Novel Antimicrobial Drugs Omadacycline Sarecycline, Eravacycline, and Plazomicin: A Review

 

Satyaprasad. B, S. Jayakumari

Department of Pharmacognosy, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies. (VISTAS), Pallavaram, Chennai-117, Tamilnadu, India.

*Corresponding Author E-mail: prasadst09@gmail.com, nisajayaa@gmail.com

 

ABSTRACT:

Resistance to antibiotics is a worldwide ongoing issue. Urgent want for brand new antibacterial agents has resulted in substantial studies efforts, with new molecules proposed for use in clinical practice. This review focuses on novel FDA approved antibacterial drugs (2018-2019): are new players in the area of resistant microorganism treatment. Omadacycline Sarecycline, Eravacycline, Plazomicin (2018-2019) are new healing options. This review focuses on novel FDA approved antibacterial agents (2018- 2019): are new players in the field of resistant bacteria treatment. Omadacycline is a modernized tetracycline with broad-spectrum activity designed to overcome tetracycline resistance. Eravacycline is a synthetic fluorocycline antibiotic belonging to the tetracycline drug class.It disrupts bacterial protein synthesis by binding the 30S ribosomal subunit, Sarecycline is a new first-in-class tetracycline-derived antibiotic indicated for adults and children aged 9 years and older with non-nodular moderate-to-severe acne vulgaris, Plazomicin has been engineered to overcome aminoglycoside-modifying enzymes, the most common amino glycoside-resistance mechanism in Enterobacteriaceae. Despite of these new developments, there is an ongoing need and urgency to develop novel antibiotic strategies and drugs to overrun the bacterial resistance to antibiotics. Many potential signs are being investigated, broadened and confirmed by future studies. Despite recent progress, it is imperative that new antibiotic drugs and new strategies be developed to com bat antibiotic resistance.

 

KEYWORDS: FDA approved drugs, Plazomicin, Eravacycline, Sarecycline, and Omadacycline.

 

 


INTRODUCTION:

Antimicrobials are drugs capable of destroying microorganisms or inhibiting their development. Their discovery revolutionized medicine and public health in the early 1900s, and led primarily to an increase in the quality of life of society1. The inappropriate and unruled use of antimicrobials, together with the genetic plasticity of bacteria and rapid adaptation ability, it contributed to the large-scale discovery, emergence and spread of antimicrobial resistance, which dramatically decreased the effectiveness of most antimicrobials. Mechanisms of resistance may be expressed by target alteration, changes in the metabolic pathway, decrease in drug uptake and activation of efflux pumps2.

 

 

The quest for new antimicrobials is therefore a matter of urgency. Antibiotics discovery and clinical use is undoubtedly one of the pillars of modern medicine. Modern medicine saw a continuous competition between new antibacterial drug research and the ability of bacteria to develop resistance1. New classes of antibiotics were created, old drugs regained interest and paradigm changes were proposed3. However, this process seems to have diminished its pace and, after less than a century since the first clinical use of an antibiotic, bacterial resistance to antibiotics is a major concern of current medical practice and research4,5. The great influenza pandemics offer an unfortunate insight of a post-antibiotic era. In the intensive care unit, dealing with resistant bacteria is a daily struggle. In this present review, we briefly address the new antibacterial agents approved during the recent years by FDA, as a hope to reinforce the current therapeutic armamentarium. New antibacterial agents were identified using FDA (www.accessdata.fda.gov, www.fda.gov) and Center Watch     sites (https://www.centerwatch.com/drug-information/fda-approved-drugs/). In the present review, four antibacterial agents which have been approved after the year 2018- 2019 have been described along with their mechanism of action, development of resistance, spectrum of activity and the stage of developmental in case of yet to be approved drugs.

 

Omadacycline:

Omadacycline is an aminomethylcycline, a semi-synthetic, tetracycline-derived compound6. This drug family has been a part of the arsenal of antimicrobial therapy for over 60 years. Omadacycline, similar to older tetracycline, exhibits activity against a wide variety of bacteria including Gram-positive, Gram-negative, anaerobic and atypical pathogens.

 

The key advantage over older tetracycline lies in the fact that omadacycline is active against bacteria that have the major determinants of efflux and target resistance. These include not only strains resistant to tetracyclines, but also resistant to other antibiotics, such as quinolones, macrolides, and amino glycosides.6,7 Omadacycline (Figure 1), also known as PTK-0796 or (4S,4aS,5aR,12aR)-4,7-bis(dimethyl- amino)-9-[(2,2-dimethylpropylamino)methyl]-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6- tetrahy-dro-4H-tetracene-2-carboxamide

 

 

Fig No.1 Structure of Omadacycline

 

Omadacycline was approved by the FDA for treatment of community acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSI) in October 2018and is not yet approved by the EMA. It should be given once daily in formulations of both I V and PO (Table 1). Omadacycline has alerts associated with tetracycline class antibiotics including: decoloration of the tooth, hypoplasia of the enamel, and suppression of bone growth in late pregnancy, infancy, or infancy up to 8 years. The most common adverse reactions (incidence of 2%) observed in omadacycline clinical trials are nausea, vomiting, reactions from the infusion site Reactions, decreased alanine amino transferase, decreased aspartate amino transferase, increased gammaglutamyl transferase, high blood pressure, headache, nausea, sleeplessness and constipati on. Omadacycline was studied only in patients 18 or older8,9,10. The sensitivity of Omadacycline to muscarinic M2 receptors causes a temporary rise in heart rate and has no effect on the QT interval.

Sarecycline:

Sarecycline is a new antibiotic derived from I class tetracycline (Figure 2), indicated for adults and children aged 9 years and older with nonnodular, mild to extreme acne vulgaris.11

 

It has a limited range of action, including less action against enteric Gram negative bacteria compared to currently available tetracyclines, and it also induces anti-inflammatory effects.12

 

 

Fig No. 2 Structure of Sarecycline

 

Product was approved for the treatment of nonnodular mild to extreme acne by the FDA in October 2018. In October 2018 the European Medicine Agency (EMA) also submitted an application for review. The medication is administered orally with food as 1.5mg/kg/day, in patients aged 9 and older, as an antibiotic once a day with clinically meaningful progress seen as early as 3rd week. More specific details about its management can be found in Table 1. Nausea was reported in 3.1 percent of patients treated with sarecycline and 2.0 percent in patients treated with placebo in clinical trials compared with placebo assessing the adverse effects; the other adverse reactions identified in les in less than 1% of female subjects. In less than 1% of female subjects treated with sarecycline: vulvovaginal mycotic infection (0.8%) and vulvovaginal candidiasis (0.6%). Sarecycline is a class tetracycline ribosomal protein inhibitor that shows effective activity against P. acnes and other Gram-positive in vitro bacteria12. In vitro the drug has also demonstrated anti-inflammatory effects13. These properties tend to be compatible with those of other tetracyclines although it is currently unclear the exact mechanism by which sarecycline works to treat acne vulgaris13. The drug was not correlated with clinically significant prolongation of the QT interval when used at a dosage approximately three times greater than recommended.14

 

Sarecycline (like other tetracycline) may impact the bactericidal effects of penicillin; co administration should therefore be avoided14. Co administering sarecycline with oral retinoid should also be avoided, as both tetracyclines and oral retinoid can increase intracranial pressure. Plasma prothrombin activity may be reduced by sarecycline (as with other tetracycline) which could elevate the bleeding risk of patients taking anticoagulants; the dosage of the anticoagulant may therefore need to be reduced.14

Some recipients of teracyclines can experience photosensitivity and sarecycline has displayed photoxic potential in mice patients should be advised to avoid/ minimize exposure to sunlight (natural and artificial) while taking sarecycline15. In animal toxicity studies of oral sarecycline, pigment deposition in the thyroid gland or tooth/bone discoloration were not considered to be toxicologically adverse; sarecycline should not be used during tooth development

 

Eravacycline:

Eravacycline is a synthetic fluorocycline antibiotic belonging to the tetracycline drug class (Figure 3). It disrupts bacterial protein synthesis by binding the 30S ribosomal subunit, thus preventing incorporation of amino acid residues into elongating peptide chains15. It is indicated in adults for treatment of complicated intra-abdominal infections caused by the following susceptible bacteria Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Enterobacter cloacae, Klebsiella oxytoca, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Streptococcus anginosus group, Clostridium perfringens, Bacteroides species, and Parabacteroides distasoni16

 

 

Fig No.3 Structure of Eravacycline

 

It approved by FDA in August 2018 and by EMA in September 2018, being indicated in the complicated intra-abdominal infections Eravacycline is administered IV in 60 min infusions, given once every 12 hours for a total of 4 to 14 days; dose is patient’s weight dependent (1mg/kg) and it is used in persons over 18 years of age with complicated intra-abdominal infections (cIAI) caused by susceptible microorganisms identified in the prescribing information (Table 1). This is the FDA Approved Antibacterial Drugs in 2018 and 2019 only indication of use for teravacycline at this moment, although it may be approved for other applications in the future, similar to other tetracyclines.17

 

The most important adverse event reported with eravacycline in clinical trials and sometimes a cause of the treatment discontinuation is the gastrointestinal (GI) upset. Other noteworthy adverse events that can appear are infusion site reactions, nausea, and vomiting. Eravacycline was compared with ertapenem and meropenem for the treatment of cIAIs in 2 no inferiority trials (IGNITE1 and IGNITE4), with similar clinical response rates Eravacycline consists of the tetracyclic core scaffold, with two unique modifications in the tetracyclic during at position C7 (addition of fluorine atom) and C9 (addition of pyrrolidinoacetamo group)19. As a consequence of these substitutions at C7 and C9, which are not present in any naturally occurring or semisynthetic tetracyclines, eravacycline exhibits in vitro activity against Gram-positive and -negative bacterial strains expressing certain tetracycline-specific acquired resistance mechanisms.18

 

Like other tetracycline’s, eravacycline exerts its antibacterial action by reversibly binding to the bacterial ribosomal 30S subunit, thereby preventing the incorporation of amino acid residues into elongating peptide chains and leading to disruption of bacterial protein synthesis. In vitro, eravacycline had a tenfold higher affinity for ribosomal binding and inhibited protein translation at fourfold lower drug concentrations than tetracycline.19.Tetracyclines, including eravacycline, typically exhibit bacteriostatic activity; however, teravacycline also exhibits bactericidal activity against certain strains of Acinetobacter baumannii, E. coli and K. pneumoniae in vitro.20

 

Plazomicin:

Plazomicin has been engineered to overcome amino glycoside (Fig no 4) modifying enzymes, the most common aminoglycoside-resistance mechanism in Enterobacteriaceae, and it has in vitro activity against extended-spectrum beta-lactamase-producing, aminoglycoside- resistant, and carbapenem-resistant isolates. It is indicated for complicated urinary tract infections (cUTIs), including pyelonephritis, caused by the following susceptible microorganisms: Escherichia coli, Lebsiella pneumonia, Proteus mirabilis, and Enterobacter cloacae.

 

 

Fig No.4 Structure of Plazomicin

 

Limited clinical safety and efficacy data are available; therefore, the prescribing information recommends reserving treatment for use in patients with cUTI who have limited or no alternative treatment option.21

 

Approved by FDA in June 2018 (Table no 1) for targeting the infections with Gram-negative aerobic bacteria in the complicated urinary tract infections (cUTIs). Application was submitted for review by European Medicine Agency (EMA) in June 2018. Plazomicin is administered intravenously (IV) every 24 hours for 4-7 days; it is primarily active against Gram-negative aerobic bacteria (e.g. Enterobacteriaceae family), to be used in patients over 18 years of age with cUTIs (including pyelonephritis), caused by susceptible Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis or Enterobacter cloacae21,22. Plazomicin is supplied as single-dose vials in an amount of 500 mg/10 mL plazomicin base. Administration recommendations can be found in Table 1 and its dosage is personalized based on the renal function and/or therapeutic monitoring of the drug, if available.22 Plazomicin might be of value in patients that have resistance to their primary treatment options or who are allergic to beta-lactam antibiotics. The most important adverse events reported with plazomicin are: nephrotoxicity (but lower incidence of nephrotoxicity than colistin), diarrhea, hypertension, headache, nausea, vomiting, hypotension. Plazomicin showed to be non-inferior to meropenem within the EPIC non-inferiority trial in treatment of cUTIs and even demonstrated superior microbiological eradication (81.7% versus 70.1%; 95% confidence interval (CI) 2.7-25.7)21. Plazomicin-based combinations also demonstrated decreased disease-complications and mortality when compared to colistin-based combination in the CARE trial (23.5% versus 50%; 90% CI -0.7 to 51.2). Plazomicin (also known as ACHN‐490) is a novel amino glycoside, synthetically derived from sisomicin, an older, naturally occurring aminoglycoside23. Similar to other amino glycosides, plazomicin exerts its effect by binding to the 30S portion of the bacterial ribosome, thereby inhibiting bacterial protein synthesis in a bactericidal manner. Although plazomicin bears some structural similarities to sisomicin, it also possesses some novelty in its chemical structure like sisomicin, plazomicin lacks a 3′‐ or 4′‐hydroxyl group that affords protection against inactivation by enzymes that inactivate amikacin, the broadest spectrum amino glycoside available.24

 

However, plazomicin is distinguished from sisomicin by the addition of a hydroxyl‐aminobutyric acid group at position 1 and hydroxyethyl group at the 6′ position of sisomicin, enhancing its spectrum of activity against organisms possessing AMEs.24,25


 

Table no. 1 FDA Approved drugs details

NAME

(generic/brand/ class)

Approval status

Indication

Administration

Dose and duration

Plazomicin (Zemdri)/ aminoglycoside antibiotic

 

FDA: approved in June 2018 EMA:

application submited (2018)

cUTIs; Enterobacte riaceae infections

IV infusion, every

24 hours for 4-7 days.

A Dosage regimen (adults with CrCl>60ml/min): 15 mg/kg every 24 hours

B.    Dosage regimen (adults with CrCl>30

<60 ml/min): 10 mg/kg every 24h

C.         Dosage regimen (adults with CrCl>15

<30 ml/min): 10 mg/kg every 48h

Eravacycline (Xerava)

/ fully synthetic fluorocycline

 

FDA: approved in August 2018 EMA: approved in September 2018

cIAI

IV 60 min

infusion, given once every 12 hours for a total of 4 to 14 days; dose is patient’s weight

dependent

Adult patients (≥18 years of age) with cIAI: administer 1mg/kg, every 12h, by IV infusion (~60min); recommended duration of treatment is 4 to 14 days

Sarecycline (Seysara) / tetracycline-derived antibiotic

FDA: approved in October 2018 EMA: not yet approved

non-nodular moderate to severe acne

PO administration with food

A. Adult <54 kg: 60 mg PO every Day

55-84 kg: 100 mg PO every Day 85-136 kg: 150 mg PO every Day

 

B. Children ≥9 years 33-54 kg: 60 mg PO every Day 55-84 kg: 100 mg PO every Day 85-136 kg: 150 mg PO every Day

 

Omadacycline (Nuzyra) / aminomethylcycline antibiotic, tetracycline class (inhibits 30S ribosomal subunit)

FDA: approved in October 2018 EMA: not yet approved

CABP, ABSSSI

Both once-daily IV and PO formulations

A.   For patients with CABP, the loading dose on day 1 is 200 mg by IV infusion over 60 minutes, or 100 mg by IV infusion over 30 minutes, given twice; the maintenance dose is 100 mg by IV infusion over 30 minutes once daily, or 300 mg PO daily for a total of 7 to 14 days.

B.   For patients with ABSSSI, the loading dose on day 1 is 200 mg by IV infusion over 60 minutes; or 100 mg by IV infusion over 30 minutes, given twice; or, on days 1 and 2, 450 mg orally once daily. The maintenance dose is 100 mg by IV infusion over 30 minutes once daily, or 300 mg PO daily, for a total duration of 7 to 14 days

 


 

 

 

CONCLUSION:

There is a noteworthy requirement for novel antibacterial medications and this innovative work endeavors as of late brought about barely any new medications or mix of

drugs proposed for use into the facility. There is a critical increment in the quantity of the new FDA endorsed sedates in the earlier years, The tale US FDA affirmed antibacterial operators over the most recent two years (2018-2019): plazomicin, eravacycline, and sarecycline, omadacycline, are new players in the field of safe microorganisms treatment for explicit signs. Be that as it may, he number and proficiency of these new medications is far from covering all the current needs, to completely battle exceptionally versatile microorganisms. Along these lines, there is a genuine need and direness to create novel anti-toxin systems and medications to defeat the bacterial protection from anti-microbial. Through this audit, we intend to further urge established researchers to proceed the advancement of new remedial specialists for focusing on bacterial obstruction.

 

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Received on 25.04.2020           Modified on 23.05.2020

Accepted on 19.06.2020          © RJPT All right reserved

Research J. Pharm. and Tech. 2021; 14(3):1755-1759.

DOI: 10.5958/0974-360X.2021.00312.7