Carbapenem Derivatives Research Articles

Impact of antibiotic stewardship program on usage of higher range of antibiotics in patients of intensive care units in a tertiary care hospital, India

Background: The aim of the study was to monitor the changes in antimicrobial use after implementation of Antibiotic Stewardship Programmed (ASP) and pattern of use of antimicrobials in the respective ICU’s.Methods: The study was conducted in three ICU’s Adult ICU(AICU), Paediatric ICU (PICU), Neonatal ICU (NICU) -Six bedded each) over a period of six months from September 2018 to February 2019 in a tertiary care hospital. Antibiotics monitored over total 155 patients and antibiotics selected for the study are β-lactam inhibitors, Carbapenem derivatives and ColistinResults: Out of total 155 patients 51% were males and the definitive therapy (Implementation of antibiotics according to the antibiotic policy of the hospital) in the respective ICU’s showed increase from 66.7% to 83.3% after implementation of ASP activity in that particular duration. Antibiotic consumption showed fluctuation in the whole duration of the study (p value <0.05).Conclusions: Analysis of the study shows a positive impact on implementation of ASP programme in intensive care units, brought an effective increase in appropriate use of antimicrobials.

Development of carbapenem-based fluorogenic probes for the clinical screening of carbapenemase-producing bacteria.

This report describes the synthesis of a library of fluorogenic carbapenemase substrates consisting of carbapenem derivatives, fluorescence dyes, and active cleavable linkers and their evaluation for specifically detecting carbapenemase-producing organisms (CPOs). We synthesized a series of compounds having three different types of linkers such as benzyl ether, carbamate, and amine using hydroxymethyl carbapenem 7a and hydroxyallyl carbapenem 7b as key intermediates. Probe 1b exhibited high stability and a prompt turn-on fluorescence signal upon hydrolysis by carbapenemases. In particular, the screening of clinical samples indicated that the probe 1b exhibited excellent selectivity to the CPOs over other β-lactamases or non-carbapenemase producing bacteria, which may be of clinical use for the rapid and accurate detection of CPOs for timely diagnosis and treatment.

Metabolic engineering of a carbapenem antibiotic synthesis pathway in Escherichia coli.

Carbapenems, a family of β-lactam antibiotics, are among the most powerful bactericidal compounds in clinical use. However, as rational engineering of native carbapenem-producing microbes is not currently possible, the present carbapenem supply relies upon total chemical synthesis of artificial carbapenem derivatives. To enable access to the full diversity of natural carbapenems, we have engineered production of a simple carbapenem antibiotic within Escherichia coli. By increasing concentrations of precursor metabolites and identifying a reducing cofactor of a bottleneck enzyme, we improved productivity by 60-fold over the minimal pathway and surpassed reported titers obtained from carbapenem-producing Streptomyces species. We stabilized E. coli metabolism against antibacterial effects of the carbapenem product by artificially inhibiting membrane synthesis, which further increased antibiotic productivity. As all known naturally occurring carbapenems are derived from a common intermediate, our engineered strain provides a platform for biosynthesis of tailored carbapenem derivatives in a genetically tractable and fast-growing species.

Virtual high throughput screening of carbapenem derivatives as new generation carbapenemase and penicillin binding protein inhibitors: a hunt to save drug of last resort.

The advent of carbapenem resistance by the production of β-lectamases and mutated penicillin binding proteins (PBPs) has challenged the treatment of Enterobacteriaceae. Hence there is an urgent need to establish drugs that can fit in the pipeline by overcoming those situations. The working hypothesis of the work is based on two facts, i.e., i) design of inhibitors against mutated PBPs to which present drugs cannot bind efficiently to kill pathogen by inhibiting cell wall formation, ii) design of molecules that can bind with β-lectamases with high affinity, so that they can supplement available drugs preventing their unwanted hydrolysis. In this work, over thousands of thienamycin (first natural carbapenem) derivatives were generated and out of which non-toxic 273 molecules were used for further study. Out of which, only few followed the first hypothesis and rest obeyed the second. Ligand L5 strictly followed the first hypothesis and L1-L4 followed to a satisfactory level. Molecular dynamic simulation was performed to check post-docking stability of the pharmacophores.

ChemInform Abstract: L‐Proline Organocatalyzed Michael Synthesis of Monobactam and Carbapenem β‐Lactam Cores.

Abstract Herein, we report the development of mild, organocatalyzed routes to novel β-lactam carbapenem derivatives through Michael type C C bond forming reactions. The same methodology, followed by a retro-Dieckmann reaction, provides a pathway to novel and highly functionalized monobactam derivatives, another class of valuable β-lactam antibiotics.

L-Proline organocatalyzed Michael synthesis of monobactam and carbapenem β-lactam cores

Herein, we report the development of mild, organocatalyzed routes to novel β-lactam carbapenem derivatives through Michael type CC bond forming reactions. The same methodology, followed by a retro-Dieckmann reaction, provides a pathway to novel and highly functionalized monobactam derivatives, another class of valuable β-lactam antibiotics.

ChemInform Abstract: Synthesis of 6-(Substituted Methylene) Carbapenem Derivatives from 6- Aminopenicillanic Acid.

The key intermediate in the preparation of novel 6-(substituted methylene) carbapenem derivatives is p-methoxybenzyl (5R,6R)-6-bromo-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate 26, which was prepared in several steps from 6-aminopenicillanic acid 14via(3R,4R)-4-allyl-3-bromoazetidin-2-one 21. Sequential treatment of the aforementioned ester 26 with either lithium diisopropylamide or lithium diphenylamide, 1-methyl-lH-1,2,3-triazole-4-carbaldehyde and acetic anhydride provided a diastereoisomeric mixture of acylated bromohydrins 28; reductive elimination then afforded the isomeric (E)- and (Z)-6-triazolylmethylene carbapenem esters 29 and 31, respectively. Lewis acid-mediated deprotection of the 6-bromo and 6-[(E)-triazolylmethylene] esters 26 and 29 gave the sodium salts of (5R,6R)-6-bromo-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 27 and (5R)-6-[(E)-(1methyl-1H-1,2,3-triazol-4-yl)methylene]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 30, respectively.In addition, condensation of the anion, generated by deprotonation of the 6-bromo ester, with acetaldehyde, followed by acylation and reductive elimination furnished the isomeric (E)- and (Z)-ethylidene carbapenem esters.Whilst the (E)-6-triazolylmethylene carbapenem displayed low levels of antibacterial activity, it possessed no β-lactamase-inhibitory activity whatsoever. The 6-bromocarbapenem was devoid of both antibacterial and β-lactamase-inhibitory activity.

Three-dimensional vector of pharmacophore atomic interaction and its applications to stereoisomeric description

A novel 3D-molecular structure characterization method, three-dimensional vector of pharmacophore atomic interaction (3D-Vpai), saving 3D-structural information of compounds by the factor of stereo-sensitive angle ( FSSA) was defined to identify stereoisomers. The predictions of 31 steroids benchmarks and 79 carbapenem derivatives using multiple linear regression analysis were carried out. The statistically significant QSAR models were obtained (steroids benchmarks: N = 25, R 2 = 0.894,; R cv 2 = 0.785; carbapenem derivatives: n = 64 , R 2 = 0.821, R cv 2 = 0.765). Finally, classification of 32 stereoisomers of perindoprilate as angiotensin-converting enzyme inhibitor using linear discriminant analysis (LDA) was carried out. All LDA models classified correctly 100% for active and inactive compounds. Our results showed 3D-Vpai models remarkably superior to others, and it provides a powerful alternative to other more common 3D-QSAR descriptors.

Relation between the Antimicrobial Susceptibility of Clinical Isolates of Pseudomonas aeruginosa from Respiratory Specimens and Antimicrobial Use Density (AUD) from 2005 through 2008

To examine the relation between annual trends in the antimicrobial susceptibility of Pseudomonas aeruginosa and drug usage, we compared annual changes in the susceptibility rates of P. aeruginosa clinical isolates during a 4-year period and annual trends in the overall usage of antimicrobials during the same period. We studied annual trends in MIC(90)/MIC(50), antimicrobial use density (AUD), and antimicrobial susceptibility rates based on clinical breakpoints for 150 strains of P. aeruginosa isolated from respiratory specimens at Dokkyo Medical University Hospital from 2005 through 2008. The MIC(90)/MIC(50) of antimicrobials effective against P. aeruginosa in years 2005, 2006, 2007, and 2008 were as follows: imipenem, 32/2, 32/1, 8/2, and 16/1 microg/mL; meropenem, 8/1, 8/1, 4/0.5, and 4/0.5 microg/mL; and biapenem, 16/1, 32/0.5, 4/0.5, and 8/0.5 microg/mL, indicating that susceptibility to carbapenems increased slightly. The MIC(90)/MIC(50) was 4/0.25, 2/0.125, 1/0.125, and 2/0.25 microg/mL for ciprofloxacin, 8/4, 8/4, 4/4, and 8/4 microg/mL for amikacin, 64/16, 64/16, 64/16, and 64/16 microg/mL for sulbactam/cefoperazone, 8/2, 16/2, 32/2, and 8/2 microg/mL for ceftazidime, indicating little change. The AUDs of fourth-generation cephalosporins increased from 2005 to 2008 (16.2, 18.4, 28.0, and 23.0), while the AUDs of carbapenems decreased (25.7, 23.7, 10.9, and 12.5). The decrease in the AUDs of carbapenems was associated with increased susceptibility rates of P. aeruginosa to carbapenem derivatives. A continuous understanding of trends in the resistance of P. aeruginosa and various other pathogens is essential for designing countermeasures against nosocomial infections, including the proper and effective use of antimicrobials.

Antibacterial Activities of Carbapenem Derivatives and Quantitative Structure–Activity Relationship for Drug Design

Abstractβ‐Lactams, a class of antibiotics including penicillins, cephems, monobactams, and carbapenems, is widely used. In this work, the Quantitative Structure–Activity Relationship (QSAR) models have been built by Partial Least Squares (PLS), Artificial Neural Network (ANN), and Genetic Algorithm optimized ANN (GA‐ANN) to study the antibacterial activities of carbapenem derivatives. Of the three methods, GA‐ANN is potentially useful in predicting QSAR properties of chemical agents. Furthermore, some novel penem derivatives are designed using classical bioisosterism strategy, and the antibacterial activities are predicted by the built GA‐ANN model without any chemical or biological experiments. In conclusion, the niapenems and thiapenems show good antibiotic activities.

Synthesis and Antibacterial Activity of 1β‐Methyl‐2‐[5‐(α,β‐disubstituted ethyl)pyrrolidin‐3‐ylthio]carbapenem Derivatives. Part 2.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Synthesis and Antibacterial Activity of 1β‐Methyl‐2‐[5‐(1,2‐disubstituted ethyl)pyrrolidin‐3‐ylthio]carbapenem Derivatives. Part 3.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Synthesis and Antibacterial Activity of 1β-Methyl-2-[5-(α,β-disubstituted ethyl)pyrrolidin-3-ylthio]carbapenem Derivatives. Part II

The synthesis of a new series of 1<TEX>$\beta$</TEX>-methylcarbapenems having 5-(<TEX>$\alpha,\beta$</TEX>-disubstituted ethyl)pyrrolidine moiety is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituents on the pyrrolidine ring was investigated. A particular compound (VIh) having <TEX>$\alpha$</TEX>-hydroxy-<TEX>$\beta$</TEX>-piperazinylethyl substituted moiety showed the most potent activity.

Synthesis and Antibacterial Activity of 1β-Methyl-2-[5-(1,2-disubstituted ethyl)-pyrrolidin-3-ylthio]carbapenem Derivatives. Part III

The synthesis of a new series of 1 <TEX>$\beta$</TEX>-methylcarbapenems having 5-(1,2-disubstituted ethyl)pyrrolidine moiety are described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituents on the pyrrolidine ring was investigated. Among them, compound (IIIc) having 1-methoxyimino-2-hydroxyethyl moiety showed the most potent antibacterial activity.

Synthesis and Antibacterial Activity of 1β‐Methyl‐2‐[5‐(1,2‐Disubstituted Ethyl)Pyrrolidin‐3‐ylthio]Carbapenem Derivatives

The synthesis of a new series of 1beta-methylcarbapenems having a 5-(1,2-disubstituted ethyl) pyrrolidine moiety is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of the substituent on the pyrrolidine ring was investigated. A particular compound IIIf having a 1-methoxyimino-2-carbamoylethyl substituted moiety showed the most potent antibacterial activity.

Synthesis and Antibacterial Evaluation of 1β‐Methyl‐2‐(5‐substituted heterocyclic carbamoyl‐pyrrolidin‐3‐ylthio)carbapenem Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis and antibacterial evaluation of 1beta-methyl-2-(5-substituted heterocyclic carbamoyl)pyrrolidin-3-ylthio)carbapenem derivatives.

The synthesis of a new series of 1beta-methylcarbapenems having a substituted heterocyclic carbamoyl pyrrolidine moiety is described. Their in vitro antibacterial activity against both gram-positive and gram-negative bacteria was tested, and the effect of heterocyclic substituents on the pyrrolidine was investigated. One particular compound (III(d)) having a substituted oxadiazole moiety showed the most potent antibacterial activity.

Synthesis and Antibacterial Activity of 1β‐Methyl‐2‐(5‐substituted oxadiazolo pyrrolidin‐3‐yl‐thio)carbapenem Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis and Antibacterial Activity of 1β‐Methyl‐2‐(5‐substituted imidazolino pyrrolidin‐3‐ylthio)carbapenem Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis and Biological Activity of 1β‐Methyl‐2‐[5‐(2‐N‐substituted aminoethylcarbamoyl)pyrrolidin‐3‐ylthio]carbapenem Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.