β- Lactam Antibiotics Renaissance

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

3. Types of Antibiotics

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

8. Beta–lactam Resistance
β-lactamase
Changes in
active site of
PBPs
Decreased
expression of
outer
membrane
proteins (OMPs)
Efflux
pumps

9. β-Lactamases
 Provide resistance to β-lactam antibiotics
 Hydrolyze β-lactam ring
 deactivate drug
 Especially prevalent in Gram (-) bacteria.

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

22. Novel β- Lactam Antibiotics

23. Antibiotic approved since 2000

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