Combating Infection VS.New Antibiotic Development

Contents

• Definitions.• Classification of Infection.• Stages of Infection.• Modes of transmission.• M/A of Antibiotics.• Several new antibiotics.• Antibiotics resistance & it’s causes.

Infection

• Invasion & multiplication of microorganisms such as bacteria, viruses, and parasites that are not normally present within the body.

Classification of infectionAccording to the clinical appearance:

a)Acute infections (Rapid onset)(ex: Influenza)b)Chronic infections (Long term)(ex: Tuberculosis)c)Acute exacerbation of a chronic infection (sudden severity)�Depending on the etiological(cause) agent:

a)Bacterialb)Viralc)Fungal�

Classification of infectionAccording to source of infection:

a) Odontogenic (Teeth)b) Secondary infections of lesions (cyst/tumors) (damage

through injury or disease)c) Infections arises from contaminated wound/traumad) Iatrogenic infections (From medical treatment)

Stages of Infection1. Entry of Pathogen:

–Portal of Entry

2. Colonization:–At site of entry

3. Incubation Period:–Asymptomatic period–Betn initial contact

with microbe & appearance of 1st symptoms

4. Prodromal Symptoms:–Initial Symptoms

5. Invasive period:–Severity increased.–Fever–Inflammation &

Swelling–Tissue Damage–Spread to Other

Sites.

Modes of Transmission

• Direct contact• Indirect contact• Droplet transmission• Hands• Vector-borne• Nosocomial

Antibiotics

• Medication that inhibits the growth of or destroys microorganisms.

Mechanism of action of Antibiotics

5 main mechanisms :

1. Inhibition of cell metabolism.2. Inhibition of bacterial cell wall synthesis.3. Interactions with the plasma membrane.4. Disruption of protein synthesis.5. Inhibition of nucleic acid transcription

and replication.

1. Ramoplanin• Ramoplanin is an antibiotic drug derived from strain ATCC

33076 of Actinoplanes.

• Company name: Oscient Pharmaceuticals Corp

• Trade name: Orpha

• Class : glycolipodepsipeptide 

• Routes of Administration: oral

• D-amino acids are shown in red letters and L-amino acids in blue.

Mechanism of Action• Ramoplanin causes alteration to cell wall

peptidoglycan linkage.

• It exerts its bacteriocidal effect by inhibiting cell wall biosynthesis, acting by inhibiting the transglycosylation step of peptidoglycan synthesis.

• It is bacteriocidal against gram-positive bacteria including methicillin-resistant staphylococci.

Use• Its development has been fast-tracked by

the U.S. Food and Drug Administration. • Treatment for multiple antibiotic-

resistant Clostridium difficile infection of the gastrointestinal tract. 

• Although it is unstable in the bloodstream, so can be taken only orally against such infections.

2. OmadacyclineOmadacycline (formerly known as PTK-0796)[1] is a as atreatment for serious community-acquired infections.

Company name: Paratek PharmaceuticalsClass: A new class aminomethylcyclines, related to the tetracycline class.Routes of administration:Both intravenous and oral

Structure–activity relationship

Mechanism of action

• Omadacycline inhibits protein synthesis while having no significant effect on RNA, DNA and peptidoglycan synthesis.

• Further, omadacycline binds to the tetracycline

binding site on the 30S subunit of the bacterial ribosome with enhanced binding based on additional molecular interactions.

Clinical trials of Omadacycline• In vitro studies have shown that omadacycline has activity against a broad range of Gram-

positive and select Gram-negative pathogens. This activity translated to potent efficacy for omadacycline in an In vivo systemic infection model in mice.

• A Phase 2 study was conducted comparing the safety and efficacy of omadacycline to linezolid for the treatment of complicated skin and skin structure infections (cSSSI).

• In June 2013, the US Food and Drug Administration (FDA) designated omadacycline as a Qualified Infectious Disease Product (QIDP).

• A 650 patient Phase 3 registration study known as OASIS began in June 2015 and A 750 patient Phase 3 study comparing omadacycline to moxifloxacin for the treatment of Community Acquired Bacterial Pneumonia (CABP) began in November 2015.

• In May 2016, a phase 1b study of omadacycline in Urinary Tract Infection was initiated.

• In August 2016, a second, pivotal phase 3 study of omadacycline in patients with ABSSSI was initiated. The study will assess the efficacy and safety of once-daily, oral-only omadacycline compared to twice-daily, oral-only linezolid in patients with ABSSSI.

3. Plazomicin• Plazomicin ,(codenamed ACHN-490) is a next-generation

aminoglycoside("neoglycoside") antibacterial drug which is in phase 3 trials for the treatment of serious gramnegative bacterial infections due to carbapenum resistant enterobacteriaceae (CRE) as of April 7,2016.

• It was originally developed by Isis Pharmaceuticals then licensed to Achaogen for co development in 2006.

• In 2012, U.S. Food and Drug Administration granted fast track designation for the development and regulatory review of plazomicin

General information• Drug Name : Plazomicin• Research code : ACHN-490• Trade name : Not Fixed yet• MOA : Protein Synthesis Inhibitor• Company : Isis Pharmaceutical

(Originator) Achagon• Status : Phase 3 active• MW : 592.68• Formula : C25H48N6O

• Achageon developed plazomicin by chemically modifying an existing aminoglycoside, sisomicin, in order to overcome common aminoglycoside resistance mechanisms. In MDR Enterobacteriaceae, including CRE, plazomicin remains active where most other antibiotics, including the commercially available aminoglycosides, have limited potency due to resistance.

• Potent in vitro activity and in vivo efficacy in nonclinical studies against MDR Enterobacteriaceae, including CRE. 

• Demonstration of comparable efficacy to levofloxacin and acceptable safety in a Phase 2 clinical trial in patients with complicated urinary tract infections caused primarily by susceptible Enterobacteriaceae. 

• Improved dosing strategy compared to existing aminoglycosides, and individualized patient dosing using our in vitro assay. 

• Potential to reduce the healthcare costs associated with the treatment of serious infections.

Indications• Complicated urinary tract infections including acute

pyelonephritis,

• Catheter- related bloodstream infections,

• Hospital-acquired bacterial pneumonia/ ventilator-associated bacterial pneumonia,

• Complicated intra-abdominal infections in patients with limited treatment options (some indications specifically target infections caused by carbapenem-resistant Enterobacteriaceae)

4. TEIXOBACTIN

• Discovery in Jan 2015.• Published in the journal “Nature”.• This discovery is also remarkable for another

reason – development of a technology iCHIP that can herald the discovery of many new antibiotics.

How iCHIP works?• A single scoop of soil contains millions of bacteria &

fungi• They survive by fighting each other by producing

what we call antibiotics

PROBLEM?• Only 1% of microbes in the soil (or sea water) can

be readily grown in Lab conditions.

•North Eastern University

•Where KIM LEWIS and SALVA EPSTEIN did their study.

• A sample soil is diluted and then poured oh the iCHIP which consists of hundreds of small holes

• It is hoped that only 1 microbe is caught in each hole

• The chip is then covered with membranes on both sides and put back into the soil sample.

• The membrane contains pores that are only large enough for chemical nutrients to flow but small enough to block movement of bacteria

• Thus single bacteria in hole grows without being contaminated with other bacteria in soil

• 75% of the ichip bacteria can be transferred and grown in lab. solutions

• One bacteria – Eleftheria terrae was found to produce the best antibiotic – TEIXOBACTIN

• MOA:Cell wall inhibition – attaches to essential precursors required for cell wall synthesis.• It attacks gm+ bacteria that have thick cell

wall but no membrane as in gm-

• They have shown promise in mice, clinical trials yet to be undertaken

The greatest developments of science are often not the discoveries but the developments that enable them. So while teixobactin is certainly a remarkable achievement, the new method to grow soil bacteria in labs. is an equally important contribution.

5. Brilacidin Brilacidin is thus an antibiotic that works by disrupting

bacterial cell membranes, mimicking defensins that play a role in innate immunity.

it is also called a defensin mimetic. an investigational new drug (IND), is a polymer-based

antibiotic. Completed Phase 2 clinical trial for the treatment of

Staphylococcus infections. developed by Polymedix.

Mechanism of action Brilacidin kills bacteria in the same manner as the human immune

system, and in this regard, can significantly reduce the risk of bacterial resistance.

solving the problems encountered by peptide-based antimicrobials has potent Gram positive activity and Gram negative coverage successful in fighting off Staphylococcus infections

Safety&Next steps

The most common adverse event experienced by patients in the study was numbness and tingling, felt by 65%-87% of treated patients

Based on the successful results of phase 2 trial, which suggests that shorter courses of therapy and lower doses could be effective

A dose-optimization Phase 2B study is planned. The Phase 2B will study lower doses and shorter courses of therapy.

6. Finafloxacin

• Finafloxacin (AL-60371) Otic Suspension 0.3% is a new chemical entity, Fourth generation, Topical Fluoroquinolone, exhibits a very broad spectrum of activity.

MOA of Finafloxacin

SAR of Finafloxacin

Uses• Acute otitis externa (AOE) • Urinary tract infections • Skin infections

Dosage forms and StrengthsXTORO (finafloxacin otic suspension) 0.3%Instill 4 gtt in affeted ear BID for 7 days.

Side Effects• Difficulty with swallowing• Dizziness• Skin rash• Itching of the ear• Nausea• Unusual tiredness

Warnings and Precautions• Growth of Resistant Organisms with Prolonged Use• Allergic Reactions

Antibiotic resistance & how it works

• Natural phenomenon.

Causes of antibiotic resistance

Conclusion

Antibiotic resistance is one of the most common problems now a days in treating most of the severe diseases & it’s impact is getting bigger in a rapid rate. Steps such as not using antibiotics to treat common disease, Only used with doctor’s prescription & ensure the proper dose helps a lot in this case. Thus we can reduce the resistance. Also increasing people awareness wouldbe a big help to reduce the resistance.

Reference• https://en.wikipedia.org/wiki/Infection• http://www.medicinenet.com/script/main/art.asp?articlekey=12923• http://www.slideshare.net/haneefmdf/head-and-neck-infections• http://www.slideshare.net/doctorrao/infection-11173778• https://commons.wikimedia.org/wiki/File:Antibiotics_action.png• https://sites.psu.edu/siowfa15/2015/11/19/antibiotic-usage-and-resistance/• http://www.who.int/mediacentre/events/2015/world-antibiotic-awareness-

week/infographic-causes.jpg?ua=1• http://www.wikinvest.com/stock/Oscient_Pharmaceuticals_(OSCI)/

Ramoplanin• https://en.wikipedia.org/wiki/Ramoplanin• https://www.ncbi.nlm.nih.gov/pubmed/16880924• https://en.m.wikipedia.org/wiki/Omadacycline?

_e_pi_=7%2CPAGE_ID10%2C1384329075

Reference• http://paratekpharma.com/science/omadacycline/• https://www.ncbi.nlm.nih.gov/m/pubmed/27469981/?

_e_pi_=7%2CPAGE_ID10%2C5458292499 • http://www.achaogen.com/plazomicin/• http://www.achaogen.com/media-all/2016/6/20/an-evaluation-of-the-bactericidal-

activity-of-plazomicin-and-comparators-against-multidrug-resistant-enterobacteriaceae

• https://www.ncbi.nlm.nih.gov/pubmed/26391381• http://www.drugbank.ca/drugs/DB09047• http://pubchem.ncbi.nim.nih.gov• http://www.fda.gov/drugs/informationondrugs/ucn129662.htm• https://en.wikipedia.org/wiki/Brilacidin#cite_note-10• http://files.shareholder.com//ABEA-4ITCYZ/1997024712x0x611205/FEA66C67-

D02F-4FF2-B230-AA711F46ED7F/PMX-30063_Antibiotic_Fact_Sheet_