New Delhi metallo-ß-lactamase - type carbapenemases producing Escherichia coli isolates from hospitalized patients: A pilot study.

BACKGROUND & OBJECTIVES: Resistances to carbapenem group of antimicrobials among Escherichia coli due to production of carbapenemases, especially the New Delhi metallo-ß-lactamase (NDM) types, pose serious challenges in the treatment of infections in healthcare settings. This study was undertaken to detect NDM producing E. coli isolates from hospitalized patients with urinary tract infection (UTI). METHODS: A total of 30 non-repetitive isolates of E. coli from hospitalized patients with clinical suspicion of UTI were subjected to antimicrobial susceptibility testing. Screening for the production of extended-spectrum ß-lactamases (ESBL) was carried out by minimum inhibitory concentration (MIC) test strip ESBL followed by phenotypic confirmation by double-disc synergy test. Phenotypic confirmation of carbapenemase production was carried out by MIC test strip metallo-ß-lactamases. Molecular identification of the blaNDM gene was carried out by polymerase chain reaction (PCR) and sequencing of the amplified fragment. RESULTS: Seventeen of the 30 isolates were detected as ESBL producers, of which three were found to be carbapenemase producers. NDM genes were detected by PCR followed by gene sequencing in all three isolates positive for ESBL as well as carbapenemase. The amino acid sequence of the three isolates showed complete identity to the reference sequences of NDM-1, NDM-4 and NDM-8, respectively. INTERPRETATION & CONCLUSIONS: Our study showed the circulation of NDM variants among the clinical isolates of E. coli that were producers of ESBL as well as carbapenemase.

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 ß-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 ß-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.

[Available carbapenems: Properties and differences]. / Los carbapenems disponibles: Propiedades y diferencias.

Carbapenems are ß-lactam antibiotics endowed with a broader spectrum, activity and resistance to ß-lactamases than other ß-lactams. Due to their qualities, these antibiotics are crucial in empirical therapy, in the monotherapy of several severe hospital-acquired infections -and even that of some community-acquired infections- as well as in the directed therapy of infections due to multiresistant Gram-negative bacteria. All the available carbapenems have a similar spectrum, although there are significant differences in their antimicrobial activity, which in the long run determines the clinical indications of each carbapenem. The spectrum of ertapenem does not cover eminently nosocomial pathogens such as Pseudomonas aeruginosa and Acinetobacter spp., and hence this antibiotic is indicated in community-acquired infections requiring hospital treatment. In contrast, doripenem shows greater intrinsic activity than other carbapenems in extended spectrum beta-lactamase-producing enterobacteria and AmpC P. aeruginosa, Acinetobacter spp. and other non-fermentative and anaerobic microorganisms. Additionally, like the remaining carbapenems, doripenem has adequate pharmacokinetic characteristics and a favorable safety profile.

[Doripenem: need for a new carbapenem]. / Le doripénème: quelle place pour un nouveau carbapénème?

Doripenem is a new member of the carbapenem family. Its spectrum is a little wider than meropenem and it is active on some Pseudomonas aeruginosa strains resistant to other carbapenems and on Burkholderia cepacia. Doripenem was evaluated in nosocomial pneumonia including ventilator-acquired pneumonia, complicated intra-abdominal infection, and complicated urinary tract infection. In nosocomial pneumonia, doripenem showed an interesting activity in P. aeruginosa infected patients. This data, along with the global increase in multiresistance, may be an opportunity to optimize our therapeutic options with a new molecule.

Novel lbeta-methylcarbapenems having cyclic sulfonamide moieties: synthesis and evaluation of in vitro antibacterial activity.

The synthesis of a new series of 1beta-methylcarbapenems having cyclic sulfonamide moieties is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituent on the pyrrolidine ring was investigated. A particular compound (IIIi) having 2-methyl-[1,2,6]thiadiazinan-1,1-dioxide moiety showed the most potent antibacterial activity.

Redefining penems.

The antimicrobial class of penems has the potential to address most of the relevant resistance issues associated with beta-lactam antibiotics because of their exceptionally broad spectrum of antibacterial activity and their intrinsic stability against hydrolytic attack by many beta-lactamases including ESBL and AmpC enzymes. The subclass of carbapenems covers the spectrum of hospital pathogens whereas the subclass of penems covers community pathogens. The only currently available penem, faropenem, has a low propensity for resistance development, beta-lactamase induction and selection of carbapenem-resistant Pseudomonas aeruginosa. This makes it attractive for the treatment of community-acquired infections and for step-down or sequential therapy following carbapenem treatment without jeopardizing the activity of carbapenems or the entire beta-lactam class in the hospital environment.

Novel 1beta-methylcarbapenems with isoxazoloethenyl moieties containing carboxylic acid sodium salt.

The synthesis of novel 1beta-methylcarbapenems 1a,b having sodium 5-(3- and 5-carboxylic acid)isoxazoloethenyl moieties at C-5 position of pyrrolidine ring and their biological evaluation are described. Both compounds showed potent and well-balanced antibacterial activity as well as high stability to DHP-I. The selected sodium 3-carboxylic acid derivative 1a possessed excellent DHP-I stability and advanced pharmacokinetic parameters in comparison with 2 and meropenem.

Synthesis and biological properties of new 1beta-methylcarbapenems containing heteroaromatic thioether moiety.

The synthesis and biological activities of a series of new 1beta-methylcarbapenems 1a-h having heteroaromatic thioether moiety at C-5 position of pyrrolidine were described. Among these compounds, 1,2,3-thiadiazole derivative 1h showed the most potent antibacterial activity and advanced pharmacokinetics in comparison with meropenem.

Dicationic dithiocarbamate carbapenems with anti-MRSA activity.

A new class of 1 beta-methylcarbapenems bearing a doubly quaternarized 1,4-diazabicyclooctane (DABCO) substituted dithiocarbamate moiety at the C-2 side chain was prepared, and the biological profiles of the compounds, including in vitro and in vivo anti-MRSA activity and DHP-I susceptibility, were evaluated to identify a carbapenem derivative that was superior to BO-3482 (1). As a result, we discovered a 1 beta-methyl-2-[4-(4-carbamoylmethyl-1,4-diazabicyclo[2,2,2]octanediium-1-yl)methyl-1,2,3,6-tetrahydropyridinylthiocarbonylthio]carbapenem, 14a showing greater than 2-fold better anti-MRSA activity in a mouse infection model and 3-fold better DHP-I susceptibility as compared with BO-3482 (1).

Synthesis and biological evaluation of new oral carbapenems with 1-methyl-5-oxopyrrolidin-3-ylthio moiety.

The synthesis and biological properties of 1beta-methylcarbapenems with 1-methyl-5-oxopyrrolidin-3-ylthio group at the C-2 position were studied. The sodium (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(R)-1-methyl-5-oxopyrro lidin-3-ylthio]-1-carbapen-2-em-3-carboxylate and its (S)-isomer at the 2-position show potent and well-balanced antibacterial activity. The pharmacokinetic parameters of the pivaloyloxymethyl esters of these two carbapenems were compared in mice. The in vivo potency of these carbapenems was compared with that of cefdinir. Good in vivo efficacy of these ester prodrugs reflected the high and prolonged blood levels in parent drugs achieved after oral administration to mice.

Efficacy of CS-834 against experimental pneumonia caused by penicillin-susceptible and -resistant Streptococcus pneumoniae in mice.

The efficacy of CS-834, a novel oral carbapenem, was assessed by using a murine model of pneumonia caused by penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae and was compared with those of oral cephems, i.e., cefteram pivoxil, cefpodoxime proxetil, cefdinir, and cefditoren pivoxil. Intranasal inoculation of 10(6) CFU of penicillin-susceptible or penicillin-resistant S. pneumoniae in the exponential growth phase induced pneumonia and bacteremia in ddY mice within 48 h. For the treatment of infections caused by the penicillin-susceptible strain the antibiotics were administered orally at 0.4, 2, and 10 mg/kg of body weight twice daily for 2 days beginning at 24 h after bacterial inoculation, and for the treatment of infections caused by a penicillin-resistant strain the antibiotics were administered at 2, 10, and 50 mg/kg twice daily for 2 days beginning at 24 h after bacterial inoculation. Among the antibiotics tested, CS-834 exhibited the most potent efficacy against both types of strains. Against infections caused by penicillin-susceptible S. pneumoniae, CS-834 at all doses significantly reduced the numbers of viable cells in both the lungs and blood. Cefpodoxime proxetil at all doses and cefteram pivoxil and cefditoren pivoxil at doses of 2 and 10 mg/kg showed comparable efficacies. Against infections caused by penicillin-resistant S. pneumoniae, CS-834 at doses of 10 and 50 mg/kg showed the most potent efficacy among the antibiotics tested, resulting in the maximum decrease in the numbers of viable cells in the lungs. Comparable efficacies were observed with cefteram pivoxil and cefpodoxime proxetil at doses of 50 mg/kg each. The concentration of CS-834 in the lungs and blood was higher than that of cefdinir and was lower than those of the other antibiotics tested, suggesting that the potent therapeutic efficacy of CS-834 reflects its strong activity against S. pneumoniae.