Plazomicin
Nature of the antibiotic
Class: Next-generation aminoglycoside (neoglycoside), semisynthetic (sisomicin based). It is capable of evading most aminoglycoside-modifying enzymes (AME).
Molecular weight: 592.68.
It is synergistic with many antibiotics, including piperacillin-tazobactam.
Mechanism of action
It binds to the aminoacyl-tRNA recognition site (A-site) of the 16S rRNA and interrupts the elongation of the nascent protein sequence during the translation phase. Hence it inhibits ribosomal protein synthesis.
Plazomicin (and aminoglycosides) entry through the inner membrane is reliant on electron transport. It is an aerobic process and also affected by low pH. Hence aminoglycosides have low/no activity against anaerobes, in anaerobic or low pH conditions (e.g. in abscess/presence of pus)
Mechanism of resistance
Enterobacteriaceae: modification of the ribosomal binding site due to expression of 16S rRNA methyltransferases.
Adverse effects
Ototoxicity – the animal study did not show ototoxicity. Few patients had mild vertigo and unilateral permanent tinnitus in phase II clinical trial [Riddle 2012].
Nephrotoxicity – Phase II clinical trial showed a comparable increase in creatinin when compared against Levofloxacin. Two patients reported azotemia and mild renal insufficiency. [Riddle 2012].
Cardiotoxicity – Statistically significant QT/QTc prolongation was seen in healthy volunteers but it was deemed clinically not significant.
Mild-to-moderate headache, tinnitus, dizziness, and somnolence.
Spectrum
Gram-positive
Staphylococcus (MSSA, MRSA, and coag neg Staphylococcus).
Streptococcus – not susceptible.
Enterococcus – More effective on E faecium. E faecalis is usually resistant.
Gram-negative
Enterobacteriaceae – sensitive except NDM + organisms.
Morganella, Proteus, Salmonella, Shigella are less sensitive.Non-fermenters-
Usually have higher MIC (Pseudomonas, Acinetobacter), but it is more active than other aminoglycosides.
Stenotrophomonas maltophilia is resistant.
Other organisms
It is active against Francisella, Yersinia and has some activity against Brucella.
Clinical trials
Phase III clinical trial ( EPIC trial) – compared plazomicin and meropenem for the management of cUTI. Plazomicin demonstrated superiority in composite cure at the test-of-cure visit (achieved enhanced sustained microbiological eradication).
Phase III clinical trial (CARE trial) – compared plazomicin-based and colistin-based combinations in patients with serious infections due to carbapenem-resistant Enterobacteriaceae. Plazomicin-based combinations were associated with numerically decreased mortality, serious disease-related complications and incidence of nephrotoxicity.