerogenes,
Enterobacter cloacae, Citrobacter freundii, Proteus spp. and Pseudomonas aeruginosa.
Dosage
2.5g (2g ceftazidime and 0.5g avibactam) given every eight hours
intravenous
for 5 to 14 days.
side effects include vomiting, nausea, constipation and anxiety.
CEFTAZIDIME
AVIBACTAM
19. β-Lactam and β- Lactamase Inhibitors
and their combinations in development
26. Conclusions
β-lactam antibiotics
play important role in treatment of multidrug resistant pathogens
Widely prescribed because of efficacy and safety profile
Interest for novel β-lactam antibiotics or β-lactamase inhibitors has
boosted
Goal is to achieve antibacterial efficacy against multidrug resistant
pathogens.
Two new families of β-lactamase inhibitors emerge
Diazabicycooctanes (DBOs) and boronic acids
Combine with cephalosporins and carbapenems
show activity against β-lactamase-producing Gram-negative bacteria
Inhibitors against class A (ESBL, KPC), class D (OXA) and class B (NDM) β-
lactamases require