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PubMed1979

In vitro synthesis of peptidoglycan by beta-lactam-sensitive and -resistant strains of Neisseria gonorrhoeae: effects of beta-lactam and other antibiotics.

The synthesis in vitro of peptidoglycan by Neisseria gonorrhoeae was studied in organisms made permeable to nucleotide precursors by treatment with ether. Optimum synthesis occurred at 30 degrees C in tris(hydroxymethyl)aminomethane-maleate buffer (0.05 M; pH 6) in the presence of 20 mM Mg(2+). The incorporation from uridine 5'-diphosphate-N-acetyl-[(14)C]glucosamine into peptidoglycan, measured after precipitation of the cells with trichloroacetic acid, was sensitive to the beta-lactam antibiotics, bacitracin, diumycin, and tunicamycin and relatively resistant to spectinomycin and tetracycline. Differences in sensitivity between preparations from a beta-lactamase producer and a laboratory segregant derived from it were not great. Synthesized peptidoglycan was also fractionated into sodium dodecyl sulfate-soluble and -insoluble portions. beta-Lactam antibiotics at concentrations equivalent to the minimal inhibitory concentrations for growth of the organisms did not inhibit peptidoglycan synthesis, but rather caused a small enhancement. At higher concentrations, above about 0.5 mug/ml, incorporation into sodium dodecyl sulfate-insoluble material was progressively inhibited, whereas the amount of sodium dodecyl sulfate-soluble product increased greatly, more than compensating for the loss of the precipitable fraction. Similar observations were made with three strains, and also with the beta-lactam clavulanic acid, normally considered as a beta-lactamase inhibitor rather than as itself an effective antibiotic.

Anti-Bacterial Agents↗
PubMed1998

Soluble penicillin-binding protein 2a: beta-lactam binding and inhibition by non-beta-lactams using a 96-well format.

High level methicillin resistance in Staphylococcus aureus is dependent upon the acquisition of the mecA gene encoding penicillin-binding protein 2a (PBP2a). PBP2a is a member of a family of peptidoglycan biosynthetic enzymes involved in assembly of the cell wall in bacteria and is poorly inactivated by beta-lactam antibiotics. We describe a 96-well-filter binding assay using recombinant, soluble PBP2a which allows for kinetic measurement of penicillin binding. The deacylation rate constant for the PBP2a-penicillin G covalent complex was found to be 5.7 +/- 1.0 x 10(-5) s-1 at 30 degrees C (half-life of approximately 200 min). For the PBP2a acylation reaction, the value of K(m) (penicillin G) = 0.5 +/- 0.1 mM and kcat = 1 x 10(-3) s-1, which yields a second-order rate constant (kcat/K(m)) for inactivation of 2.0 M-1 s-1. Using this assay, several non-beta-lactam inhibitors including Cibacron blue have been found which exhibit IC50 values between 10 and 30 microM. The binding affinities of several carbapenems and beta-lactams correlated well between the filter binding assay described in this report and an electrophoretic assay for PBP2a using membranes prepared form methicillin-resistant S. aureus.

Anti-Bacterial Agents↗
PubMed2006

In vitro activity of beta-lactam and non-beta-lactam antibiotics in extended-spectrum beta-lactamase-producing clinical isolates of Escherichia coli.

The activity of different beta-lactam and non-beta-lactam antibiotics was assessed against extended-spectrum beta-lactamase (ESBL)-producing and non-ESBL-producing clinical isolates of Escherichia coli. A phenotypic study to discover the presence of ESBLs in 399 clinical isolates of E. coli was made by the disk diffusion method following the Clinical and Laboratory Standards Institute (formely NCCLS, 2004) guidelines. The activity of different antibiotics was subsequently studied using the automated VITEK 2 system (bioMérieux, Marcy l'Etoile, France). One hundred fifteen isolates proved to be ESBL-producing and 284 non-ESBL-producing. Among the former, percentage susceptibilities to the antibiotics assayed were meropenem and amikacin, 100%; piperacillin/tazobactam, 97.4%; cefepime, 94.8%; amoxicillin/clavulanic acid, 84.3%; tobramycin, 84.3%; gentamicin, 83.5%; cefoxitin, 83.5%; nitrofurantoin, 71.3%; cotrimoxazole, 46.1%; norfloxacin, 29.6%; ciprofloxacin, 27%; and ofloxacin, 26.1%.

Anti-Bacterial Agents↗
PubMed1981

Intestinal absorption mechanism of amphoteric beta-lactam antibiotics I: Comparative absorption and evidence for saturable transport of amino-beta-lactam antibiotics by in situ rat small intestine.

The disappearance of various beta-lactam antibiotics from in situ rat small intestinal loops was studied at pH 7.4. For monobasic penicillins, despite the wide variety of apparent partition coefficients in isobutyl alcohol-water, the disappearance from the jejunal loops was almost 30% (+/- 5% SD). On the other hand, the disappearance of amphoteric derivatives of penicillins and cephalosporins having very low lipid solubility varied widely between 12 and 80%. The peak blood levels after intraduodenal administration to the rats correlated well with the extent of disappearance of amphoteric penicillins from the intestinal loops. Absorption studies utilizing in situ intestinal loops were performed at variable dose ranges to yield a clear dose-dependent disappearance. It is suggested that certain carrier-mediated transport systems underlie the absorption mechanism of amphoteric beta-lactam antibiotics.

Animals↗
PubMedDate not supplied

Antibiotic use in the emergency department. III. The quinolones, new beta lactams, beta lactam combination agents, and miscellaneous antibiotics.

This article reviews several new, relatively broad-spectrum antibiotics that have utility in the emergency department (ED). The quinolones have excellent activity against gram-negative organisms, including gonococcus, and are characterized by very high bioavailability after oral administration. The new beta-lactams aztreonam and imipenem have broad spectra but limited usefulness to the emergency physician, and should be reserved for judicious use in severe infections, particularly those involving Pseudomonas. Clavulanate, sulbactam, and tazobactam are themselves antimicrobials that have been combined with beta-lactams such as ampicillin and ticarcillin to produce agents with significant potential utility in the ED; these are typically not first-line agents, however, and their use should be governed by both clinical and cost concerns. Finally, three older antibiotics--vancomycin, metronidazole, and clindamycin--are reviewed with respect to updated indications for their use in the ED.

Anti-Bacterial Agents↗
PubMed2006

Trough serum concentrations of beta-lactam antibiotics in cancer patients: inappropriateness of conventional schedules to pharmacokinetic/pharmacodynamic properties of beta-lactams.

Serum concentrations of beta-lactams that continuously exceed the minimum inhibitory concentration may improve therapeutic outcomes for immunosuppressed patients. The trough serum levels of ceftazidime (CAZ), cefepime (FEP) or imipenem (IMP) were prospectively determined on days 1 and 3 of treatment in cancer patients. Seventy-eight episodes of suspected infection were analysed. Trough serum levels were higher than 4 mg/L in 62%, 24% and 0% of cases in the CAZ, FEP and IMP groups, respectively, and were higher than 20 mg/L in 24% of cases in the CAZ group compared with 0% both in the FEP and IMP groups. For suspected infectious episodes in cancer patients, the traditional intermittent regimen of beta-lactams does not appear to be appropriate for the pharmacokinetic/pharmacodynamic properties of these antibiotics.

Adult↗
PubMedDate not supplied

Toward an in vitro test for the diagnosis of allergy to penicillins. Synthesis, characterization, and use of beta-lactam and beta-lactam metabolite poly-L-lysines which recognize human IgE antibodies.

Conjugates of poly-L-lysine (PLL) containing a penicillin or a penicilloyl residue were prepared and characterized by 1H NMR and by size-exclusion (SE) HPLC. These conjugates were used in a radio allergo sorbent tests (RAST) test for the determination of allergy toward beta-lactams. The chemiometric evaluation of the data indicates that allergy to amoxycillin is different from allergy to the other beta-lactams tested. Furthermore, careful chemical characterization of the conjugates appears to be crucial to obtain meaningful information from the RAST data.

Chromatography, High Pressure Liquid↗
PubMed1995

Mechanism of inhibition of human leucocyte elastase by beta-lactams. 3. Use of electrospray ionization mass spectrometry and two-dimensional NMR techniques to identify beta-lactam-derived E-I complexes.

A combination of NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS) was used to probe the identity of beta-lactam-derived complexes with serine proteases. The carbon and proton NMR chemical shifts of the human leucocyte elastase (HLE)-inhibitor complex derived from [4-13C]-L-680,833, [S-(R*,S*)]-4-[(1-(((1-(4- methylphenyl)butyl)amino)carbonyl)-3,3-diethyl-2-oxo-4- azetidinyl)oxy]benzeneacetic acid, were consistent with an sp3 hybridized carbon. The ESI-MS spectrum of the L-680,833-derived HLE-I complex indicated an increase of 333 Da over the mass of the free enzyme. The data are consistent with acylation of the active site serine, loss of p-hydroxybenzeneacetic acid, and formation of a carbinolamine at the carbon deriving from C-4 of the lactam ring. The complexes produced from HLE and the diastereomers of L-680,833 display identical masses. Since the 4R-isomers produce more stable complexes [Green et al. (1995) Biochemistry 34, 14331-14343], these data suggest that these complexes differ in their stereochemistry or conformation. The structural model of the HLE-I complexes derived from the diastereomers predicts that the hydroxyl of the carbinolamine derives from a structurally observed water molecule yielding S-stereochemistry in all cases. In this model, the 4S- and 4R-diastereomers produce complexes that differ by the location of the side chain of a phenylalanine residue. The mass of HLE was increased by that of L-684,481, (R)-1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-3,3-diethyl-2-azetidino ne, which lacks a leaving group at C-4 in the complex derived from this compound. L-691,886, [S-(R*,S*)]-4-[(1-(((1-(4-ethoxyphenyl)butyl)amino)carbonyl)- 3,3-diethyl-4-oxo-2-azetidinyl)-oxy]benzeneacetic acid, produces two complexes of different mass that reactivate with different rates. The mass of the less stable complex is consistent with the acyl-enzyme of 2,2-ethyl-3-oxopropanoic acid while the mass of the more stable complex is analogous to the carbinolamine observed during L-680,833 inactivation. Porcine pancreatic elastase (PPE) produces a complex with a mass consistent with replacement of the C-4 leaving group by water to produce a carbinolamine from L-684,248, [S-(R*,S*)]-4-[(1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-3,3-dimethy l - 2-oxo-4-azetidinyl)oxy]benzoic acid. The C-4 diastereomer, L-684,249, produces two PPE-I complexes with different masses. One of these complexes has a mass identical to the mass of the complex derived from L-684,248 while the mass of the other complex indicates the presence of the entire inhibitor molecule.(ABSTRACT TRUNCATED AT 400 WORDS)

Humans↗
PubMed2005

Electrophile-induced ring expansions of beta-lactams toward gamma-Lactams.

[reaction: see text] An efficient and straightforward route toward 3,4-cis-4-isopropenylazetidin-2-ones was developed from 4-(1-chloroalkyl)azetidin-2-ones. Starting from the latter beta-lactams, a new synthesis of pyrrolidin-2-ones was achieved. When 4-isopropenylazetidin-2-ones were treated with bromine in dichloromethane, diastereoselective electrophile-induced ring expansions toward 5-bromopyrrolidin-2-ones were performed. Further oxidation of 3-benzyloxypyrrolidin-2-ones with bromine toward 3-bromopyrrolidin-2-ones was also established. When 4-isopropenyl-beta-lactams were added to a mixture of NBS and TMSN(3), 5-azidopyrrolidin-2-ones were obtained in moderate to high yields.

Azetidines↗
PubMed2005

Organocatalytic ring expansion of beta-lactams to gamma-lactams through a novel N1-C4 bond cleavage. direct synthesis of enantiopure succinimide derivatives.

Tetrabutylammonium cyanide (20 mol %) catalyzes ring expansion of 4-(arylimino)methylazetidin-2-ones 2 to 5-aryliminopyrrolidin-2-ones 3 through a novel N1-C4 bond cleavage of the beta-lactam nucleus. New, efficient one-pot protocols to enantiopure succinimide derivatives 3 and 4 from beta-lactam aldehydes 1 have also been developed. [reaction: see text]

Catalysis↗
PubMed2003

Beta-lactams or gamma-lactams by 4-exo-trig or 5-endo-trig anionic cyclisation of lithiated acrylamide derivatives.

Substituted acrylamide derivatives of benzylamine are lithiated alpha to nitrogen by LDA. The benzyllithium thus formed undergoes either 5-endo-trig anionic cyclisation, formally by intramolecular conjugate addition to the acrylamide, to yield 5-membered lactams, or, if the acrylamide bears a beta-electron withdrawing group, 4-exo-trig cyclisation to a beta-lactam.

Acrylamide↗
PubMed1987

Binding of amino beta-lactam antibiotics to soluble protein from rat intestinal mucosa--II. Mutual inhibition of binding among amino beta-lactam antibiotics and binding characteristics.

The characteristics of binding of amino beta-lactam antibiotics including ampicillin, amoxicillin, cephalexin and cephradine to fraction b obtained from the 105,000 g supernatant of rat small intestinal mucosa was investigated. The mutual inhibition of binding among these antibiotics was observed, and these were dependent on the concentration of inhibitors. It was found that dipeptides such as L-carnosine and glycylglycine significantly reduced the binding of cephalexin to fraction b, but the binding of cephradine was only slightly decreased by these dipeptides. Furthermore, the binding of cephalexin and cephradine was not influenced by amino acids (L-phenylalanine, glycine). Although ANS(1-anilino-8-naphthalenesulfonic acid magnesium salt), which is a hydrophobic probe, bound to the fraction b, there was no competitive inhibition in binding between ANS and amino beta-lactam antibiotics. The Scatchard plot of binding data of cephalexin gave two dissociation constant (Kd) values (1.37 and 15.7 microM). On the other hand, one Kd value (11.2 microM) was obtained for ampicillin.

Ampicillin↗
PubMed2005

Diastereoselective ring expansion of beta-lactams toward gamma-lactams via N-acyliminium intermediates.

[reaction: see text] The diastereoselective synthesis of highly functionalized gamma-lactams starting from 4-(1-bromoalkyl)-2-azetidinones via N-acyliminium intermediates is described. The carbenium ions, formed by dissociation of bromide from 4-(1-bromoalkyl)-2-azetidinones in polar medium, are converted via a ring expansion toward N-acyliminium ions, which are susceptible to attack of oxygen, nitrogen, and carbon nucleophiles. In this way, a variety of 5-hydroxy-, 5-alkoxy, 5-cyano-, 5-allylamino- and 5-azido-4,4-dimethyl-2-pyrrolidinones were synthesized. It was found that dehydrobromination of 4-(1-bromoalkyl)-2-azetidinones constituted an important side reaction when the title reactions were carried out in DMSO. When THF was used as a solvent, generally no dehydrobromination was observed, implying that higher yields of gamma-lactams were obtained in THF compared to reactions performed in DMSO. Also substituents of the 4-(1-bromoalkyl)-2-azetidinones play an important role concerning the obtained diastereoselectivity and the degree of dehydrobromination.

Journal Article↗
PubMed1996

Molecular genetics of resistance to both ceftazidime and beta-lactam-beta-lactamase inhibitor combinations in Klebsiella pneumoniae and in vivo response to beta-lactam therapy.

The molecular basis of ceftazidime resistance in 2 isolates of Klebsiella pneumoniae was studied. The first (21300) expressed resistance to ceftazidime and piperacillin-tazobactam. The second (26139) expressed resistance to ceftazidime but remained susceptible to piperacillin-tazobactam. The 2 strains harbored similar large plasmids that hybridized to TEM- and SHV-related beta-lactamase genes. An Escherichia coli strain harboring the plasmid conferring resistance to both compounds (pLRM7) produced beta-lactamases of pI 5.9 (TEM-6) and pI 7.6 (SHV-1). E. coli harboring the other plasmid (pLRM8) expressed only the TEM enzyme because of insertion of IS15 within blaSHV-1. In vivo studies suggested that resistance to beta-lactam-beta-lactamase inhibitor combinations conferred by pLRM7 will be clinically important. Clinical resistance to both extended-spectrum cephalosporins and beta-lactam-beta-lactamase inhibitor combinations is achievable via the production of two enzymes, with only one possessing an extended spectrum of activity.

Abdominal Abscess↗
PubMed1994

Interaction of oxyimino beta-lactams with a class C beta-lactamase and a mutant with a spectrum extended to beta-lactams.

The class C beta-lactamase of Citrobacter freundii GN346 is a typical cephalosporinase comprising 361 amino acids, and substitution of the glutamic acid at position 219 in the enzyme by lysine was previously shown to broaden its substrate spectrum to oxyimino beta-lactams (K. Tsukamoto, R. Ohno, and T. Sawai, J. Bacteriol. 172:4348-4351, 1990). To clarify this spectrum extension from the kinetic point of view, the interactions of cefuroxime, ceftazidime, and aztreonam with the wild-type and mutant enzymes were analyzed. In addition to aztreonam, known as a progressive inhibitor of class C beta-lactamases, cefuroxime and ceftazidime were found to act as progressive inhibitors of the wild-type enzyme. On the other hand, only aztreonam showed weak progressive inhibition of the mutant enzyme. On the basis of kinetic parameters, a minimum scheme for interaction of the oxyimino beta-lactams with the wild-type enzyme was proposed, and the rate-limiting step of the hydrolysis of unfavorable substrates was indicated to be conversion of the stable acyl-enzyme intermediate to the unstable intermediate. In aztreonam hydrolysis by the mutant enzyme, the reaction rate at the rate-limiting step was 2,000 times that of the wild-type enzyme. These results indicate that the mutation at position 219 disturbs the stabilization of the stable intermediate.

Anti-Bacterial Agents↗
PubMed1984

Basic design of beta-lactam antibiotics: penams and analogues and monocyclic beta-lactams.

Improved microbiological and chemical techniques have resulted in the development of a range of new beta-lactam antibiotics with valuable clinical properties. The work on semi-synthetic penicillins demonstrated that by alteration of the side chain in the 6-position of the penam structure it was possible to significantly affect the antibacterial activity of the compounds and their stability against degradation by acids and beta-lactamases. Esterification of the carboxyl group in the 3-position may improve the pharmacokinetic properties of the compounds whereas substitution in the bicyclic penam structure may give compounds with strong inhibitory action against beta-lactamases. Penems are available by chemical synthesis and may have potent antibacterial activity and good stability against beta-lactamases. Carbapenems can be obtained microbiologically and chemically. The latter, include compounds which have high and broad antibacterial activity as well as those which are potent inhibitors of beta-lactamases. Many of the compounds are, however, chemically rather labile and may also be degraded by a dehydropeptidase present in the kidneys. Clavulanic acid is a microbial oxapenam with modest antibacterial activity but potent inhibitory activity against beta-lactamases. Two types of monocyclic beta-lactams with antibacterial properties, the nocardicins and the monobactams, have so far been found to be produced by microorganisms. They have modest in vitro activity, but at least in case of the monobactams it has been possible to obtain compounds by chemical derivatization with high activity against Gram-negative bacteria and with high stability against beta-lactamases.

Anti-Bacterial Agents↗
PubMed1979

LY127935, a novel oxa-beta-lactam: an in vitro comparison with other beta-lactam antibiotics.

The in vitro activities of LY127935 (LY) were compared with those of other beta-lactam antibiotics. LY was highly active (minimal inhibitory concentration [MIC] range 0.06 to 0.25 micrograms/ml) against the common Enterobacteriaceae (including Providencia stuartiia, Enterobacter, and Serrati marcescens), 8 to 16 times more active than cefoxitin, cefuroxime, or cefazolin, and from one-half to one-eighth as active as cefotaxime (HR756). The activity of LY against Pseudomonas aeruginosa (with MICs of 4 and 64 micrograms/ml for 50 and 90% of test strains, respectively) was essentially similar to that of cefotaxime, but was only one-half as active as CGP 7174/E. LY, cefoxitin, and cefotaxime were essentially equally active against Bacteroides fragilis--each was more active than cefuroxime and cefazolin. Against Staphylococcus aureus, LY (50% MIC and 90% MIC of 4 and 16 micrograms/ml, respectively) was less active than cefotaxime, cefoxitin, or cefuroxime and one-eighth as active as cefazolin. The composition and pH of the culture medium had little effect on the activity of LY, although 7.2 appeared to be the optimum pH.

Anti-Bacterial Agents↗
PubMed1980

Comparative in vitro activity of 1-oxa-beta-lactam (LY127935) and cefoperazone with other beta-lactam antibiotics against anaerobic bacteria.

The in vitro activity of 1-oxa-beta-lactam (LY127935), cefoperazone (T-1551), cefuroxime, cefsulodin, cefaclor, cefotaxime, and cefoxitin on 85 anaerobic clinical isolates (30 Bacteroides, 30 Clostridium, 25 Peptococcaceae) was simultaneously determined by the agar dilution test in two different media, Brucella Agar (Difco Laboratories) and Wilkins-Chalgren agar. In Wilkins-Chalgren agar, 90% of Bacteroides were inhibited by (micrograms per milliliter): LY127935, 0.5; T-1551, 64; cefoxitin or cefuroxime, 8; cefsulodin or cefotaxime, 32; and cefaclor, 128. All Clostridia were inhibited in Wilkins-Chalgren by (micrograms per milliliter): LY127935, 4; T-1551, 2; cefoxitin, 6; cefuroxime, 0.12; cefsulodin, 0.5; cefaclor, 1; and cefotaxime, 8. All Peptococccaceae were inhibited by T-1551, cefsulodin or cefotaxime at 4 microgram/ml and by cefoxitin or cefuroxime at 1 to 2 microgram/ml. With cefaclor at 8 microgram/ml, 92% of strains were inhibited, and LY127935 at 16 microgram/ml only inhibited 64% of strains. LY127935 was the most active of the antibiotics tested against Bacteroides, showing good activity against Clostridia and poor activity on Peptococcaceae, whereas T-1551 was more active against Peptococccaceae and had similar activity against Clostridia and poor activity on Bacteroides. There are no significant differences between minimal inhibitory concentrations obtained in Brucella Agar and those obtained in Wilkins-Chalgren.

Anaerobiosis↗