A Review on Meropenem

 

Mohsina Abed1, Sara Yousuf2

1Assistant Professor, Deccan School of Pharmacy, Hyderabad.

2Deccan School of Pharmacy, Hyderabad.

*Corresponding Author E-mail: sughrafatimadsop@gmail.com

 

ABSTRACT:

Meropenem is a new Carbapenem antibacterial agent with wide spectrum of activity for intravenous administration. It is synthetic derivative of Thienamycin. Three analogues of Meropenem are evaluated and active against 18 bacterial strains. Meropenem causes rapid bacterial cell death by covalently binding to penicillin binding proteins (PBS). Structural modification at C-2 position, produced double promoiety prodrug of Meropenem and increases bioavailability of oral administration. Other forms of drug such as liposome and nanoparticles are also available with enhanced absorption. 14C labelled Meropenem prepared from 14C Dimethylamine hydrochloride is used for the analysis of M. tuberculosis transpeptidase. ICI213,689 is the only metabolite of Meropenem and it is inactive. Meropenem penetrates well into the body fluids and tissues including cerebrospinal fluid. Its bioavailability is 100% on intravenous administration. Hence it is used in the treatment of meningitis, febrile neutropenia, anthrax and various other skin and skin structure infections. Dosage reduction is required in patient with reduced renal function but not in hepatic impairment. Seizures, gastrointestinal haemorrhage are observed in patients. Vabmoere is the combination of Meropenem and Vaborbactam which is active against the Carbapenem resistant Enterobacteriacea. Meropenem is an effective broad-spectrum antibacterial drug for the treatment of wide range of infection including polymicrobial infection in both children and adult.

 

KEYWORDS: Meropenem, Carbapenem, Antibacterial agent, Spectrum of activity, Thienamycin, Vaborbactum.

 

 


INTRODUCTION:

Meropenem belongs to ‘Carbapenem’ group of antibacterial agents with a broad spectrum of activity against gram-negative, gram-positive and anaerobic microorganisms. Meropenem is a new carbapenem antibacterial agent with wide spectrum of activity. It is stable against most β-lactamases produced by Gram negative bacteria and has greatest utility in treating severe infections. It has good CSF penetrability and useful in treatment of childhood meningitis and infections in neutropenic children.1

 

Carbapenems are a class of highly effective antibiotic agents commonly used for the treatment of severe or high-risk bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections.2,3

 

Fig 1 General Structure of Carbapenems

 

Meropenem is a carbapenemcarboxylic acid in which the azetidine and pyrroline rings carry 1-hydroxymethyl and 5-(dimethylcarbamoyl) pyrrolidin-3-ylthio substituents respectively.4 Meropenem is a sterile, pyrogen-free, synthetic, broad-spectrum, carbapenem antibiotic for intravenous administration. It has a role as an antibacterial drug, an antibacterial agent and a drug allergen. It is a carbapenemcarboxylic acid, a pyrrolidinecarboxamide, an alpha, beta-unsaturated monocarboxylic acid and an organic sulfide.4

 

 

Fig 2 (4R,5S,6S)-3- [[(3S,5S)-5-(Dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6- [(1R)-1­ hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid trihydrate

 

Analogues of meropenem:

Three new Meropenem analogues against 18 bacterial strains are synthesized.

 

Fig 3 Structures of Meropenem and the target compounds Ia–c.

 

Our general synthetic route leading to new carbapenem derivatives involved the preparation of appropriately protected thiols containing pyrrolidine ring as a side chain and coupling reaction with the carbapenem diphenylphosphate, followed by deprotection of the resulting protected carbapenems in a usual manner.5

 

Carbapenems are one of the most potent types of antibacterial agents and are among those used as a last resort against infections in the clinical field. Recently, they have been classified into three classes according to their chemical structures. According to this classification, meropenem belongs to 1β-methylcarbapenems containing (3S)-pyrrolidine-3-ylthio moiety. The 1β-methyl group slows renal hydrolysis by dehydropeptidase-I (DHP-I) and allows usage as a single agent. Carbapenems with (3S)-pyrrolidine-3-ylthio moiety are reported for their broad-spectrum and potent antibacterial activity. In the present investigation, we report the synthesis and in vitro antibacterial evaluation of three new meropenem analogues against 18 bacterial strains. Our target is to discover new carbapenem derivatives with improved antibacterial activity.6

 

Mechanism of action:

1.     The bactericidal activity of meropenem results from the inhibition of cell wall synthesis.

2.     Meropenem penetrates the cell wall of most gram-positive and gram-negative bacteria to reach penicillin-binding-protein (PBP) targets.

3.     Meropenem binds to PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa; and PBPs 1, 2 and 4 of Staphylococcus aureus.

4.     Cause rapid bacterial cell death by covalently binding to penicillin-binding proteins (PBPs) involved in the biosynthesis of mucopeptides in bacterial cell walls.

5.     Bactericidal effects result through inhibition of cellular growth and division and the loss of cell wall integrity, eventually causing cell wall lysis.

6.     The primary target is PBP 2.

7.     It is highly resistant to degradation by β-lactamases or cephalosporinases. resistance arises due to mutations in penicillin-binding proteins, production of metallo-β-lactamases, or resistance to diffusion across the bacterial outer membrane.7

 

Fig 4 Mechanism of Action of Meropenem

 

Resistance:

There are several mechanisms of resistance to meropenem:

1.     Decreased permeability of the outer membrane of gram-negative bacteria (due to diminished production of porins) causing reduced bacterial uptake

2.     Reduced affinity of the target PBPs

3.     Increased expression of efflux pump components

4.     Production of antibacterial drug-destroying enzymes (carbapenemases, metallo-β-lactamases8

 

Cross-Resistance:

Cross-resistance is sometimes observed with isolates resistant to other carbapenems.

 

Spectrum of activity:

Meropenem exerts its bactericidal action by interfering with vital bacterial cell wall synthesis. The ease with which it penetrates bacterial cell walls, its high level of stability to all serine β-lactamases and its marked activity for the penicillin binding proteins (PBPs) explain the potent bactericidal action of meropenem against a broad spectrum of aerobic and anaerobic.

 

VIBRATIONAL ASSIGNMENTS:

1.     A number of bands corresponding to the vibrations of the β-lactam and pyrrolidine 4:5 bicyclic fused rings and of certain substituents were identified in the IR absorption and Raman scattering spectra of meropenem.

2.     Bands located at 653 and 690 cm-1. These modes also contained components corresponding to the bending vibrations of the C-O-H bond in a carboxyl group.

3.     In the experimental IR spectra they were located at 668 and 705 cm-1. The bands corresponding to the bending vibrations of the carboxyl group C-O-H bond were also observed at 771 and 768 cm-1 in the calculated and experimental IR spectra, respectively.

4.     The bending vibrations of the C-O-H bond were observed at 1202 and 1188 cm-1 .

5.     This mode also showed components corresponding to the stretching vibration of the C-N bond in the β-lactam ring. The bands related to the stretching vibrations of the C-N bond in the β-lactam ring were also observed in the calculated spectra at 1135 and 1417 cm-1. In the experimental spectra, they were located at 1143 and 1388/1391 cm-1

6.     The band at 1135 cm-1 was corresponding also to the wagging and twisting vibrations of the C-H bonds present in the entire structure.9

7.     The band at 1417 cm-1 was complex and composed of many normal modes of vibrations. This mode had additional components corresponding to the stretching vibrations of the C-C bond between the pyrrolidine ring and the carboxyl group and to the scissoring vibrations of the C-H bond in the methyl group in the trans-hydroxyethyl group at C2. The band related to the stretching vibrations of the C-C bond in the β-lactam ring was also observed at 994/989 cm-1

8.     The range 1600–1900 cm-1 in the calculated spectra exhibited distinct bands related to the stretching vibrations of the C=C and C=O bonds.

9.     The band associated with the stretching of the C=C bond in the β-lactam and pyrrolidine 4:5 bicyclic fused rings was located in the calculated spectra at 1616 cm-1.  The band associated with the stretching of the C=C bond in the β-lactam and pyrrolidine 4:5 bicyclic fused rings was located in the calculated spectra at 1616 cm-1. The stretching vibrations of the C=O bond in the β-lactam ring were located at 1887/1749 cm-1 .

10. Lower wavenumbers in the calculated spectra (1751 and 1818 cm-1) revealed bands corresponding also to the stretching vibrations of the C=O bonds but in the trans-hydroxyethyl and carboxyl substituents.

11. In the experimental IR spectra a split was observed into those bands and bands related to the vibrations at 1749, 1604 and 1651 cm-1, which resulted from the fact that the bonds located in the external part of meropenem molecules were likely to be affected by intermolecular interaction.

12. A band corresponding to the breathing of the pyrrolidine ring was identified in the theoretic Raman spectrum at 784 cm-1

13. In contrast, the stretching vibrations of the C-N bond between the nitrogen atom and the methyl groups in the dimethyl-carbamoyl substituents in the experimental spectra were shifted to 810 cm-1.

14. A greater band shift was observed for the bands located in the calculated Raman spectra at 991 cm-1, which was related to the stretching vibrations of the C-C bond of the β-lactam ring, especially between the carbonyl group and the C-N bond in that ring whereas between the nitrogen atom and the methyl group in the dimethyl-carbamoyl substituents the stretching vibrations of the C-N bond were identified at 1289 cm-1 in the calculated spectra.

15. The stretching vibrations of the C-N bond in the dimethyl-carbamoyl substituents were also observed at 1430/1388 cm-1

16. Fairly distinct bands associated with the stretching vibrations of the C-C bond in the pyrrolidine ring as well as the wagging and twisting vibrations of the C-H bonds at the β-lactam ring were located at 1049 cm-1 in the calculated and at 1056 cm-1 in the experimental spectrum.

17. The band corresponding to the stretching of the C-C bond present in the β-lactam and pyrrolidine 4:5 bicyclic fused rings and between the carbon atom in the carboxyl group was observed at 1330/1307 cm-1

18. bending vibrations of the O-H bonds in the carboxyl group were observed at 575/603 and 635/668 cm-1

19. The bands related to the wagging and twisting vibrations of the C-H bonds in the trans-hydroxyethyl group and in the β-lactam and pyrrolidine 4:5 bicyclic fused rings were located in the experimental IR spectrum at 1075 and 1335 cm-1

20. A band associated with the stretching vibrations of the C-H bonds in the dimethyl-carbamoyl group was identified at 2900 cm-1

21.  Bands corresponding to the twisting vibrations of the C-H bonds in the same part of the molecule were observed at 1143/1147 cm-1 10

 

Fig 5.1 Vibrational Assessment of Meropenem

 

Fig 5.2 Vibrational Assessment of Meropenem

 

1.     Assessment of changes in the structure of meropenem as a consequence of exposure to temperature and humidity.

2.     The degradation of meropenem at increased relative air humidity (simulation of storage in a damaged container) and at increased temperature at RH = 0% (simulation of storage in an airtight container) was analysed during a stability study (RH ≈ 76.4%, T= 313 K, t = 1.0 h and RH = 0%, T = 323 K, t = 5.0 h).

3.     It was found that by analysing the FT-IR spectra of meropenem it was possible to assess changes in the structure of its samples at increased temperature, at RH = 0%.

4.     Regarding changes in the molecular structure of meropenem associated with the cleavage of bonds in the structure of the β-lactam and pyrrolidine 4:5 bicyclic fused rings, their manifestations included an increase in band intensity at 879 cm-1

5.     Changes in the shapes of the bands and in the ratios of the intensities between the bands in the range 1350–1800 cm-1, changes in the band at 1749 cm-1 corresponding to the stretching vibrations of the C=O bond in the β-lactam ring as well as the occurrence of a band at 695 cm-1 in samples degraded at T = 323 K, RH = 0%.

6.     The changes at 1500–1600 cm-1 could be explained by the formation of a new bond between the nitrogen and the hydrogen atoms in the pyrrolidine ring.

7.     Also, the intra- and inter-molecular impact of the open β-lactam ring might be responsible for the degradation process.11

 

DISCRETE FOURIER TRANFORM STUDIES:

The analysis of the optimized geometry of meropenem indicated that the interring stress is a result of the fusion of the heterocyclic moieties with the substituents, which can be spatial obstacles to each other.  Such molecular configuration of meropenem ensures its binding with PBP (penicillin-binding protein) enzymes that is responsible for antibacterial activity. At the same time that configuration determines the significant susceptibility to degradation of meropenem under the conditions of acid–base hydrolysis and in the presence of oxidizing factors as well as during thermolysis.11

 

Fig 6.1 Vibrational Assessment of Meropenem and Substituent

 

Fig 6.2 Vibrational Assessment of Meropenem and Substituent

 

Fourier transform-infrared spectroscopy (FT-IR):

The chemical structure and complexes formation of meropenem-loaded CS nanoparticles were analysed using Nicolet 6700 FT-IR spectrometer. Samples were first lyophilized to obtain dry powder. Then, samples were mixed with potassium bromide (spectroscopic grade) at a ratio of 1:20 and compressed to form disks. Disks were scanned in the spectral region of 4000–500 cm−1. [11-12]

 

Fig 7 FTIR of Meropenem

FT-IR spectra of meropenem(A)

Meropenem-loaded CS nanoparticles (CS: TPP weight ratio of 5:1) (B)

 

 

Determination of bacterial susceptibility:

The antibacterial activity of the meropenem-loaded nanoparticles and the free drug was compared by determining the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) against several bacterial strains. In a liquid growth medium, two-fold serial dilutions of the free drug and drug-loaded nanoparticle dispersions were prepared over drug concentration ranges of 0.015–15.4 and 0.146–150 g/mL, for the sensitive and resistant strains, respectively.15 Wells were inoculated with diluted broth culture to provide initial concentration of 105 CFU/mL and incubated at 37 C for 18 h. Then, wells were examined for the minimal concentration of the drug (MIC) that inhibits the bacterial growth (i.e. no visible growth of bacteria).13 Bacteria suspended in broth were utilized as the positive controls for bacterial growth. Each assay was repeated three times. Based on the results from the MIC experiments, bacterial growth inhibitions were also evaluated by measuring the optical densities (OD) at 600 nm for the bacterial cultures that have the lowest concentration of the drug-loaded nanoparticles and showed no visible growth, and the same concentration of the free drug that either partially or completely inhibited the bacterial growth, using Q5000 micro-volume UV–visible spectrophotometer. The percentages of growth inhibitions (% GI) were estimated using the following equation:

 

                                       OD untreated well – OD treated well

% Growth inhibitin  = ––––––––––––––––––––––––––––––––– × 100

                                                     OD untreated well

 

The MBC was determined by sub-culturing 5 L from wells that showed no visible bacterial growth on a Mueller–Hinton agar medium. After incubation for 18 h at 37 C, plates were examined for the lowest concentration of the drug that killed 99.9% of the bacterial cells (i.e. MBC).11-13

 

Current Therapeutic Status of Meropenem:

Meropenem is likely to be most useful in treatment of serious (including nosocomial) bacterial infections in intensive care settings and neonatal units. The utility is likely to be greatest in resistant and difficult-to-treat gram negative infections. Its CSF penetrability and lack of neurotoxicity makes it suitable for childhood meningitis. It can also be used as a monotherapy for treatment of infections in febrile neutropenic patients. As Meropenem is not effective against methicillin resistant staphylococci (including MRSA) and enterococcus, it should not be depended upon for treating suspected staphylococcal infections after failure of conventional anti-staphylococcal agents. However, the drug should only be used as a reserve agent when the conventional therapy fails or when resistance to other antibiotics has been documented. This strategy is important to prevent the emergence of resistant strains against this useful antibiotic. Resistance to the tune of 12% has already been documented in Pseudomonas aeruginosa strains isolated from hospitalized patients. Also, the high cost of the drug currently restricts its use to selected situations.10-13

 

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7.      Indian Pharmacopoeia, Ministry of health and family welfare, The Indian pharmacopoeia Commission, Ghaziabad, volume III 2018, page no. 2533-2536

8.      L Moellering RC Jr, Eliopoulos GM, Sentochnik DE. “The carbapenems: new broad spectrum β -lactam antibiotics.” J Antimicrob Chemother 1989; 24(suppl A):1 -7.

9.      Neu, H. C. and Labthavikul, P. Comparative in vitro activity of N-formimidoyl thienamycin agent Gram-Positive and Gram-Negative aerobic and anaerobic species and its β-lactamase stability. Antimicrob. Agents Chemother. 21, 180–187 (1982).

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11.    Patel JB, Giles RE. Meropenem: evidence of lack of proconvulsive tendency in mice. J Antimicrob Chemother 1989; 24(suppl A): 307 -9.

12.    Sanders CC, et al 3-lactam antibiotics. In: Gorbach SL, Bartlett JG, Blacklow NR, eds. Infectious diseases. Philadelphia: WB Saunders, 1992: 182-8.

13.    Sunagawa M, et al. SM-7338, a new carbapenem antibiotic: structure-activity relations and physicochemical properties [abstract no. 752]. In: Program and abstracts of the 27th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1987: 228

 

 

 

Received on 31.03.2020           Modified on 26.07.2020

Accepted on 23.09.2020         © RJPT All right reserved

Research J. Pharm. and Tech. 2021; 14(9):5034-5038.

DOI: 10.52711/0974-360X.2021.00878