Recent Advances to overcome Antibiotic

Resistance

Dr.Akhilesh M-5698

M.V.Sc ScholarVETERINARY MEDICINE

MINOR CREDIT SEMINAR

Contents Introduction

History

Common causes

Common modes of AR

Most resistant pathogens

Newer antibacterials

New Targets for the Next Generation of Antimicrobial drugs

Possible Solutions for Antibiotic Resistance

Introduction Antimicrobial resistance (AMR) is the ability of a

microorganism to stop an antimicrobial from working against it. As a result, standard treatments become ineffective, infections persist and may spread to others.

Antibiotic / Antimicrobial resistance is the ability of microbes

to resist the effects of drugs. The ability of pathogens that works against the antibiotics, is

termed Antibiotic Resistance.

[1]

(1. www.who.int/drugresistance/en/)

Superbug An informal term for a bacterium that has become resistant

to antibiotics that usually are used to treat it.

Ex:Methicillin-resistant Staphylococcus aureus (MRSA) Vancomycin-resistant Enterococcus (VRE)

(Rakel RE and Rakel D,2015 )

(Fri, Sep 16,2016)

History PAUL EHRLICH

Coined the term “CHEMOTHERAPY”

Discovered Salvarsan (for Syphilis)

FATHER OF CHEMOTHERAPY

He used the term ‘MAGIC BULLETS’

(Stefan H. E. Kaufmann,2008)

…..historyALEXANDER FLEMING

Penicillin

Discovered in London in Sep,1928

Accidental discoverywhile working on S.aureus

…..history Domagk discovered “Sulphonamides”

Selman Waksman discovered “Streptomycin”

In 1947, “chloramphenicol” was first used clinically to treat Typhus

G.Brotzu discovered “Cephalosporins”

Benjamin M. Duggar isolated“Chlortetracycline” from a mud sample obtained from a river in Missouri.

…..history 1960 onwards second generation

antibiotics like “Methicillin” were discovered

Following this, semi synthetic derivatives of older antibiotics with more desirable properties & different spectrum of activity were produced e.g. Fluroquinolones, Oxazolidinones etc.

Antimicrobial Targets

Evolution of Antibiotic Resistance

Common modes of antibiotic resistance

Why do we need newer antimicrobials

Bacterial resistance to antimicrobials-health and economic problem

Chronic resistant infections contribute to increasing health care cost

Increase morbidity & mortality with resistant microorganisms

[D.M. Livermore ,Clinical Microbiology & Infection Volume 10, Supplement 4, Pages 1-36 (2004)]  

OxazolidinonesConsidered 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

(Prasad Vara JV, 2007)

Mechanism of Resistance to

older Oxazolidinones Occurs due to mutations in ribosomal RNA

(rRNA)

Resistance overcome by: Newer oxazolidinones by additional hydrogen bond interactions with 23S rRNA

(Jaswant Rai et al, 2013)

Newer glycopeptides Vancomycin & Teicoplanin are already in

use

Recently APPROVED DRUG Telavancin :Approved in 2009 for complicated

skin and skin structure infections(MRSA)

DRUGS IN PIPELINE Oritavancin : Phase III trial Dalbavancin : Phase III trial

Mechanism of resistance to older glycopeptides.

Synthesis of low-affinity precursors in which C-terminal D-Ala residue is replaced by:

D-lactate (D-Lac) or by D-serine (D-Ser)

Resistance overcome by:

High binding affinity for both substrates (D-Ala-D-Lac precursor substrate OR D-Ala-D-Ser) due to presence of hydrophobic side chain. (Mandeep Kaur et al,2014)

Ketolides Drug resistance in community acquired

respiratory tract infections discovery and development of ketolides.

Carbonyl group at the C3 position, responsible for sensitivity to macrolide resistant strains.

Newer ketolides APPROVED DRUG Telithromycin –Approved in 2004

DRUGS IN PIPELINE Cethromycin- Phase III trails Solithromycin – Phase III trails

Mechanism of action

Glycylcyclines New class of antibiotic derived from

tetracycline

Designed to overcome two common mechanisms of tetracycline resistance Resistance mediated by acquired efflux pumps Ribosomal protection

Only one glycylcycline antibiotic for clinical use : TIGECYCLINE

(Frampton JE & Curran MP, Tigecycline Drugs,2005)

Newer Carbapenems Beta-lactum antibiotics with a broad

spectrum of antibacterial activity

NEWER CARBAPENEMS : Ertapenem : Approved in 2001 Doripenem : Approved in 2007

DRUG IN PIPELINE : Razupenem : Phase II clinical trail

 (Livermore DM, Mushtaq S, Warner M, 2009)

Newer Cephalosporins Approved Cephalosporins Ceftaroline: Approved in 2010 For the treatment of o Community – acquired pneumoniao Complicated skin and soft – tissue

infections

Drugs in pipeline Ceftobiprole : awaiting FDA approval

(Saravolatz LD et al, 2011)

New Targets for the Next Generation of Antimicrobial

drugs Targeting virulence factors

Targeting bactericidal functions of bacterial proteins

Modulating host response pathways

Peptides derived from vertebrates, invertebrates and microorganism.

(Gurpreet Kaur Randhawa et al, 2013)

Possible Solutions for Antibiotic Resistance

Stop unnecessary antibiotic prescriptions. Finish antibiotic prescriptions. Use the right antibiotic in an infectious situation

as determined by antibiotic sensitivity testing. Use antibiotics in rotation. Use combination of antibiotics if necessary. Promote Vaccine recommendations. Implement infection control measures, such

as hand washing, isolation precautions, and immunization.

Improve communication, education and training.

Conclusion 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.

References www.who.int/drugresistance/en/ www.cdc.gov › Antibiotic / Antimicrobial Resistance › U.S.

Activities to Combat AR http://www.sciencedaily.com/articles/a/

antibiotic_resistance.html Andrea Gyyot, Graham Layer,2006 MRSA Bugbear of a surgical

practice reducing the incidence of MRSA surgical site infection, Ann R Coll Surg Engl: 88: 222-223.

Archibald L(1997).Antimicrobial resistance in isolates from inpatients and outpatients in the United States: increasing importance of the intensive care unit. Clinical Infectious Diseases. 24(2):211-215

Ceasr A, Arias, M.D. and Balbara E. Murray, M.D.N., 2009. Antibiotic resistant Bugs in the 21st Century. A clinical super challenge. Eng. J. Med.: 360: 439-443

Microbiology, A clinical Approach -Danielle Moszyk-Strelkauskas-Garland Science 2010

Jaswant Rai, Gurpreet Kaur Randhawa, and Mandeep Kaur, Recent advances in antibacterial drugs, Int J Appl Basic Med Res. 2013 Jan-Jun; 3(1): 3–10.

D.M. Livermore ,Clinical Microbiology & Infection Volume 10, Supplement 4, Pages 1-36 (2004)

Vikas Manchanda, Sinha Sanchaita, and NP Singh J. Glob Infect Dis. 2010 Sep-Dec; 2(3): 291–304.

Losee L. Ling et al, A new antibiotic kills pathogens without detectable resistance, Journal Nature 517, 455–459 (22 January 2015)