Development and Clinical Evaluation of Novel Metallo-Β-Lactamase Inhibitors
R. S. Tomar1*, Dr. Prashant Kumar Sharma2
1 Research Scholar, Department of Chemistry, Mewar University, Chittorgarh, Rajasthan, India
Email: rustamsinghtomar7@gmail.com
2 Supervisor, Department of Chemistry, Mewar University, Chittorgarh, Rajasthan, India
Email: prashantsharma.chem@gmail.com
Abstract - Resistant to carbapenems the very restricted treatment options for Enterobacteriaceae make them one of the most dreaded groups of infections. Three new blactamase inhibitors have been discovered to combat this danger and keep our present antimicrobial treatments going strong. Currently, clinical studies are showing promising results for the azole antibiotics the inhibitor medications avibactam, vaborbactam, and relebactam have a high affinity for Ambler class A and C blactamases. While these medicines have some fundamental commonalities, they also have some distinct distinctions that might have significant therapeutic ramifications. We take a look at the pharmacokinetics, microbiologic spectra, and important clinical studies for these new drugs. We take a look at a possible therapeutic function and some new possible combinations.
Keywords: novel b-lactamase, avibactam, carbapenemases, clinical studies
INTRODUCTION
Modern antibacterial chemotherapy relies on antibiotics, especially those belonging to the β-lactam family. The use of β-lactam medicines is prevalent in a significant number of recent hospital prescriptions. Penicillins, cephalosporins, carbapenems, and monobactams are the four primary chemical classes represented by compounds that include β-lactam. γ-lactamases have been categorized using Ambler's molecular structure categorization and Bush and Jacoby functional classifcation. Zinc is used by class B β-lactamases, whereas serine is used by classes A, C, and D β-lactamases. But β-lactamases are divided into classes 1 through 3 based on Bush and Jacoby's functional categorization according to their β-lactam substrate breaking down abilities and the effects of inhibitors on these abilities.
Emerging multi-drug resistant bacteria pose a significant challenge to healthcare systems worldwide, particularly when they cause illnesses that patients get while hospitalized. β-lactam resistance is seen as a global issue in public health [5]. Aside from making treatment difficult, outbreaks of carbapenem-and extended-spectrum β-lactam-resistant bacteria significantly impact the prognosis of ill persons.
Examples of Class A enzymes include β-lactamases encoded on chromosomes or on plasmids, which exhibit wide spectra extended spectra and carbapenemase activity. Penicillins, cephalosporins, and carbapenems may be hydrolyzed by Class B enzymes, also known as metallo-β-lactamases (MBLs), as stated by Kumarasamy et al. (2010). Some examples of cephalosporinases encoded on the chromosome include the inducible Pseudomonas aeruginosaAmpC gene and the P99 β-lactamase found in Enterobacter spp., whereas CMY-2 is an example of a plasmid-mediated variant which was first discovered in Escherichia coli. The oxacillin substrate is preferred by Class D enzymes, which are known as such as oxacillinases (OXA-1). Recent studies have shown that a fast-growing category of β-lactamases known as Class D enzymes has the potential to hydrolyze several medicines, including carbapenems and extended-spectrum cephalosporins. Pseudomonas aeruginosa, Acinetobacter baumannii, and, to a lesser degree, Escherichia coli and Klebsiella pneumoniae are among the prevalent non-fermenting bacteria that possess the class D enzyme.
Due to its continued use as a first-line treatment Gram-negative bacteria, in particular, pose a significant threat due to their resistance to carbapenem, which is a medicine that many MDR bacteria utilize to treat their infections. In the family Enterobacteriaceae, the most prevalent vectors of enzymatic carbapenem resistance are carbapenemases that belong to the Klebsiella pneumoniae carbapenemase (KPC) family. Carbapenemases like VIM, oxacillinase-48-like (OXA-48), SARS-CoV, and others and New Delhi metallo-b-lactamases (NDM) are also significant. There is a great deal of geographical variation in the worldwide distribution of carbapenemases. nations in South America, Greece, Italy, and the United States seem to have more KPC-producing Enterobacteriaceae, while the Indian subcontinent and other European nations, such Romania, Denmark, Spain, and Hungary, tend to have more MBL. Turkey and the countries bordering it have the highest concentration of OXA-48. This global epidemiology highlights the incidence of the disease and the possibility of regional spread as a result of growing medical tourism, increased use of critical care units, and global interconnectedness.
Three new inhibitors will be covered in this review. These three new compounds—avibactam, relebactam, and vaborbactam—were formerly known as AVE1330A, NXL104, and MK7655, respectively. Referring to the chemical structures in Figure 1, each has distinct pharmacokinetic and pharmacodynamic characteristics. Unlike avibactam, which is marketed in the US in a combination with ceftazidime and has been authorized by the EMA (June 2016), none of the other agents are commercially accessible at this time. The capacity to block certain beta-lactamases with expanded spectrum and carbapenemases include most noticeable advantage of these newer drugs over tazobactam, clavulanate, and sulbactam, which are older-generation b-lactamase inhibitors.
Figure 1 Chemical structures of avibactam, vaborbactam
LITERATURE REVIEW
Essack, S.Y. (2021), Because of their specificity, great effectiveness, and the availability of many derivatives, β-Lactam antibiotics are the most popular class of antimicrobials. This class includes drugs like penicillin and its variants, cephalosporins, cephamycins, carbapenems, monobactams, and monocarbams. Bacteria may develop resistance to these antibiotics in the most prevalent and clinically important method via the expression of β-lactamases, which are enzymes that reduce the efficacy of β-lactam antibiotics. Developing β-lactam antibiotics has been a continuous challenge create novel molecules that can resist inactivation by the diverse array of β-lactamases. The essay follows the evolution of β-lactamases as it tracks the development of antibiotics.
Bacteria may circumvent the effects of almost all currently available β-lactam antibiotics due to the ability of carbapenemases and other β-lactamases (BLs) to hydrolyze them, as stated by Spyrakis, F., Santucci, M., Maso, L. et al. (2020). Among the most well-known and extensively studied bacterial resistance mechanisms, BL generation stands out. All BLs, the results show, tend to cluster around electron pair donors on scaffolds: Specifically, sulfonamide and tetrazole-based derivatives inhibit KPC-2, compounds having a group consisting of thiol, thiosemicarbazide, or thiosemicarbazone inhibit NDM-1, and molecules containing triazole inhibit VIM-2. Compound 40 is one of the few discovered broad-spectrum BLs inhibitors; The two compounds that showed the greatest promise in binding NDM-1 and VIM-2 were identified via the use of high-resolution binary complexes. This work provides important information for improving molecular docking simulations, especially when it comes to the interaction between MBLs and inhibitors.
Shungube et al. (2023) found that β-lactamases may hydrolyze β-lactam antibiotics, rendering them useless, according to their study. The two forms of β-lactamases that have been discovered are methoxy β-lactamases (MBLs) and serine β-lactamases (SBLs). There are currently two approaches to address β-lactamase-induced resistance. The first is to develop novel β-lactam antibiotics that can withstand hydrolysis by these enzymes; and second, by creating inhibitors that deactivate the enzyme, so that the co-administered antibiotics can work again. When it comes to treating infections that are resistant to antibiotics, many people turn to SBL inhibitors that are already on the market. However, very few MBL inhibitors are currently being tested in clinical studies. The results of this research have shown a new class of β-lactam MBLIs that show promise as therapeutic MBLIs due to their potency, effectiveness, and lack of side effects.
Nahar, (2024), The most potent kind of carbapenemase, known as the NDMs, or New Delhi metallo-beta-lactamases, can hydrolyze all beta-lactam medicines and frequently cause the microbe to become resistant to more than one treatment. With the hope of paving the way for future treatments for hard-to-treat infections, this study aims to synthesise the present scientific evidence on NDM inhibitors. End result: Our database search turned up 1,760 publications; however, only 91 of them fulfilled we used to determine who could participate in the research. Of the 47 substances included in the 37 publications, 8 of which had previously been authorized employing the checkerboard test to determine their fractional inhibitory concentration index, were reviewed by the US Food and Drug Administration (FDA). Infections in humans did not seem to have been the target of any of them. In conclusion, several possible NDM inhibitors have been discovered via ongoing research; however, no such medications are yet available for clinical use. The only way to tackle this is to expand our own perspectives and work together across disciplines and in complex ways.
A group of researchers including Lee, J. H., Jang, K. M., Shin, K., Jin, H., and Kim, D. W. have published a paper. In 2024, Lee (S. H.) Making novel metallo-β-lactamase inhibitors (MBLIs) is compelled by the pressing need for efficient defenses against metallo-β-lactamases (MBLs). Important chemical moieties in existing MBLIs are the focus of this research, and key MBLs should be the endpoint of any MBLI assessments. The abundance profile and taxonomic distribution of MBLs and their variant types were obtained from the NCBI RefSeq genome database. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) technique was utilized to perform the systematic literature analysis. We provided crucial information for rational medication design by elucidating essential chemical moieties of MBLIs using two separate systematic techniques. Our focus on MBLs and their variants is a call to action for thorough testing of the newly created MBLIs to guarantee their effectiveness and potency. The area of antibacterial drug development may benefit greatly from the data provided by this method.
Microbiologic Spectrum of Avibactam
The ability of avibactam to inhibit a wide range of This b-lactamase inhibitor has the advantage over its predecessors in that it can inhibit a broad range of b-lactamases, including ESBL, AmpC, and carbapenemases from Classes A and D, such KPC and OXA-48. A ceftazidime-avibactam MIC was found in eleven out of twenty thousand clinical US Enterobacteriaceae isolates of eight ligands per milliliter in an extensive in vitro investigation. Of the eleven resistant strains, two showed evidence of an MBL, making them inherently resistant to the inhibitory effects of avibactam. This exemplifies avibactam's main drawback: it has no effect on class B MBLs. Avibactam restored ceftazidime's activity against bacterial strains possessing the OXA-48 enzyme, according to Livermore et al.
The results of these investigations demonstrated the presence of avibactam resistance mechanisms other than MBL. Different variants of SHV-1 and KPC-2, both resulting from a single mutation, provided resistance to avibactam. In experimental testing, the MIC for was significantly increased when ceftaroline and avibactam were administered together three Enterobacter cloacae isolates that had their AmpC gene suppressed. Out of the three isolates, one exhibited a combined OmpC and OmpF deficit, whereas the other two had AmpC point mutations. Our results are consistent with the hypothesis that resistance to ceftazidime-avibactam is due to an overabundance of AmpC and a combination of impermeability and inhibitor capacity. Note that certain clinical isolates have shown resistance to avibactam after ceftazidime-avibactam therapy. The resultant KPC3 enzyme was shown to be ineffective against avibactam due to a number of blaKPC-3 mutations. It is concerning that these altered genes were discovered to be transmitted via plasmids. Isolates sensitive to carbapenems resulted from several of these alterations, which reduced KPC-3's carbapenemase activity.
Beyond its function in multidrug-resistant Enterobacteriaceae, A combination of ceftazidime and avibactam may kill drug-resistant strains of Pseudomonas aeruginosa. Even Pseudomonas aeruginosa strains resistant to ceftazidime were shown to be very susceptible to ceftazidime-avibactam, according to 4-year research conducted in the United States [...]. However, ceftazidime's efficacy against Acinetobacter baumannii is unaffected by the addition of avibactam.
Table 1 Evasion of different b-lactamase classes by avibactam, vaborbactam, and relebactam
There is no credible evidence that ceftazidime-avibactam has anaerobic action, Bacteroides fragilis, Clostridium perfringens, Prevotella, and Porphyromonas species were all shown to be more effectively treated by the combination. Additionally, there is a lack of anti-staphylococcal and anti-streptococcal action.
Pharmacokinetics/Pharmacodynamics of Avibactam
There was no significant change in the pharmacokinetics of either drug when given together in two groups of eight participants given 1000/250 and 2000/500 mg dosages of ceftazidime-avibactam, respectively, compared to those given alone [8]. To determine the efficacy and safety of a 4:1 ratio of ceftazidime and avibactam, Merdjan et al. performed preliminary Phase 1 trials. Based on the results of these investigations, avibactam exposure increased as the degree of renal impairment increased, and there was a consistent relationship between avibactam plasma concentrations and renal function [17]. For dosages between 50 and 2000 mg, avibactam showed linear pharmacokinetics, according to further Phase 1 data in healthy participants. With a half-life of just 1.7–2.1 hours, rapid dispersion, and predominantly (95%) renal clearance at a rate depending on creatinine clearance characterize avibactam after infusion [8]. Dialysis eliminated 54% of avibactam in six anuric individuals receiving renal replacement treatment [8]. Therefore, avibactam seems to have pharmacokinetics and clearance that are comparable to ceftazidime, its partner drug, according to the early findings.
Based on the findings of Phase 1, the recommended dosage for individuals with normal renal function is 2000 mg/500 mg ceftazidime-avibactam, administered every 8 hours. Patients whose creatinine clearances fall within the 31–50 mL/min range should take 1.25 g every 8 hours. For CrCLs in the 16–30 mL/min range, 0.94 g every 12 hours is recommended. For CrCLs in the 6–15 mL/min range, 0.94 g every 24 hours is recommended. And for CrCLs below 5 mL/min, 0.94 g every 48 hours is recommended. Patients undergoing hemodialysis should take ceftazidime and avibactam following their treatments, since they are both hemodialyzable, according to the product information. In a Phase 1 trial conducted on healthy people, it was discovered that both ceftazidime and avibactam penetrated the lung's epithelial lining fluid (ELF) at a dose-proportional rate, with equal exposure of the ELF to the two medications. ***A third of plasma exposure
Avibactam: Clinical Studies
Tabulated below are the key points from the clinical trials. To determine if ceftazidime-avibactam would be effective, two Phase 2 studies were conducted. For the first, researchers For the treatment of cUTI, Vazquez et al. randomly assigned 137 patients to either imipenem or ceftazidime-avibactam. In comparison, 24 out of 35 (71.4%) in the imipenem group and 19 out of 27 (70.4%) in the ceftazidime-avibactam group had a microbiologic response [19]. The renal dosage adjustment procedure employed was noticeably different from the one on the current FDA label. Compared to the current package insert advice (2 g/500 mg ceftazidime-avibactam every 8 hours), this trial looked at a dose of 500 mg ceftazidime and 125 mg avibactam every 8 hours, which is four times lower. In their second Phase 2 study, Lucasti et al. evaluated meropenem in comparison to ceftazidime/avibactam with metronidazole for the treatment of cIAI. Of the patients, 91.2% (62/68) had a positive reaction and 93.4% (71/76) had a negative one.
All of the clinical data is based on two important Phase 3 studies. When it came to treating cUTIs, the RECAPTURE trial compared doripenem with ceftazidime-avibactam. One hundred and twenty-one Doripenem or ceftazidime-avibactam was given to patients at random [21]. With the purpose to treat, 393 patients in the ceftazidime-avibactam group and 417 patients in the doripenem group underwent microbiologic changes. The co-primary objectives of symptomatic resolution and microbiological eradication were achieved at the test of cure, as were the patient-reported symptomatic resolution goals on day 5, with 276 out of 393 (70.2%) and 276 out of 417 (66.2%) patients, respectively, reaching non-inferiority. At the conclusion of therapy, the microbiologic response was 95.2 and 94.7 percent in the ceftazidime-avibactam group, respectively, which was comparable in the doripenem class. When looking at the susceptibility of pathogens at baseline, ceftazidime-avibactam was effective against 311/400 (77.8% of the organisms) and doripenem against 297/419 (70.9%) of the organisms. Notably, among the patients who had non-ceftazidime-susceptible bacterial isolates, microbiological cure was achieved in 47 out of 75 (62.7%) patients treated with ceftazidime-avibactam and 51 out of 84 (60.7%) patients treated with doripenem [21]. Nobody was included in the study unless they were on dialysis or had a creatinine clearance lower than 30 mL/min included in this research since renal impairment was not shown to impact clinical outcome.
Mazuski et al. conducted a Phase 3 randomized double-blind experiment to compare the efficiency of ceftazidime-avibactam with metronidazole in treating cIAI to that of meropenem. We continued to exclude individuals whose creatinine clearance was less than 30 mL/min. Another drawback is that appendicitis was the main diagnosis for most of the patients in the study. Bacteremia was rare in the B10 group (4.2% vs. 2.7% in the ceftazidime-avibactam and metronidazole group) and not all patients were severely sick; for instance, more than 80% of patients had an APACHE II score. Research found that patients with ceftazidime-resistant Gram-negative infections had a clinical cure rate of 83.0% (39/47) and 85.9% (55/64) when treated with ceftazidime-avibactam with metronidazole, respectively. In comparison to the meropenem and ceftazidime-avibactam groups, the mortality rates were 2.5% (13/520) and 1.5% (8/523) respectively. In this experiment, meropenem was shown to be superior to ceftazidime-avibactam with metronidazole. According to the subgroup analysis, the cure rates for patients with moderate renal impairment who took ceftazidime/avibactam + metronidazole were 45%, which was lower than the 74% rate for patients who took meropenem. Patients suffering from this condition had an estimated creatinine clearance of 30–50 mL/min. One possible explanation is that patients' doses were not adjusted to full dosage until they regained renal function. Specifically, those who have mild Administering 1000/250 mg ceftazidime/avibactam every 12 hours was the protocol for patients with renal failure in the Phase 3 cIAI studies. Product insert instructions as of late suggest that 1000/250 mg ceftazidime/avibactam should be used every 8 hours by those with mild renal insufficiency.
Table 2 Research on ceftazidime-avibactam in clinical settings
A randomized, open-label experiment called REPRISE when it came to treating patients with catheter-associated infections, comparing ceftazidime-avibactam to BAT. (cUAIs) or catheter-transmitted infections (cUTIs) caused by Pseudomonas aeruginosa or Enterobacteriaceae that are resistant to ceftazidime. Noteworthy, the authors justified their lack of formal power estimates and statistical comparisons between treatment groups by stating that enrolling significant quantities of individuals infected with Gram-negative bacteria that are resistant was not feasible. Instead, best-available treatment was used to generate descriptive estimates of ceftazidime-avibactam efficacy, which were based on matching confidence intervals for the effectiveness. Out of the 154 patients treated with ceftazidime-avibactam, 144 developed cUTI; the objective of this method was to compare these two groups. 148 patients were treated with BAT. In terms of numbers, the ceftazidime-avibactam group had slightly better microbiologic responses and comparable clinical responses.
The findings of a research that compares medicine that reduces the risk of infection HABP and VABP (also known as ventilator-associated bacterial pneumonia) should be available soon. The study was just completed (clinicaltrials.gov identifier NCT01808092).
Reports of ceftazidime-avibactam's post-marketing clinical experience are beginning to trickle in from observational studies. Patients infected with Registrational studies sometimes exclude the target species, such as carbapenemase-producing Enterobacteriaceae, therefore these data are crucial. Presented at IDweek 2016 was a case study of sixty individuals treated with ceftazidime-avibactam for CRE infections. Overall, 36% of patients in this cohort died in the hospital from any reason, 66% achieved clinical success according to the researchers' criteria, and 51% achieved a microbiologic cure. For the purpose of treating CRE infection, Shields et al. recorded 37 patients in a single-center observational study using ceftazidime-avibactam. Pneumonia was the most prevalent infectious syndrome among the patients (12/37), but other notable instances included infections of the abdomen, ventriculitis, mediastinitis, and subdural empyema (two each), as well as infections of soft tissues and primary bacteremia. While none of the isolates showed signs of VIM, IMP, NDM, or OXA-48 carbapenemase expression, a whopping 78% (29/37) did. Clinical success was at 59% (22/37), while thirty-day survival was at 76% (28/37). Ten patients had microbiologic failures as a result of infection recurrence; three of these patients' isolates showed resistance to ceftazidime-avibactam. Taken together, these results show that ceftazidime-avibactam is a reasonable alternative that has a similar clinical response to other treatments. But it does bring up the worrying possibility of resistance developing after treatment. How well ceftazidime-avibactam works in treating invasive infections caused by Enterobacteriaceae that produce carbapenemase compared to other drugs has to be studied more firmly via randomized controlled studies.
Adverse Effects of Avibactam
A variety of doses of avibactam were well-tolerated in the first phase of the drug's development. In general, avibactam has been associated with minimal documented side effects. Even when administered supratherapeutic dosages three thousand milligrams of ceftazidime and two thousand milligrams of avibactam each, the combination was generally well-tolerated; nevertheless, 30% of volunteers did report side effects, the most common of which were nausea, vomiting, and headache. The adverse event rate in Phase 3 studies was low and comparable to comparator drugs. The most frequent adverse events were headaches, nausea, and diarrhea, and the treatment was seldom discontinued due to these side effects.
Vaborbactam: Clinical Studies
Table 3 provides a summary of the clinical trials. Griffith et al. found that 36 healthy volunteers tolerated 250–1500 mg of vaborbactam well in phase 1 clinical trials that used 3-hour infusions. In 2014, two significant Phase 3 studies were launched to assess the therapeutic effectiveness of meropenem-vaborbactam. At the beginning of 2016, enrollment in the TANGO-1 trial was the first to be completed. For individuals suffering from cUTIs, the TANGO-1 research compared comparing piperacillin-tazobactam's effectiveness to that of meropenem-vaborbactam in a 1:1 randomized, double-blind fashion. When microbiologic eradication was achieved and subsequent urine culture reductions were fewer than 104 CFU/mL, A cure or improvement in symptoms was considered a clinical success. Treatment with piperacillin-tazobactam was successful in 171 out of 182 patients (94.0%), whereas treatment with meropenem-vaborbactam was successful in 188 out of 192 patients (98.4%).
Table 3 Research on meropenem-vaborbactam in clinical settings
This experimental medication research is assessing combined meropenem and vaborbactam to treat infections caused by a kind of bacteria that is known to be resistant to carbapenems. It is 60 sites strong and is now underway (ClinicalTrials.gov Identifier: NCT02168946). Comparing BAT to other possible infectious disorders, such as cUTI, HABP/VABP, cIAI, and bacteremia, is important. Additional plans include TANGO-3 (NCT03006679, ClinicalTrials.gov Identifier). In patients with HABP/VABP, it will compare piperacillin-tazobactam with meropenem-vaborbactam. The meropenem-vaborbactam Phase 1 research has already started recruiting patients (ClinicalTrials.gov Identifier: NCT02687906) to determine the drug's efficacy, safety, and tolerability in children.
Adverse Effects of Vaborbactam
Few statistics on medication tolerance have been released for vaborbactam because it is still in clinical trials. But early results indicate it should be well-tolerated. Results from the TANGO-1 study indicated that 15.1% of patients 12.8% in the group treated with piperacillin-tazobactam and 12.2% with vaborbactam had treatment-emergent side events. Vaborbactam had a non-significant incidence of 2.6% and piperacillin-tazobactam of 5.1% for study medication withdrawal due to adverse impact.
While studying the pharmacokinetics of meropenem-vaborbactam in a group of 26 healthy people, Wenzler et al. found that one participant had to stop taking the treatment because of adverse effects such as chest pain, vertigo, and dyspnea. Without observable side effects on laboratory tests, vital signs, electrocardiograms, or physical examinations, the remaining 25 patients were able to tolerate the study medication at dosages ranging from 2 grams to 2 grams.
CONCLUSIONS
In terms of shared characteristics and little clinical experience, the two drugs are very similar. Comparators have shown similar clinical results to a small number of studies. A lack of randomized data from patients infected with carbapenem-resistant bacteria is a limitation, too. It has already been shown with avibactam that increased rates of resistance development will accompany future, more extensive usage. Therefore, it is up to the therapeutic community to establish the best contexts for using these novel drugs and to promote prudent usage. If we want to make the most of these treatment choices for as long as possible, we need to put more effort into integrating antimicrobial stewardship, infection control, and medication.
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