1. - 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. -lactam antibiotics Contain -lactam ring -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 -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: -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 -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. Betalactam Resistance -lactamase Changes in active site of PBPs Decreased expression of outer membrane proteins (OMPs) Efflux pumps
9. -Lactamases Provide resistance to -lactam antibiotics Hydrolyze -lactam ring deactivate drug Especially prevalent in Gram (-) bacteria.
10. 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 -lactam antibiotics or -lactamase inhibitors play a significant role Avenues: Identify novel -lactams Identify novel -lactamase inhibitors
11. -Lactamase Inhibitors Used in conjunction with -Lactam antibiotics Examples: Clavulanic acid+ amoxicillin or ticarcillin Sulbactam + ampicillin or cefoperazone Tazobactam + piperacillin Efficacy against -lactamases class A -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 -lactamases, such. Among these, only avibactam and MK-7655 are under development Sulbactam
12. Combinations of -lactam antibiotics and - lactamase inhibitors Commercially available (i) Amoxicillin-clavulanate. first -lactam--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
13. (ii) Ticarcillin-clavulanate Introduced in 1985 first combination for parenteral administration. ticarcillin effective against non--lactamase-producing Haemophilus spp., E. coli, Proteus spp., Enterobacter spp., Morganella spp., Providencia spp., and P. aeruginosa. ticarcillin + clavulanate increase activity against -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
14. (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 -lactamases In combination with sulbactam, the activity extends to -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
15. (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 -lactamase producing strains of Enterobacteriaceae, H. influenzae, N. gonorrhoeae, and M. catarrhalis and has the potential to lower MICs against these strains expressing ESBLs
16. CXA-101 (Zerbaxa) ceftolozane + tazobactam Ceftolozane- cephalosporin Active against MDR P. aeruginosa Have enhanced affinity for the PBPs Stable to -lactamase AmpCs Tazobactam- sulfone penam -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 .
17. CAZ104 (AVYCAZ) Ceftazidime + avibactam Ceftazidime third-generation cephalosporin good activity against Gram-negative pathogens Avibactam Inhibits class A -lactamases;including ESBLs and KPCs less active against AmpCs Inactive towards metallo--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
18. -Lactam and - Lactamase Inhibitors and their combinations in development
19. Novel - Lactam Antibiotics
20. Antibiotic approved since 2000
21. Conclusions -lactam antibiotics play important role in treatment of multidrug resistant pathogens Widely prescribed because of efficacy and safety profile Interest for novel -lactam antibiotics or -lactamase inhibitors has boosted Goal is to achieve antibacterial efficacy against multidrug resistant pathogens. Two new families of -lactamase inhibitors emerge Diazabicycooctanes (DBOs) and boronic acids Combine with cephalosporins and carbapenems show activity against -lactamase-producing Gram-negative bacteria Inhibitors against class A (ESBL, KPC), class D (OXA) and class B (NDM) - lactamases require