Plazomicin

Structural formula
General
Non-proprietary name	Plazomicin
other names	6 '- (Hydroxyethyl) -1- (HABA) -sisomicin (2 S ) -4-amino- N - [(1 R , 2 S , 3 S , 4 R , 5 S ) -5-amino-4 - {[(2 S , 3 R ) -3-amino-6 - {[(2-hydroxyethyl) amino] methyl} -3,4-dihydro-2 H -pyran-2-yl] oxy} -2 - {[(2 R , 3 R , 4 R , 5 R ) -3 , 5-dihydroxy-5-methyl-4- (methylamino) oxan-2-yl] oxy} -3-hydroxycyclohexyl] -2-hydroxybutanamide
Molecular formula	C 25 H 48 N 6 O
External identifiers / databases
CAS number 1154757-24-0 PubChem 42613186 ChemSpider 26390008 DrugBank DB12615 Wikidata Q15426988
Drug information
Drug class	Antibiotic , aminoglycosides
properties
Molar mass	592.68 g mol −1
safety instructions
GHS hazard labeling no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Plazomicin ( international non-proprietary name ) is a "next-generation" aminoglycoside antibiotic . It is a derivative of sisomicin which is sold in the USA under the trade name Zemdri . Prior to launch, the code name in publications was ACHN-490.

discovery

Aminoglycosides have been used as broad spectrum antibiotics to fight bacterial infections since the 1950s. These drugs bind to the A side of bacterial ribosomes, thereby blocking protein synthesis. Over the years, however, various resistant bacterial strains developed. The mechanisms of resistance are summarized under the term AME (aminoglycoside-modifying enzymes). For example, aminoglycosides have been an AAC (aminoglycoside acetyltransferase ) N -acetyliert by an ABT (aminoglycoside nucleotidyltransferase ) O -adenyliert or by APH (aminoglycoside phosphotransferase ) O -phosphoryliert. The working group around Aggen tried to develop aminoglycosides that could overcome this resistance. Plazomicin was particularly promising among 400 derivatives. Plazomicin was tested by the Achaogen company for the treatment of infections with multi-resistant pathogens. In 2012 the US FDA approved a so-called "fast-track" approval test. In January 2015, the FDA awarded Plazomicin the “Qualified Infectious Disease Product” (QIDP) certificate. In June 2018, plazomicin received FDA approval for the treatment of complicated urinary tract infections without sepsis. The application for approval for septic urinary tract infections was rejected by the FDA because the proof of effectiveness was not provided.

Extraction

Plazomicin can be synthesized from sisomicin by the addition of hydroxy aminobutyric acid (HABA) at position 1 and a hydroxyethyl group at position 6 '.

Spectrum of activity

In in-vitro are Studies was demonstrated that Plazomicin in combination with daptomycin or Ceftobiprole against MRSA ( Methicillin -resistant Staphylococcus aureus ) and VRSA ( Vancomycin synergistically effective -resistant Staphylococcus aureus). Plazomicin inhibits in combination with cefepime , doripenem , imipenem or piperacillin / tazobactam the growth of Pseudomonas aeruginosa . Furthermore, an effectiveness against carbapenem -resistant Acinetobacter baumannii could be determined. Plazomicin alone did not sufficiently inhibit streptococci (including Streptococcus pneumoniae ), enterococci (including Enterococcus faecalis , Enterococcus faecium ), anaerobes , Stenotrophomonas maltophilia and Acinetobacter spp, and variable inhibition of Pseudomonas aeruginosa.

Clinical application

In a phase III CARE study, the efficacy of plazomicin in community-acquired pneumonia or sepsis was tested with CRE (carbapenem-resistant Enterobacteriaceae). One group received plazomicin 15 mg / kg body weight daily, the other group received colistin 5 mg / kg daily, each in combination with meropenem or tigecycline . The survival rate was higher with plazomicin than with colistin.

In the EPIC study, the effect of plazomicin was tested in a phase III study in patients with complicated urinary tract infections. One group received plazomicin 15 mg / kg body weight, the other meropenem 1 g every 8 hours. As a result, plazomicin was not inferior to meropenem. Fewer patients relapsed after plazomicin.

Plazomicin is given as an intravenous infusion once a day. One ampoule contains 500 mg plazomicin sulfate for 10 ml of solution (50 mg / ml).

Contraindications

Plazomicin should not be used if there is hypersensitivity to any aminoglycoside . Like all aminoglycosides, plazomicin damages the fetus in pregnant women. The substance passes through the placenta and is transferred to the fetus.

Side effects

Nephrotoxicity

Plazomicin can damage the kidneys. Creatinine increases of 0.5 mg / dL or more were seen in 21 out of 300 patients. In most cases, kidney function returns to normal after stopping the drug. An increased risk exists with pre-existing kidney dysfunction, in elderly patients and with the simultaneous use of other kidney-damaging drugs.

Ototoxicity

Inner ear damage can manifest itself as hearing loss , tinnitus (whistling sound) or dizziness . If these symptoms occur after treatment with plazomicin, they can be irreversible. In some cases, the signs of inner ear damage did not appear until after treatment was completed. There is an increased risk of inner ear damage if the patient has a family history of hearing loss, if kidney function is impaired, and if the drug is used at higher doses or for longer than recommended.

Neuromuscular blockade

Like all aminoglycosides, plazomicin can increase muscle weakness in patients with pre-existing neuromuscular disease. After the administration of muscle relaxants , the recovery of muscle function can be delayed. Special monitoring is necessary in patients with myasthenia gravis .

Anaphylaxis

Serious, possibly fatal, hypersensitivity reactions have rarely been observed. In these cases there is a hypersensitivity to all aminoglycosides. Before using plazomicin, careful inquiries have been made about previous reactions to aminoglycosides.

CDAD ( Clostridium difficile -associated diarrhea)

With all antibiotics, the natural intestinal flora is disturbed and Clostridium difficile can grow rapidly. Depending on the severity, this can lead to a mild diarrheal illness or even life-threatening colon inflammation. CDAD can also occur up to 2 months after antibiotic treatment.

Development of resistance

Antibiotics should never be prescribed unless there is a strong suspicion of bacterial infection. Frequent prescriptions lead to the development of antibiotic-resistant germs.

Individual evidence

1. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
2. ↑ ^{a b} ZEMDRI (plazomicin) injection. For adult patients with CUTI, including pyelonephritis, due to certain Enterobacteriaceae. ACHAOGEN ,, October 2018, accessed on March 12, 2019 (English). 
3. ↑ ^{a b c} James B Aggen, Eliana S Armstrong, Adam A Goldblum, Paola Dozzo, Martin S Linsell: Synthesis and spectrum of the neoglycoside ACHN-490 . In: Antimicrobial Agents and Chemotherapy . tape 54 , no. 11 , November 2010, p. 4636-4642 , doi : 10.1128 / AAC.00572-10 , PMID 20805391 , PMC 2976124 (free full text).
4. ↑ Candice Knoll: Achaogen Announces Plazomicin Granted QIDP Designation by FDA. GlobeNewswire, January 8, 2015, accessed March 12, 2019 . 
5. ↑ Jennie Walters: FDA approves plazomicin for cUTI, but not blood infections. Biocentury, January 8, 2015, accessed March 12, 2019 . 
6. ↑ ^{a b} George G Zhanel, Christopher D Lawson, Sheryl Zelenitsky, Brandon Findlay, Frank Schweizer: Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin . In: Expert Review of Anti-Infective Therapy . tape 10 , no. 4 , April 2012, p. 459-473 , doi : 10.1586 / eri.12.25 , PMID 22512755 .
7. ↑ Cristina García-Salguero, Iciar Rodríguez-Avial, Juan J Picazo, Esther Culebras: Can Plazomicin Alone or in Combination Be a Therapeutic Option against Carbapenem-Resistant Acinetobacter baumannii? In: Antimicrobial Agents and Chemotherapy . tape 59 , no. 10 , October 2015, p. 5959–5966 , doi : 10.1128 / AAC.00873-15 , PMID 26169398 , PMC 4576036 (free full text).
8. ↑ CENTER FOR DRUG EVALUATION AND RESEARCH: Drug Approval Package: ZEMDRI (plazomicin). FDA, October 27, 2017, accessed March 12, 2019 . 
9. ↑ James A. McKinnell, Jamie P. Dwyer, George H. Talbot, Lynn E. Connolly, Ian Friedland: Plazomicin for Infections Caused by Carbapenem-Resistant Enterobacteriaceae . In: New England Journal of Medicine . tape 380 , no. 8 , February 21, 2019, p. 791-793 , doi : 10.1056 / NEJMc1807634 .
10. ↑ Florian ME Wagenlehner, Daniel J Cloutier, Allison S Komirenko, Deborah S Cebrik, Kevin M Krause: Once-Daily Plazomicin for Complicated Urinary Tract Infections . In: New England Journal of Medicine . tape 380 , no. 8 , February 21, 2019, p. 729-740 , doi : 10.1056 / NEJMoa1801467 .
11. ↑ Medscape Log In .

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