New treatments for microorganisms

1. KABUUKA RICHARD
VICTORIA UNIVERSITY
EMERGING TRENDS IN
ANTIBIOTICS

2. NEED FOR NEW THERAPIES
Bacterial resistance to antimicrobials – health
and economic problem
Chronic resistant infections contributing to
increasing health care cost
• Increase in mortality and morbidity with
resistant microorganisms

3. DRUG RESISTANT BACTERIA
• Three classes of drug resistant bacteria are a
major cause of concern
• Methicillin resistant staphylococcous aureus
• Multi drug resistant and pan drug resistance
• Extensively drug resistant

4. ESKAPE
• Organisms posing great danger have been clubbed
together under the term “ESKAPE”
• Enterococcuus faecium
• Staphylococcus aureus
• Klebsiella pneumoniae
• Actinobacter baumanii
• Pseudomonas aeuroginosa
• Enterobacter species
as these bacteria have the ability to escape
the ability of antimicrobial drugs

5. Emerging trends
• Non traditional therapies
• Adjunctive and Synergistic approach
• Novel drugs

6. • CEPHALOSPORINS
• ceftalozone 2014 superheros of gram
-ve bacteria
• Ceftazidime 2015
• Ceftaroline 2010 bacterial infections
• Ceftabiprole approval awaited
BETA LACTUM ANTIBIOTICS
Ceftaroline fifth generation cephalosporin
Ceftabiprole

7. CEFTAROLINE:
• Developed from cefozopran(4th
gen)
• Anti MRSA activity
• FDA approval in october 2010
• Indication:
• Acute bacterial skin and skin structure infections
• Community acquired bacterial pneumonia
• SPECTRUM:
• MRSA,VISA,VRSA,Gram –ve pathogens,inactive against extended
spectrum b lactamase producing bacteria
MOA:
• Acts by binding to PBP 1-4
• High affinity for PBP2 in S. aureus for methicillin resistance
• Dose: 600mg IV 12th
hourly
• Side effects: nausea, dysgeusia, caramel like taste disturbances,
vomiting, diarrhoea and headache

8. CEFTABIPROLE:
• Awaiting FDA approval, completed clinical trail in 2007
• SPECTRM:
• MRSA, penicillin resistant S.pneumoniae, P.aeruginosa,
enterococci
• MOA:
• Affinity for PBP2a of MRSA and PBP2x of s. pneumoniae
• Dose:
• 1hr IV infusion of 500mg every 12 hrs for gram+ve
infection
• 2hr infusion of 5500mg every 8 hrs for gram –ve
• Side effects: well tolerated with nausea and dysgeusia

9. CARBAPENEMS
• IMIPENEM-CILASTIN
• AZTREONAM
• DORIPENEM 2007 gram+ve
• MEROPENAM CNS infections
• RELEBACTUM phase 3 imipenem
resistant inf
• RAZUPENEM clinical trial

10. IMIPENEM-CILASTIN:
• INDICATION:
• Lower resp tract,urinary tract, intra abdominal, bone and
joint, skin and skin structure, endocarditis, polymicrobic
infections and septicemia
• SPECTRUM:
• Broad spectrum of activity against gram +ve cocci and
gram-ve bacilli, including P. aeuroginosa and anaerobes
• Cautions: b lactum safety profile(rash, esinophilia), nausea,
seizures
• Cilastin possess no antibacterial activity, reduces renal
imipenem metabolism. Primarly renally eliminated
• Drug interaction:possibly ganciclovir

11. DORIPENEM:
• INDICATIONS:
• Complicated UTI infections
• Intra abdominal infections
• MOA:
• High binding affinity to PBP 2 AND 3 may enhance its activity against
drug resistant P.aeuroginosa
• SPECTRUM:
• Unique spectrum of activity
• Activity against gram+ve cocci like imipenem
• Against gram –ve cocci like meropenem
• It is stable to ESBLs by E.coli& klebsiella spc. And to AmpC b lactamase
enzymes; but vulnerable to acquired b lactamases like class B metallo b
lactamases by someP. Aeuroginosa and carbapenems bysome
Enterobacteriacea and actinobacter sps
• DOSE: 500mg IV 8th
hourly
• Sideeffects: headache, rash,diarrhoea, phlebitis
• Stevenjohnson syn,toxic epidermal necrolysis, interstitial pneumonia,
seizures

12. MEROPENEM: similar to imipenem
• Preferred carbapenem for treatment of CNS infections
• CAUTION: b lactum safety profile, 80% renal elimination
• Drug interaction:probenecid
AZTREONAM:
• Monobactum antibiotic
• SPECTRUM:
• Gram –ve aerobic bacteria , Enterobacteriaceaand P.
aeuroginosa
• Useful in penicillin and cephalosporin allergies as no
sensitivity and cross reactivity occurs
• SIDE EFFECTS: rash, thrombophlebitis, esnophilia,
• Drug interaction:probenecid

13. • VANCOMYIN
• ORITAVANCIN phase III gram +ve
• DALBAVANCIN phase III gram +ve
• TEICOPLANIN in clinical use
• TELAVANCIN 2009 gram +ve
GLYCOPEPTIDES

14. VANCOMYCIN:
• Acts on MRSA
• Similar MOA of b lactams
• Resistance : genetic mutation changing the target
protein
• VRE causes nosocomial infections
• Emergence of VRSA
• Parenteral route
• Adverse effects: rashes,
thrombophlebitis,ototoxicity, nephrotoxicity
• Redman or redneck syndrome: maculopapular rash
over head, neck and back with fever and chills

15. TELEVANCIN:
• Derivative of vancomycin toxic to gram +ve bacteria
• MOA: inhibits celwall synthesis and also damages cell
membrane and increases its permiability
• Dose: once daily , vibantin: 250/750 mg IV
TEICOPLANIN:
• Actinoplanes teichomyceticus
• INDICATIONS: osteomylitis and endocarditis dur to
MRSA and enterococci
• DOSE: IM 200-400mg/day
• Relatively least toxic

16. DAPTOMYCIN:
• Obtained from streptomyces roseosporus
• FDA approval in 2003 for SSTIs and 2006 for blood stream
infections
• Indicated for complicated SSTIs alternative to vancomycin
• MOA: binds to bacterial membrane and cause rapid
depolarization leads to inhibition of protein, RNA, DNA
• SPECTRUM:MRSA, MRS epidemidis ,VRE strains
• Bactericidal
• It is synergistic with gentamicin
• ADVERSE EFFECTS:
• myopathy
• Life threatening esinophilic pneumonia
LIPOPEPTIDES

17. • LINEZOLID clinical use
• RADEZOLID phase II
• TOREZOLID phase II
• SPECTRUM:Gram +ve including MRSA and
Stretococcus pneumoniae
• Mycobacterium tb and nocardia
OXAZOLIDINONES

18. • LINEZOLID:
• bacteriostatic
• INDICATIONS:
• VRE infections
• Nosocomial and community acquired pneumonia
• SSTIs
• MOA: inhibits protein synthesis on binding to 50s ribosomes
• Resistance:mutations in the peptidyl transferase center of the r RNA
• Dose: good oral bioavailability
• oral/IV
• 600mg BD
• ADVERSE EFFECTS:
• Nausea,diarrhoea, dizziness
• Prolonged use of >2weeks causes mylespression with
thrombocytopenia(reversible), peripheral neuropathy and lactic acidosis
• Torezolid:
• 4-16 fold greater potency than linezolid

19. QUINPRISTIN AND DALFOPRISTIN
• Obtained from streptomyces pristinaespiralis
• A combination in ratio of 30:70 is bactericidal against gram
+ve cocci including MRSA,VISA, VRE
• MAO:inhibits protein synthesis by binding to 50s ribosomes
• IND: serious infection wwith VISA, VRE MRSA when
vancomycin is not tolerated
• DOSE:
• IV, not efffective orally
• ADVERSE EFFECTS: arthralgia, myalgia,nausea,
vomiting, diarrhoea, pain at injection site
STREPTOGRAMINS

20. • Newer class of macrolides designed particularly
for respiratory tract pathogens that have acquired
resistance to macrolide antibiotics
• Ketolides are semi synthetic derivatives of 14
membered macrolide , erythromycin
• TELITHROMYCIN
• CETHROMYCIN phase III
• SOLITHROMYCIN phase III
KETOLIDES

22. TELITHROMYCIN:
• First ketolide to entrer clinical use for the treatment of CAP,
chronic bronchitis,acute sinusitis
• MOA: protein synthesis inhibitor acts by binding to 50s ribosome
• 10 times higher affinity tp 50s than erythromycin
• SPECTRUM: S. pneumoniae, macrolide resistant
strains(S.pyogenes)
• Well tolerated orally400mg tablet
• Acheives high tissue concentrations in respiratory fluids and
tissuues including saliva, alveolar macrohages, epithelial lining
fluid, bronchial mucosa
• Drug is cleared by hepatic metabolism
• Adverse effects: hepatotoxicity,myaesthenia gravis exacerbation,
visual disturbances

23. • Newer class of antibiotics that are chemical derivatives of minocycline
TIGECYCLINE
• FDA approval 2005
• SPECTRUM:aerobic and anarobic Gram+ve and –ve organisms
• INDICATIONS: cSSTIs, intra abdominal infections, CAP
• It is designed to overcome 2 common mechanisms of tetracycline resistance
;
• Resistance mediated by acquired efflux pumps and by ribosomal protection
• MOA: inhibition of protein synthesis by binding to 30s ribosomes
• 20 fold more efficient than tetracycline
• DOSE:
• Parenteral use
• Loading dose: 100mg; maintenance dose: 50mg 12th
hourly
• Side effects: mild GIT disturbances, diarrhoea, vomiting
GLYCYLCYCLINES

24. • FINOFLOXACIN phase2
• GEMIFLOXACIN,BESIFLOXACIN
• DELAFLOXACIN phase 3
• TROVAFLOXACIN 4th
gen quinolone
• AVOROFLOXACIN , NEMONAXACIN
• Newer fluoroquinolones have anti pseudomonal activityand additional
anti MRSAactivity
• The activity of nemonoxacin against gram +ve bacteria(including MRSA
and MDR streptococcus pneumoniae) is better than ciprofloxacin,
levofloxacin, moxifloxacin GATIFLOXACIN:It is a fourth generation fluro-
quinolone agent.
• Greater affinity for topoisomerase IV.
• Active against gram +ve cocci.
• Oral and intravenous route.
• Dose – 200 to 400 mg orally or i.v. once daily (+½ shown)
• Active against – Streptococcus pneumonias.
• Chlamydia pneumonias.
• banned due to severe hyperglycemia
FLORQUINOLONES

25. GEMIFLOXACIN:
• Oral quinolones approved in 2003 for treatment of acte bacterial exacerbation
of chronic bronchitis , CAP
• SPECTRUM: enhanced activity on gram +ve bacteria(strep, staph) and
atypical pathogens(chlamydia, mycoplasma,legionella) but less against
pseudomonas .poor activity on methicillin resistant strains
• Anaerobic activity +
• High affinity for DNA gyrase and topoisomerase IV
• Good activity aghainst fluorquinolone resistant H.influenza
• Oral administration
• Respiratory tract infections
BESIFLOXACIN: opthalmic ointment
DELAFLOXACIN:
• Aproved by FDA for adult
• lts with bacterial skin and skin structure infection caused by susceptible
organisms
• Withdrawn due to risk of hepatotoxicity

26. PLAZOMICIN : phase 3 trail
• Refered as next gen aminoglycoside
• MOA: inhibition of protein synthesis
• SPECTRUM: gram+ve and gram-ve
• Synergism :
• Plazomicin+cefepime/imipenem/doripenem/piperacillin
tazobactum= P. aeuroginosa
• Plazomicin+ daptomycin/ceftobiprole= MRSA, VISA,VRSA
• Superiority to colistin for bloodstream infections or
nosocomial pneumonia
AMINOGLYCOSIDES

27. • ERAVACYCLINE phase 3
• Tetracycline compound modiffied at c-7 and c-9 positions
• SPECTRUM: MDR gram+ve,gram –ve,anaerobic infections
• The drgs activity is not hindered by effluxpmps and ribosomal
protection mechanism of drug resistance
• Being evaluated for oral formulation ffor ease pf IV to oral transition
• OMADACYCLINE phase 3
• SPECTRUM: MRSA, b hemolytic streptococci,penicillin resistant
s.pneumonia, H.infleunza, legionella
• Acute bacterial SSTIs
• It works against those bacteria that are resistant to other tetracyclines,
mrthicillin, vancomycin,erythromycin , ciprofloxacin
TETRACYCLINES

28. FIDAXOMICIN
• First drug in this class of antibiotics wit narrow spectrum of activity
• MOA: inhibition of bacterial enzyme DNA polymerase
• SPECTRUM: active against CDI, limited activity on intestinal flora
• It is alternative to currently used treatment regimens of vancomycin
and metronidazole against CDI
• In phase 3 trail,fidaxomicin 200mg (twice a day) was fond to be non
inferior to vancomycin 125mg( 4 times a day) for the treatment of
first recurrence of CDI
• Oral, 200mg twice daily
MACROCYCLIC ANTIBIOTICS

29. • Polymixin and cilastin
• Given topically,too toxic to be given systematically
• Polymixin- Bacills polymyxa
• Cilastin- Bacillus colistinus
• MOA:alter permeability of cell membrane
• The global roblem of advancing antimicrobial resistance
led to renewed interest in its use
• USES:
• Topically for skin, ear and eye infections
• Oral colisytin in children for diarrhoea
POLYPEPTIDE ANTIBIOTICS

30. • Targeting virulence factors
• Bacterial phage
• Crispar Cas system
• Targeting bactericidal functions of bacterial
proteins
• Modulating host response pathways
• Peptides derived from vertebrates,
invertebrates and microorganism
NON TRADITIONAL APPROACH

31. • 1.targeting virulence factors
• Inhibition of bacterial adhesion
• Inhibition of toxin production
• Inhibition of toxin delivery
• Inhibition of virulence regulators

32. 2. Targeting bactericidal functions of
bacterial proteins:
Targeting enzymes like
B-ketoacyl-acyl-carrier-protein synthase I/II
Required for fattyacid biosynthesis in bacteria
DRUGS IN PIPELINE:
platensimysin- preclinical trails in an effort to combat
MRSA in a mouse model

33. 3. modulating host response
pathways:
• toll like receptor activators and modulators cold potentially
have an antimicrobial role by producing antimicrobial peptides
that activates the adaptive immune response to combat the
infection

34. 4.Antimicrobial peptides from living
organisms
Novel potential therapeutic target
They act by interfering with metabolism, targeting cytoplasmic
components and disrupting cell membranes
They may enhance immunity by functioning as immunomodulators
Eg : dermaseptin- from dog skin
defensin & crustin- crustacean
DRUGS in pipeline:
omiganan clinical trails
pexiganan

35. 5. Combination of antibiotics with
bioenhancers
• A bioenhancer is an agent capable of enhancing the bio
availability and efficacy of a drug with which it is co
administered, without any pharmacological activity of its own at
the therapeutic dose
• Bioenhancers can be used to increase the efficacy of commonly
used antibiotics, combining antibiotictetracycline with non
antibiotic drug loperamide
• Cow Urine Distillate(CUD) can act asa potential therapeutic target
to enhance activity of antibacterial agents
• CUD+ rifampicin, increased the activity by about 5-7 times
against E.coli and 3-11 timesagainst gram+ve bacteria

36. 6. Engineer a prodrug that gets converted into
highly potent drug within a microbe
• Engineer hybrid antibacterial drugs for high
potency against two targets
• Alternative form of drug delivery methods
• Herbal derivatives as lead molecules

37. 7.Bacteriophage
Use of viruses (phages) that specifically infect
and lyse bacteria.
Highly specific, can target MDR pathogens like
Pseudomonas aeruginosa and Acinetobacter
baumannii.
• Compassionate use in treating pan-resistant
Klebsiella pneumoniae infections.

38. 8.CRISPR CAS system
Gene-editing tools designed to selectively target bacterial
resistance genes or virulence factors.
Delivers CRISPR-Cas systems via bacteriophages or
nanoparticles to cut resistance genes.
Precision targeting, minimal off-target microbiome effects.
• Mostly preclinical research, promising for future MDR
control.

39. 9.Monoclonal Antibodies
Antibodies engineered to neutralize bacterial
toxins or virulence factors.
Bezlotoxumab (FDA-approved) neutralizes C.
Difficile toxin B, reducing recurrence rates.
Target-specific, adjunctive to antibiotics, reduces
resistance pressure.
High cost and limited to certain infections.

40. 10.Adjunctive & synergistic strategies
β-lactam/β-lactamase inhibitor combinations
(e.g., ceftazidime-avibactam).
Host-directed therapies to boost immunity.
Nanoparticle drug delivery to penetrate biofilms

41. Role of pharmacogenomics
• Genetic polymorphisms affect drug
metabolism, transport, and targets:
• CYP450 variants (e.g., CYP2C19 &
fluoroquinolones).
• G6PD deficiency and sulfonamide
toxicity.Tailoring therapy minimizes toxicity &
optimizes efficacy.

42. • Pharmacology and pharmacotherapeutics: R.S.SATOSKAR
• PADMAJA UDAYKUMAR: pharmacology for dental and
allied health sciences
• GOODMAN AND GILMAN: the pharmacological basics of
the therapeutics; 9th
edition
• Insights into newer antimicrobial agents against gram negative
bacteria: neelima taneja and harsimran kaur; microbiology
insights 2016:9
• Recent advances in antibacterial drugs; international journal of
applied and basic medical research;jan-jun 2013
• Mechanism of use of newer antibiotics for gram positive
pathogens: http:inffection.thelanet.com vol 5 april 2005
• Ten new antibiotics in the pipeline for resistant infections:
medscape
REFERENCES