Plazomicin

Last updated

Plazomicin
Plazomicin structure.svg
Clinical data
Pronunciationpla" zoe mye' sin
Trade names Zemdri
Other namesACHN-490,
6'-(Hydroxylethyl)-1-(HABA)-sisomicin
AHFS/Drugs.com Monograph
MedlinePlus a618037
License data
Routes of
administration
Intravenous
Drug class Aminoglycoside
ATC code
Legal status
Legal status
Identifiers
  • (2S)-4-Amino-N-[(1R,2S,3S,4R,5S)-5-amino-4-[[(2S,3R)-3-amino-6-[(2-hydroxyethylamino)methyl]-3,4-dihydro-2H-pyran-2-yl]oxy]-2-[(2R,3R,4R,5R)-3,5-dihydroxy-5-methyl-4-(methylamino)oxan-2-yl]oxy-3-hydroxycyclohexyl]-2-hydroxybutanamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
Chemical and physical data
Formula C25H48N6O10
Molar mass 592.691 g·mol−1
3D model (JSmol)
  • CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3OC(=CC[C@H]3N)CNCCO)[C@@H](N)C[C@H]2NC(=O)[C@@H](O)CCN)OC[C@]1(C)O
  • InChI=1S/C25H48N6O10/c1-25(37)11-38-24(18(35)21(25)29-2)41-20-15(31-22(36)16(33)5-6-26)9-14(28)19(17(20)34)40-23-13(27)4-3-12(39-23)10-30-7-8-32/h3,13-21,23-24,29-30,32-35,37H,4-11,26-28H2,1-2H3,(H,31,36)/t13-,14+,15-,16+,17+,18-,19-,20+,21-,23-,24-,25+/m1/s1
  • Key:IYDYFVUFSPQPPV-PEXOCOHZSA-N

Plazomicin, sold under the brand name Zemdri, is an aminoglycoside antibiotic used to treat complicated urinary tract infections. [2] As of 2019 it is recommended only for those in whom alternatives are not an option. [2] It is given by injection into a vein. [2]

Contents

Common side effects include kidney problems, diarrhea, nausea, and blood pressure changes. [2] Other severe side effects include hearing loss, Clostridium difficile-associated diarrhea, anaphylaxis, and muscle weakness. [2] Use during pregnancy may harm the baby. [2] Plazomicin works by decreasing the ability of bacteria to make protein. [2]

Plazomicin was approved for medical use in the United States in 2018. [3] [4] It is on the World Health Organization's List of Essential Medicines. [5]

Medical uses

Plazomicin is approved by the U.S. Food and Drug Administration (FDA) for adults with complicated urinary tract infections, including pyelonephritis, caused by Escherichia coli , Klebsiella pneumoniae , Proteus mirabilis , or Enterobacter cloacae , in patients who have limited or no alternative treatment options. Zemdri is an intravenous infusion, administered once daily. [6] [7] [8] [9] The FDA declined approval for treating bloodstream infections due to lack of demonstrated effectiveness. [3] The lack of demonstrated effectiveness was not so much about the antibiotic itself being ineffective so much as the low enrollment rate for the study. Studies using mouse models however, showed a high survival rate. [10]

Plazomicin has been reported to demonstrate in vitro synergistic activity when combined with daptomycin or ceftobiprole versus methicillin-resistant Staphylococcus aureus, vancomycin-resistant S. aureus and against Pseudomonas aeruginosa when combined with cefepime, doripenem, imipenem or piperacillin/tazobactam. [11] It also demonstrates potent in vitro activity versus carbapenem-resistant Acinetobacter baumannii . [12] Plazomicin was found to be noninferior to meropenem. [13] [14]

History

The drug was developed by the biotech company Achaogen. In 2012, the U.S. Food and Drug Administration granted fast track designation for the development and regulatory review of plazomicin. [15] The FDA approved plazomicin for adults with complicated UTIs and limited or no alternative treatment options in 2018. [6] Achaogen was unable to find a robust market for the drug, and declared bankruptcy a few months later. [16] A generic version is manufactured by Cipla USA. [17]

Synthesis

It is derived from sisomicin by appending a hydroxy-aminobutyric acid substituent at position 1 and a hydroxyethyl substituent at position 6'. [18] [11] The latter makes it impervious to acetylation (deactivation) by Aminoglycoside Acetyltransferase 6'-N- Type Ib (AAC(6')-Ib), the most prevalent AAC enzyme. [19]

Names

Plazomicin is the international nonproprietary name (INN). [20]

Related Research Articles

<span class="mw-page-title-main">Urinary tract infection</span> Infection that affects part of the urinary tract

A urinary tract infection (UTI) is an infection that affects a part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidney infection (pyelonephritis). Symptoms from a lower urinary tract infection include pain with urination, frequent urination, and feeling the need to urinate despite having an empty bladder. Symptoms of a kidney infection include fever and flank pain usually in addition to the symptoms of a lower UTI. Rarely the urine may appear bloody. In the very old and the very young, symptoms may be vague or non-specific.

<span class="mw-page-title-main">Ertapenem</span> Antibiotic medication

Ertapenem, sold under the brand name Invanz, is a carbapenem antibiotic medication used for the treatment of infections of the abdomen, the lungs, the upper part of the female reproductive system, and the diabetic foot.

<i>Klebsiella pneumoniae</i> Species of bacterium

Klebsiella pneumoniae is a Gram-negative, non-motile, encapsulated, lactose-fermenting, facultative anaerobic, rod-shaped bacterium. It appears as a mucoid lactose fermenter on MacConkey agar.

<i>Acinetobacter</i> Genus of bacteria

Acinetobacter is a genus of Gram-negative bacteria belonging to the wider class of Gammaproteobacteria. Acinetobacter species are oxidase-negative, exhibit twitching motility, and occur in pairs under magnification.

<span class="mw-page-title-main">Meropenem</span> Broad-spectrum antibiotic

Meropenem, sold under the brand name Merrem among others, is an intravenous carbapenem antibiotic used to treat a variety of bacterial infections. Some of these include meningitis, intra-abdominal infection, pneumonia, sepsis, and anthrax.

<span class="mw-page-title-main">Pyelonephritis</span> Medical condition

Pyelonephritis is inflammation of the kidney, typically due to a bacterial infection. Symptoms most often include fever and flank tenderness. Other symptoms may include nausea, burning with urination, and frequent urination. Complications may include pus around the kidney, sepsis, or kidney failure.

<span class="mw-page-title-main">Carbapenem</span> Class of highly effective antibiotic agents

Carbapenems are a class of very effective antibiotic agents most commonly used for treatment of severe bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. Similar to penicillins and cephalosporins, carbapenems are members of the beta-lactam antibiotics drug class, which kill bacteria by binding to penicillin-binding proteins, thus inhibiting bacterial cell wall synthesis. However, these agents individually exhibit a broader spectrum of activity compared to most cephalosporins and penicillins. Furthermore, carbapenems are typically unaffected by emerging antibiotic resistance, even to other beta-lactams.

<span class="mw-page-title-main">Amikacin</span> Antibiotic medication

Amikacin is an antibiotic medication used for a number of bacterial infections. This includes joint infections, intra-abdominal infections, meningitis, pneumonia, sepsis, and urinary tract infections. It is also used for the treatment of multidrug-resistant tuberculosis. It is used by injection into a vein using an IV or into a muscle.

<i>Acinetobacter baumannii</i> Species of bacterium

Acinetobacter baumannii is a typically short, almost round, rod-shaped (coccobacillus) Gram-negative bacterium. It is named after the bacteriologist Paul Baumann. It can be an opportunistic pathogen in humans, affecting people with compromised immune systems, and is becoming increasingly important as a hospital-derived (nosocomial) infection. While other species of the genus Acinetobacter are often found in soil samples, it is almost exclusively isolated from hospital environments. Although occasionally it has been found in environmental soil and water samples, its natural habitat is still not known.

<span class="mw-page-title-main">Fosfomycin</span> Chemical compound

Fosfomycin, sold under the brand name Monurol among others, is an antibiotic primarily used to treat lower urinary tract infections. It is not indicated for kidney infections. Occasionally it is used for prostate infections. It is generally taken by mouth.

β-Lactamase inhibitor Family of enzymes

Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. In bacterial resistance to beta-lactam antibiotics, the bacteria have beta-lactamase which degrade the beta-lactam rings, rendering the antibiotic ineffective. However, with beta-lactamase inhibitors, these enzymes on the bacteria are inhibited, thus allowing the antibiotic to take effect. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although β-lactamase inhibitors have little antibiotic activity of their own, they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.

<span class="mw-page-title-main">Nathaniel David</span> American scientist and entrepreneur

Nathaniel David is an American scientist and entrepreneur who co-founded a series of technology companies in the biotechnology and sustainable energy sectors, including Syrrx, Achaogen, Kythera Biopharmaceuticals, Sapphire Energy and Unity Biotechnology. These companies have collectively raised more than $1.5 billion in financing.

<span class="mw-page-title-main">Eravacycline</span> Chemical compound

Eravacycline is a synthetic halogenated tetracycline class antibiotic by Tetraphase Pharmaceuticals. It is closely related to tigecycline. It has a broad spectrum of activity including many multi-drug resistant strains of bacteria. Phase III studies in complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI) were recently completed with mixed results. Eravacycline was granted fast track designation by the FDA and is currently available in USA.

<span class="mw-page-title-main">Ceftolozane/tazobactam</span> Antibiotic

Ceftolozane/tazobactam, sold under the brand name Zerbaxa, is a combination antibiotic medication used for the treatment of complicated urinary tract infections and complicated intra-abdominal infections in adults. Ceftolozane is a cephalosporin antibiotic, developed for the treatment of infections with gram-negative bacteria that are resistant to conventional antibiotics. It was studied for urinary tract infections, intra-abdominal infections and ventilator-associated bacterial pneumonia.

<span class="mw-page-title-main">Ceftazidime/avibactam</span> Combination antibiotic medication

Ceftazidime/avibactam, sold under the brand name Avycaz among others, is a fixed-dose combination medication composed of ceftazidime, a cephalosporin antibiotic, and avibactam, a β-lactamase inhibitor. It is used to treat complicated intra-abdominal infections, urinary tract infections, and pneumonia. It is only recommended when other options are not appropriate. It is given by injection into a vein.

<span class="mw-page-title-main">Vaborbactam</span> Chemical compound

Vaborbactam (INN) is a non-β-lactam β-lactamase inhibitor discovered by Rempex Pharmaceuticals, a subsidiary of The Medicines Company. While not effective as an antibiotic by itself, it restores potency to existing antibiotics by inhibiting the β-lactamase enzymes that would otherwise degrade them. When combined with an appropriate antibiotic it can be used for the treatment of gram-negative bacterial infections.

ESKAPE is an acronym comprising the scientific names of six highly virulent and antibiotic resistant bacterial pathogens including: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. The acronym is sometimes extended to ESKAPEE to include Escherichia coli. This group of Gram-positive and Gram-negative bacteria can evade or 'escape' commonly used antibiotics due to their increasing multi-drug resistance (MDR). As a result, throughout the world, they are the major cause of life-threatening nosocomial or hospital-acquired infections in immunocompromised and critically ill patients who are most at risk. P. aeruginosa and S. aureus are some of the most ubiquitous pathogens in biofilms found in healthcare. P. aeruginosa is a Gram-negative, rod-shaped bacterium, commonly found in the gut flora, soil, and water that can be spread directly or indirectly to patients in healthcare settings. The pathogen can also be spread in other locations through contamination, including surfaces, equipment, and hands. The opportunistic pathogen can cause hospitalized patients to have infections in the lungs, blood, urinary tract, and in other body regions after surgery. S. aureus is a Gram-positive, cocci-shaped bacterium, residing in the environment and on the skin and nose of many healthy individuals. The bacterium can cause skin and bone infections, pneumonia, and other types of potentially serious infections if it enters the body. S. aureus has also gained resistance to many antibiotic treatments, making healing difficult. Because of natural and unnatural selective pressures and factors, antibiotic resistance in bacteria usually emerges through genetic mutation or acquires antibiotic-resistant genes (ARGs) through horizontal gene transfer - a genetic exchange process by which antibiotic resistance can spread.

Meropenem/vaborbactam, sold under the brand name Vabomere among others, is a combination medication used to treat complicated urinary tract infections, complicated abdominal infections, and hospital-acquired pneumonia. It contains meropenem, a β-lactam antibiotic, and vaborbactam, a β-lactamase inhibitor. It is given by injection into a vein.

<span class="mw-page-title-main">Cefiderocol</span> Antibiotic

Cefiderocol, sold under the brand name Fetroja among others, is an antibiotic used to treat complicated urinary tract infections when no other options are available. It is indicated for the treatment of multi-drug-resistant Gram-negative bacteria including Pseudomonas aeruginosa. It is given by injection into a vein.

Imipenem/cilastatin/relebactam, sold under the brand name Recarbrio, is a fixed-dose combination medication used as an antibiotic. In 2019, it was approved for use in the United States for the treatment of complicated urinary tract and complicated intra-abdominal infections. It is administered via intravenous injection.

References

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  2. 1 2 3 4 5 6 7 "Plazomicin Sulfate Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 10 October 2019.
  3. 1 2 "FDA Approved Drug Products: Zemdri". U.S. Food and Drug Administration . Retrieved 28 June 2018.
  4. "Drug Approval Package: Zemdri (plazomicin)". U.S. Food and Drug Administration . 5 July 2018. Retrieved 25 December 2019.
  5. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  6. 1 2 "Zemdri (plazomicin)- plazomicin injection". DailyMed. 30 July 2020. Retrieved 11 October 2020.
  7. "plazomicin (Rx)". Medscape . Retrieved 14 September 2019.
  8. Brown T (3 May 2018). "FDA Panel Recommends Plazomicin for cUTI but Not BSI". Medscape. Retrieved 14 September 2019.
  9. "BioCentury - FDA approves plazomicin for cUTI, but not blood infections". www.biocentury.com. Retrieved 28 June 2018.
  10. https://www.fda.gov/media/113289/download
  11. 1 2 Zhanel GG, Lawson CD, Zelenitsky S, Findlay B, Schweizer F, Adam H, et al. (April 2012). "Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin". Expert Review of Anti-Infective Therapy. 10 (4): 459–473. doi:10.1586/eri.12.25. PMID   22512755. S2CID   31496981.
  12. García-Salguero C, Rodríguez-Avial I, Picazo JJ, et al. (October 2015). "Can Plazomicin Alone or in Combination Be a Therapeutic Option against Carbapenem-Resistant Acinetobacter baumannii?". Antimicrob Agents Chemother. 59 (10): 5959–66. doi:10.1128/AAC.00873-15. PMC   4576036 . PMID   26169398.
  13. Clinical trial number NCT02486627 for "A Study of Plazomicin Compared With Meropenem for the Treatment of Complicated Urinary Tract Infection (cUTI) Including Acute Pyelonephritis (AP) (EPIC)" at ClinicalTrials.gov
  14. Wagenlehner FM, Cloutier DJ, Komirenko AS, et al. (21 February 2019). "Once-Daily Plazomicin for Complicated Urinary Tract Infections". New England Journal of Medicine. 380 (8): 729–740. doi: 10.1056/nejmoa1801467 . ISSN   0028-4793. PMID   30786187.
  15. "Achaogen Announces Plazomicin Granted QIDP Designation by FDA" (Press release). Achaogen, Inc. 8 January 2015. Retrieved 27 April 2016 via GlobeNewswire.
  16. Jacobs A (25 December 2019). "Crisis Looms in Antibiotics as Drug Makers Go Bankrupt". The New York Times .
  17. "Generic Zemdri Availability". Drugs.com. Retrieved 26 December 2019.
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  19. Cox G, Ejim L, Stogios PJ, Koteva K, Bordeleau E, Evdokimova E, et al. (June 2018). "Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes". ACS Infectious Diseases. 4 (6): 980–987. doi:10.1021/acsinfecdis.8b00001. PMC   6167752 . PMID   29634241.
  20. "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended INN: List 68". WHO Drug Information. World Health Organization. 26 (3): 314. September 2012. Archived from the original on 2 October 2014. Retrieved 27 April 2016.

Further reading