We at India - a third world country or developing country, are commonly bothered with Gram Negative bacteria (GNB) while developed countries are bothered with Gram positive bacteria (GP cocci).
WHO has made a list of pathogens which are termed as 'superbug'. The acronym, ESKAPEE is used for these pathogens
Enterococcus faecium
Staphylococcus aureus
Staphylococcus aureus
Klebsiella pneumoniae
Acinetobacter baumannii
Pseudomonas aeruginosa
Escherichia coli
Enterobacter species
Apart from these bacteria, which are often MDR and associated with HABI (hospital acquired bacterial infection), there are two more bacteria we should be concerned of. First Mycobacterium tuberculosis and C. diff.
IDSA (Infectious Diseases Society of America) announced ''10 x '20 initiative'' in 2010, under which 10 new antibiotics would be developed by 2020. The best part is by 2019 the target is over-achieved with 14 FDA approved antibiotics.
The problem is out of 14, six of these new antibiotics are more like a software bug fix. Bug reported, fix comes in. Newer beta lactamase inhibitors added to Cephalosporins or carbapenems. These candidates will not take long to be resistant.
Ceftaroline fosamil | October 2010 | now co-marketed by AstraZeneca |
Dalbavancin | May 2014 | |
Tedizolid phosphate | June 2014 | Previously known as Terizolid |
Oritavancin | August 2014 | |
Ceftolozane and Tazobactam | December 2014 | formerly CXA-201 |
Ceftazidime and Avibactam | February 2015 | |
Delafloxacin | June 2017 | |
Meropenem and Vaborbactam | August 2017 | |
Plazomicin | June 2018 | |
Eravacycline | August 2018 | |
Omadacycline | October 2018 | |
Imipenem/Cilastatin/ Relebactam | July 2019 | |
Lefamulin | August 2019 | |
Cefiderocol | November 2019 |
Indian scenario - what are the newer Antibiotics?
Among this above-mentioned list, only Ceftazidime/Avibactam was launched in India under brand name of Zavicefta by Pfizer.
In early 2023 this antibiotic got some price cut as Indian pharma companies are bring their own packages. While Zavicefta costs Rs 5000 approx. for 2.5Gm Injection, Alkem and BDR Pharma's brands would cost almost half - Zidavi and Xavitaz will cost Rs 2700 and Rs 2600 respectively.
At present we at Indian critical care units using some regime for pan-drug resistant infections like double carbapenem therapy, CZ+A + Aztreonam, Meropenem + Tigecycline + Colistin/Polymyxin B etc.
Biapenem is another carbapenem launched in India, first by BDR Pharma. Biapenem's dose is 300mg IV 12hlry. Later Zuventus, Lupin, Cadila, Alkem, Intas also launched it.
Wockhardt developed Levonadifloxacin (intravenous, WCK-771) and alalevonadifloxacin (oral prodrug, WCK-2349) - benzoquinolizine subclass of fluoroquinolone which are highly potent againt MRSA, multi drug resistant penumococci and anaerobes. These drugs got license for clinical use in India in 2019.
In February 2024, Cipla announce that the company will launch a novel aminoglycoside - Plazomicin (indicated in cUTI) in India. Timeline expected for launch is August '24.
In June 2024 Cipla and Orchid Pharma announced to launch Cefepime-Enmetazobactam in India with indication in cUTI, VAP, HAP. Enmetazobactam - a novel BLI was discovered by Indian scientists, lead by Dr. Mukut Gohain (Assam) in 2008 under financial backing by Orchid. Later the molecule was out-licensed to Allecra Therapeutics for further development and global marketing.
Mumbai based Wockhardt, one of the oldest drug makers of India, has been working on WCK-5222. It is actually combination of Cefepime and novel BLI zidebactam, being launched under brand name of Zaynich and being used in severe sepsis in cancer/post-transplant patients in India & US under compassionate use policy - results are very promising. However phase III trials are expected to end by middle of 2025. Zidevactam has shown dual actions - high affinity penicillin binding protein 2 (PBP2) binding and inhibition of Ambler class A and C enzyme.
Bangaluru based Bugworks is also working on a molecule BWC0977 to tackle the drug resistant infections. It is presently on Phase I trials.
Nafithromycin - is a novel lactone ketolide (advanced generation macrolide) - it overcomes all 3 macrolide resistance mechanisms - Erm, efflux and ribosomal protein mutations in S. pneumoniae. It is found to be 10X potent than Azithromycin and achieves comparable outcomes with just a 3-day regimen in community acquired bacterial pneumonia (CABP). It also has superior safety and tolerability, minimal gastrointestinal side effects and no significant drug interactions.
On 20th November, 2024, Union minister of Science and Technology, Dr. Jitendra Singh has formally launched the first indigenous antibiotic "Nafithromycin" (brand name Miqnaf) for resistant infections, aimed at tackling Antimicrobial Resistance (AMR).
It is developed by Wockhardt over 14 years (as WCK 4873) with the support of "Biotechnology Industry Research Assistance Council" (BIRAC), a unit of the Department of Biotechnology, Government of India, with clinical trials spanning the U.S., Europe, and India.
Wockhardt has other antibiotics in pipeline.
WCK 6777 (Ertapenem/Zidebactam) completed phase I trial and got fast-track designation by US-FDA in October 2024. It is being developed as a MDR-active effective outpatient parenteral antimicrobial therapies (OPAT).
WCK 4282 is actually Cefepime/Tazobactam in 2g:2g ratio. Currently in Phase 3 stage of development, WCK 4282 would provide a superior replacement for piperacillin/tazobactam and cefoperazone/sulbactam and drastically minimize the dependence on carbapenems such as meropenem and imipenem, enable clinicians in reinstating antibiotic stewardship practice, and provide a much safer work horse therapy for hospitalized patients. WCK 4282 has also been designated as qualified infectious disease product (QIDP) by US FDA.
Jawaharlal Nehru Centre for Advanced Scientific Research is also working on antimicrobials - https://www.jncasr.ac.in/faculty/jayanta/research-highlights/research-antimicrobial-research-laboratory
Indian Council of Medical Research (ICMR) is also involved in AMR research, focusing on surveillance and developing strategies to combat antibiotic resistance.
Future sepsis treatments are not limited to antibiotics, some therapies are set to reduce inflammation. Monoclonal antibodies are being tested for infection prevention. Phage virus is also being deployed to counter super bugs.
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