newer antibacterials are needed because of increasing antimicrobial resistance and no progression in discovery of new drugs as we are kind of stuck with our fight against bugs

1. Newer Antibacterials
Dr. Subodh Gyawali
Internal medicine resident
1st year

2. History
• Alexander Fleming discovered Penicillin 1928
• Domagk discovered Sulphonamides 1935
• Selman Waksman discovered Streptomycin 1943
• G.Brotzu discovered Cephalosporins 1945
• Macrolides 1952
• George Lesher and coworkers fluoroquinolones 1962

3. Between 1962 and 2000, no major classes of
antibiotics were introduced

4. NEWER ANTIBACTERIALS

5. Oxazolidinones
• Considered to be the first truly new class of antibacterial drugs introduced in
the past 3 decades
• Linezolid- Approved for adults use in 2000, approved for pediatric use in
2005
• Tedizolid – Approved for adult use in 2014.

6. Linezolid
MOA: inhibit protein synthesis by binding to 50 S subunit and preventing formation of the initiation complex
Bioavailability: 100%
Half life: 4-5 hrs
Excretion: hepatic
Use: Gram +ve species including MRSA and VRE.
S/E: bone marrow suppression( esp. thrombocytopenia), peripheral neuropathy, serotonin syndrome, optic
neuritis
Mech. of resistance: point mutation of ribosomal RNA
Dose : 600 mg iv/oral twice a day

7. Tedizolid
• Similar to linezolid
• FDA approved for >12 yrs of age
• Bioavailability: 91%
• Half life : 12 hrs
• Elimination : 82% faecal, 18 % urine
• Dose : 200mg IV/oral once a day.

8. Newer Oxazolidinones
• Radezolid -Phase II clinical trial Uncomplicated skin and skin structure
infections
• Torezolid -Phase II clinical trial Complicated skin and skin structure
infections
MOA: Bind to the 23S portion of the 50S subunit preventing translation
initiation
Advantage over linezolid : Improved potency, Aqueous solubility, Reduced
toxicity, overcomes resistance by additional hydrogen bond interactions with
23S rRNA

9. Newer glycopeptides
• Telavancin : Approved in 2009 for complicated skin and skin structure
infections(MRSA)
• Dalbavancin : Approved in 2014.
• Oritavancin : Approved in 2014.

10. • MOA: Inhibits peptidoglycan biosynthesis by inhibiting transglycosylation +
transpeptidation
• Additional mode of action shown by newer drugs-
• Causes disruption of membrane potential
• Increases cell permeability causing rapid bactericidal activity
• Dalbavancin, oritavancin, and telavancin half lives in humans are approximately 7
days, 15 days, and 7.5 hrs respectively
• Excretion : renal

11. Advantage over Vancomycin
• Additional mechanisms of action
• Rapid bactericidal activity against Vancomycin Resistant Enteroccoci (VRE)
and VRSA, unlike vancomycin which is bacteriostatic.
• More potent and lesser potential for resistance
• Less frequent dosing
• Longer t 1/2 life

12. Lipopeptides
• Developed for the treatment of vancomycin-resistant enterococcal infections
• Daptomycin- approved by FDA in 2003 for the treatment of SSTIs and
approved in 2006 for the treatment of blood stream infections
• MOA: inserting its lipophilic tail into the cell membrane of gram-positive
organisms This calcium dependent process leads to the formation of
channels from which intracellular potassium is lost disrupting the bacterial
cell membrane potential and causing cell death.

13. • Half life: 8 hrs
• Excretion: renal
• Bactericidal against Methicillin resistant staphylococcus aureus (MRSA),
Methicillin-resistant Staphylococcus epidermidis and VRE inclusive of
linezolid-resistant isolates.
• In July 2010, a warning was issued by FDA about the potential of
daptomycin to cause life threatening complication i.e., eosinophilic
pneumonia

14. Ketolides
• Semisynthetic 14 membered ring macrolides
• Carbonyl group at the C3 position, responsible for sensitivity to macrolide
resistant strains
• Telithromycin- Approved in 2004
• Cethromycin- Phase III trials
• Solithromycin- Phase III trials

15. Telithromycin
• First ketolide antibiotic to enter clinical use
• Approved by the FDA in 2004
• For community acquired pneumonia: 800 mg OD for 7-10 days.
• Excretion in urine and faeces.
• Half life. : 10 hrs

16. Glycylcyclines
• New class of antibiotics derived from tetracycline
• Designed to overcome two common mechanisms of tetracycline resistance
resistance mediated by
• acquired efflux pumps ,
• ribosomal protection
• TIGECYCLINE : approved in 2005
• PTK0796(Omadacycline) : approved in 2018

17. Tigecycline
• Approved in 2005
• MOA: Acts by binding to 30-S subunit of ribosome, thus inhibiting protein
synthesis which is 20 fold more efficient than tetracycline.
• Indication: Complicated skin and skin structure infections & Intra-abdominal
infections. New Delhi metallo-β-Lactamase producing Enterobacteriaceae
has also shown susceptibility to tigecycline. Also active against MRSA

18. • DOSE: Only I/V formulation available. Slow I/V infusion of 100 mg
followed by maintenance dose(50 mg BD)
• No dose adjustment in renal failure (in comparison to tetracycline) Primary
route of elimination is the biliary excretion so dose adjustment is
recommended in hepatic disease.
• Half-life : 27 hrs.

19. Eravacycline
Approved in 2018
• Disrupts protein synthesis by binding to 30 S ribosomal subunit
• Structural changes overcomes the tetracycline resistance mechanisms.

20. Newer carbapenems
• Beta-lactam antibiotics with a broad spectrum of antibacterial activity
Ertapenem: Approved in 2001
Doripenem :Approved in 2007 ,Suitable alternative to currently available
antipseudomonal carbapenems (i.e, imipenem, meropenem)
Razupenem: Phase II clinical trial

21. Doripenem
• Indication: Complicated urinary tract infections , Intra-abdominal infections
• MOA: Bind to penicillin binding proteins (PBPs) and inhibit crosslinking of the
peptidoglycan structure
• Half life: 1 hr
• Excretion : renal
• The most common ADRs are headache, nausea, diarrhea, rash, and phlebitis.
Postmarketing reports have also identified Stevens-Johnson syndrome, toxic
epidermal necrolysis, interstitial pneumonia, and seizures as adverse drug reactions

22. • Advantage :
1.Spectrum of activity similar to that of meropenem against gram-ve & similar
to imipenem against gram+ve bacteria
2. Slightly better in vitro activity against P. aeruginosa
3. Not degraded by renal dehydropeptidase
Dose: Available as I/V formulation only 500mg by I/V infusion every 8 hours

23. • Ertapenem
Long half life carbapenem
Once daily dosing
High protein binding
Not for P. aeruginosa
Low toxicity

24. Newer cephalosporins
• Ceftaroline:
• Approved in 2010
• It is a novel broad-spectrum antibiotic effective against Methicillin Resistant
Staphylococcus aureus (MRSA), penicillin and cephalosporin resistant S. pneumoniae,
vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant S. aureus (VRSA).
• It is also active against many gram-negative pathogens but inactive against
extended-spectrum β-lactamase (ESBL) producing bacteria
• acts by binding to penicillin binding proteins 1-4 (PBPs 1-4)

25. • half-life (t½) of 1.6 hr (for a single dose) to 2.7 hr (following multiple doses)
• It is given as 600 mg intravenous dose, every 12 hourly.
• Dose adjustment is required in patients with renal impairment as it is
primarily eliminated by the kidneys
• The most common side effects observed during clinical trials were nausea,
dysgeusia and caramel-like taste disturbances, vomiting, diarhoea and
headache.

26. Ceftobiprole
• Is awaiting FDA approval due to additional safety data being demanded by
FDA.
• It is the broad-spectrum antibiotic which shows good spectrum of activity
against MRSA, penicillin-resistant S. pneumoniae, P. aeruginosa and
Enterococci.

27. Cefiderocol
• Siderophore conjugated cephalosporin approved in 2019

28. Novel Dihydrofolate reductase inhibitors
• Iclaprim
• Diaminopyrimidine that inhibit DNA/RNA synthesis
• Awaiting FDA approval
• Indication: For the treatment of complicated skin and soft tissue
infections caused by antibiotic-resistant bacteria
• Designed to overcome trimethoprim resistance
• Active against MRSA, penicillin resistant S. pneumoniae

29. Pleuromutilins
• Newer class of antibiotic
• MOA: Bind to 50S subunit of ribosomes inhibiting protein synthesis
• Retapamulin: Approved in 2007, topical antibiotic used in treatment
of skin infections such as impetigo S. aureus (methicillin-susceptible
only) or S. pyogenes
• Lefamulin approved in 2019 for treatment of community acquired
bacterial pneumonia.

30. Macrocyclic antibiotic drugs.
• Fidaxomicin
• Narrow spectrum bactericidal agent
• Alternative to the currently used treatment regimens of vancomycin and
metronidazole against Clostridium difficile , approved in 2011.
• MOA: Inhibit bacterial enzyme RNA polymerase
• Dose : 200 mg po twice daily.

31. Ceftolozane and Tazobactam
(approved in 2014)

32. Ceftazidime and avibactam
(approved in 2015)

33. Meropenem and vaborbactam
• Approved in 2017

34. Plazomycin
• An aminoglycoside approved in 2018.
• MOA : binds to 30S subunit inhibiting protein synthesis
• Not inhibited by most aminoglycoside modifying enzymes
• Activity against enterobacteriaceae in the presence of class A and D beta-lactamases
• May have reduced activity against enterobacteriaceae that overexpresses efflux
pumps or lower expression of porins
• No activity against acinetobacter sp and variable activity v. P. aeruginosa.

35. Plazomycin

36. Imipenem, cilastin and relebactam
(approved in 2019)

37. Take home message
• There is a great need of newer antibiotics because of increasing microbial
resistance
• Because of increase cost of development and increasing resistant, only few
drugs are in pipeline
• Some of the newer agents are effective against resistant strains
• Programs like Antibiotic stewardship can be helpful to combat the resistance
• Rational use of antibiotics remains the most important measure

38. References
• Newer antibacterials in therapy and clinical trials - PubMed (nih.gov)
• Antibiotics in the clinical pipeline in October 2019 | The Journal of
Antibiotics (nature.com)
• Bertram Katzung, Anthony Trevor - Basic and Clinical Pharmacology-Mc
Graw Hill LANGE

39. Thank you