Recarbio v Vabomere FINAL

Recarbrio & Vabomere

Treating cUTIs by Comparing

K2054446 - Abdulla Al-JanabyK1802077 - Nawaf Al-MaajunK1906961 - Alya AliK2053252 - Zaid Al-TameemiK1940891 - Ghadier MohammedK2012525 - Mohamed AbdulbakiK2030022 - Aseel Azeez

Index

What are these drugs

01

Pathophysiology

02

03

04

05

Detection

Statistics

Treatment

06

β-lactams

07

08 - 09

10

11

Bacterial Resistance

Old Inhibitors

Lactone Products

12

13 - 15

Relebactam

Mechanism

16

Vaborbactam

17

20

Antibiotics

Excipients

26

18

Formulation

Pharmacokinetics

β-lactams and Resistance

Mechanism

Recarbio

19

Vabomere

21

22

23-24

25

Side Effects

Conculsion

27

Hypotheses

• Both used to treat complicated bacterial infections [1]

• Both are combinatory drugs containing:
• β-Lactams - carbapenems
• β-Lactamase inhibitors [1]

• Last line treatments
• when there is fear the patient may go into sepsis [1]

wHAT aRE tHESE dRUGS?

How do complicated UTIs occur?

PathophySIOLOGY

• Complicated urinary tract infections (cUTIs) is an umbrella term used to describe anything that can go wrong with a UTI [2]

• Lower UTIs, located in the urethra and bladder, are considered to be normal UTIs [2]

• However, The bacterial infection can spread to the uretra, kidneys (pyelonephritis) - these are known as upper UTIs/cUTIs [3]

Kidneys

Right Ureter

Left Ureter

Urethra

Bladder

kidney and back pain

Right Lumbar

Left Lumbar

Umbilical Region

Left Hypochondrium

Right Iliac Region

Left Iliac Region

Hypogastrium

Right Hypochondrium

Epigastric region

Detection

high temperature (>37.9)

kidney and back pain

Nausea and Vomiting

50%

23%

of infections [4]

women in UK [4]

HAVE GOTTEN A UTI

ARE UTIs

Elderly

Immunocompromised

Males

TREATMENT

First line:

• Co-Amoxiclav 1.2g IV every 8 hrs
• + Gentamicin / Amikacin [5]

Second line:

• Ciprofloxacin 500mg PO 12 hourly

If pateints has features of sepsis - particularly hypotension - refer to consultant

Four membered cyclic amide ring functional group

Attack peptidoglycan envelope which consists of PBPs [6]

β-LACTAMS

B-lactams are similar to the D-Ala D-Ala terminal dimer of peptidoglycans

This triggers cross recognition with PBPs, weakening the envelope and causing cell lysis [8]

Carbapenems have become a great resourse in counteracting ESBLs due to their tans-1alpha-hydroxyethl substuent at carbon 6

Bacterial resistance

Efflux pumps [9]

Modification of porins

Modification of PBPs

Production of β-lactamases

TREATMENT

Monobactam

Carbapenem

Cephlasporin

Penicillin

BACTERIAL RESISTANCE

TETRAHEDRAL INTERMEDIATE

BACTERIAL RESISTANCE

ACYL-ENZYME INTERMEDIATE

PRODUCT

OLD INHIBITORS

Sulbactam

Clavulanic acid

LACTONE PRODUCT

Due to carbapenem resistance, mutations in some resistnant D strains have resulted in the formation of an alterative lactone prouct which is quicker to form [10]. this product still inhibits the beta lactamses but is much less effective than the parent carbapenem and reduces the rate of inhibition [11].

Lactone product

Hydrolysis product

RELEBACTAM

Avibactam

Relebactam

Relebactam is structurally related to avibactam, differing by the addition of a piperidine ring to the 2-position carbonyl group [12].

Relebactam is highly reactive due to its highly strained bicyclic urea core and electron-withdrawing aminooxy sulfate moiety [12].The high reactivity results in limited stability in the presence of base or nucleophiles; however, this is also the same property that makes this compound a potent b-lactamase inhibitor [13].

MECHANISM

MECHANISM

MECHANISM

VABORBACTAM

Cephalothin

Vaborbactam

Vaborbactam’s boronic ester ring was designed with the intention of constraining the inhibitor into a preferred conformation to increase potency.

The boron atom in vaborbactam acts as an electrophile and forms a reversible covalent bond with the catalytic serine of specific b-lactamases [15].

Vaborbactam also has a 2-thienylacetyl side chain similar to the side chains of cephalothin and cefoxitin.

MECHANISM

RECARBRIO

Why is Cilastatin given?

• Imipenem is susceptible to degradation by dehydropeptidase-1 (DHP-1) [18].

• Therefore, imipenem must be administered with Cilastatin, as it is an inhibitor of DHP-1 [18].

How is Recarbrio used?

• Administered intravenously (500mg/500mg/250mg) over a 30-minute period, every 6 hours; for adults with a creatine clearance between 90-150ml/minute.

• Administrated over 5-14 days depending on the infection [17].

• No adjustment based on age or hepatic impairment is needed [17].

• Only used in patients who are 18y/o and over .

VABOMERE

Why no Cilastatin?

• Unlike Imipenem, Meropenem is resistant to DHP-1 degradation due to the addition of a methyl group at the C1 position.

How is Vabomere used?

• Administered by IV, each vial contains 1g of Meropenem and vaborbactam over 3hrs, every 8 hrs.

• Creatine clearance needs to be 40ml/minute or greater.

• Treatment can be from 5-14 days [18].

• Should only be used in those aged 18 years and older.

ANTIBIOTICS OF CHOICE

The differentiating factor between Imipenem and Meropenem and other β-Lactams is its ability to bind to a variety of PBPs.

Imipenem has weak affinity for PBP3 but preferentially binds to PBP2, followed by PBPs 1a and 1b . Alternatively, meropenem preferentially binds to PBP2, followed by PBPs 3, 1a, and 1b [20].

The low affinity of carbapenems to PBP3 is responsible for their ability to achieve cell lysis without filamentation. This means the cell does not gain as much mass before lysis and as a result less lipopolysaccharides are released [21].

Imipenem

Meropenem

Sodium Carbonate

01

Sodium Chloride

02

Vabomere

Sodium Hydrogen Carbonate

01

Recarbio

EXCIPIENTS

02

Sodium Chloride

• Both drugs display hydrophilic properties which limit passive diffusion, are orally inactive, and would have poor bioavailability. Thus, they are orally inactive and given as I.V only

• IV administration is the preferred route of administration as it allows the antibiotics to have a bioavailability of 1.0; thus exerting a greater therapeutic effect [23]

• Intravenous (IV) drug administrations allow multiple administrations of drugs without the need for needle re-insertion.

FORMULATION

PHARMACOKINETICS

METABOLISM

• Imipenem metabolised by DHP-1 via hydrolysis of beta-lactam ring; thus low urinary recovery of 15-20%. With Cilastatin; urinary recovery increases to 70% [13]​

• Cilastatin recovery in urine is 77%, indicating mild metabolism [13]​

• In Relebactam, no clinically significant metabolism; 90% recovered in urine [13]

Racrbrio

• Meropenem undergoes beta-lactam ring hydrolysis; 22% of hydrolysis product is eliminated through urine. Rate of Meropenem urine recovery averages 50% [18]​

• In Vaborbactam, no clinically significant metabolism; 85% recovered in urine [17]

Vabomere

PHARMACOKINETICS

Elimination:

• Imipenem: CL of 123ml/min & t1/2 of 1hr [13,15]​

• Cilastatin: CL of 188ml/min [13]​

• Relebactam: CL of 135ml/min & t1/2 1.2hrs. Relebactam’s passive filtration rate of 94ml/min is less than the renal clearance; indicating active secretion [13,15]

Racrbrio

• Meropenem: CL of 130ml/min & t1/2 of 1.2hrs [18]​

• Vaborbactam: CL of 148ml/min & t1/2 of 1.7hrs. Vaborbactam’s passive filtration rate of 83ml/min is less than the renal clearance; indicating active secretion [17,18]

Vabomere

PHARMACOKINETICS

DISTRIBUTION

• Plasma Proteins binding: Imipenem 20%; Cilastatin 40%; Relebactam 22% [15]​

• Steady State Volume: Imipenem 24.3L; Cilastatin 13.8L; Relebactam 19.0L [15]

Racrbrio

• Plasma Proteins binding: Meropenem 2%; Vaborbactam 33% [18]​

• Steady State Volume: Meropenem 20.2L; Vaborbactam 18.6L [18]​

Vabomere

sIDE EFFECTS

Hypotheses

Adding an ethyl or propyl group to Meropenem could make it more effective in it’s resistance to DHP-1; greater steric hinderance. 70% is recovered in urine, could a longer alkyl chain increase this figure and by extension therapeutic effect? [9]

Given their effectiveness in treating cUTIs, why not create versions of Recarbrio and Vabomere with a longer half-life? This would avoid multiple daily administration, saving costs, and allow for oral dosing; facilitating patient comfort, removed from a medical setting. [7]

Theoretical research demonstrates that by fusing Vaborbactam’s Boronate ring with the aromatic group, a matching binding pattern of the carboxylate group can bind to the Zn(II) binding site; inhibiting class B beta-lactamases’ actions against Carbapenems. Could other group 13 metals be used to counter further evolutionary resistant measures by beta-lactamases?

conclusion

Making a decision of whether to use Vabomere or Recarbio is predominantly based on the patient's background and situation.

In our opinion Recarbio is the superior drug because of its ability to act on a broader range of ESBLs, requiring a slower infusion time, higher success rate, and it being cleared much easier in the kidneys.

This doesn’t mean Vabomere doesn't have its positives, such as being cheaper per vial (£55.67 per vial) compared to recarbio (£153.55 per vial) [10] and having much fewer side effects.

thanks

FOR LISTENING

Reference List

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[8] Zhanel G. et al. Comparative review of the carbapenems. Drugs. 2007; 67(7):1027–52. doi:10.2165/00003495-200767070-00006 [9] Zhanel G. et al. Imipenem–Relebactam and Meropenem–Vaborbactam: Two Novel Carbapenem-β-Lactamase Inhibitor Combinations. Drugs. 2017; 78:65-98. doi:10.1007/s40265-017-0851-9. [10] Fisher J. et al. Bacterial resistance to beta-lactam antibiotics: Compelling opportunism, compelling opportunity. American Chemical Society. 2005; 105:395–424. doi:10.1021/cr030102i. [11] Ambler R.P. The Structure of Beta-Lactamases. Philosophical Transactions of the Royal Biological Soceity. 1980; 289:321–331. doi:10.1098/rstb.1980.0049. [12] National Institute for Health and Care Excellence (NICE). Antimicrobial Prescribing: Imipenem with Cilastatin and Relebactam. 2020. https://www.nice.org.uk/advice/es30/evidence/evidence-review-pdf-8895526237. [Accessed 12th November 2022]. [13] European Medicines Agency. EMEA/H/C/004808/0000. Assessment Report: Recarbio. Amsterdam. Committee for Medicinal Products for Human Use. 2019. [14] Mangion I. et al. A Concise Synthesis of a β-Lactamase Inhibitor. American Chemical Society. 2011; 13(20): 5480-5483. doi: 10.1021/ol202195n.[15] Food and Drug Administration. 4462927. Recarbio for Injection, for Intravenous use. Whitehouse Station. Merck Sharpe & Dohme Corp. 2019.

[16] National Institute for Health and Care Excellence (NICE). Antimicrobial Prescribing: Meropenem with Vaborbactam. 2019. https://www.nice.org.uk/advice/es21/evidence/evidence-review-pdf-6965792605. [Accessed 12th November 2022]. [17] European Medicines Agency. EMEA/H/C/004669/0000. Assessment Report: Vabomere. London. Committee for Medicinal Products for Human Use. 2018. [18] Food and Drug Administration. 4146252. VABOMERE for Injection, for Intravenous use. Parsippany. The Medicines Company. 2017. [19] Hecker S. et al. Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases. American Chemical Society. 2015; 58(9): 3682-3692. doi:10.1021/acs.jmedchem.5b00127[20] Melinta Therapeutics. VABOMERE®: a combination of meropenem and vaborbactam designed to address resistant Enterobacterales. http://www.vabomere.com/about-vabomere.html. [Accessed 14th November 2022]. [21] National Centre for Biotechnology Information. PMID: 33630278. Imipenem/Cilastatin/Relebactam: A Review in Gram-Negative Bacterial Infections. Auckland: National Library of Medicine; 2021. [22] Saito T, Sawazaki R, Ujiie K, Oda M, Saitoh H. Possible factors involved in oral inactivity of Meropenem, a carbapenem antibiotic. Pharmacology & Pharmacy. 2012Jan12;03(02):201–6. [23] Craig, William A. “The Pharmacology of Meropenem, a New Carbapenem Antibiotic.” Clinical Infectious Diseases, vol. 24, 1997, pp. S266–75. JSTOR, http://www.jstor.org/stable/4480989. Accessed 5 Dec. 2022.

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