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PubMed1997

Susceptibility of 100 strains of Stenotrophomonas maltophilia to three beta-lactams and five beta-lactam-beta-lactamase inhibitor combinations.

One hundred clinical strains of Stenotrophomonas maltophilia were investigated for their susceptibility to ticarcillin, piperacillin, ceftazidime and five combinations with beta-lactamase inhibitors (clavulanic acid, tazocillin or sulbactam) at three concentrations; 26% of the strains were susceptible to ticarcillin, 23% to ceftazidime and 12% to piperacillin. Eighty-two percent of the strains were susceptible to ticarcillin/clavulanic acid. In most cases, no synergy was observed with tazobactam or sulbactam. For eight ticarcillin-susceptible strains, antagonism was observed between ticarcillin and clavulanic acid.

Anti-Bacterial Agents↗
PubMed1991

In vitro inactivation of aminoglycosides by sulbactam, other beta-lactams, and sulbactam-beta-lactam combinations.

At clinically achievable levels (e.g., 25 micrograms/ml), sulbactam exerted no effect on aminoglycoside concentrations when incubated together in pooled serum at 37 degrees C for up to 24 h. Sulbactam alone and in combination with ampicillin or cefoperazone inactivated tobramycin, gentamicin, netilmicin, and amikacin in vitro when the sulbactam concentration was 200 to 225 micrograms/ml. At 75 micrograms/ml, sulbactam inactivated only tobramycin. Inactivation of tobramycin by high concentrations of sulbactam occurred even at -20 degrees C, but not at -70 degrees C, and was influenced by the serum matrix.

Amikacin↗
PubMed1983

Quaternary heterocyclylamino beta-lactams. II. The in vitro antibacterial properties of L-640,876, a new type of beta-lactam antibiotic.

A new semisynthetic cephalosporin antibiotic designated 7-beta-(1-benzylpyridinium-4-yl)-amino-3-[( (1-methyl-1H-tetrazol-5-yl) thio]methyl)ceph-3-em-4-carboxylate (L-640,876) was compared for antibacterial activity in vitro with mecillinam, cefoxitin and cefotaxime. The antibacterial spectrum of L-640,876 and the effect of culture medium composition and inoculum size on activity are most similar to those of mecillinam. In some cases the inoculum effect on MICs correlated with instability of the compound to certain beta-lactamases and in others to the presence of ionized compounds such as sodium chloride in the medium. On balance, L-640,876 was superior to mecillinam in potency and breadth of spectrum.

Amdinocillin↗
PubMed1999

Allergy to beta-lactam antibiotics in children.

BACKGROUND: Skin tests with soluble beta-lactams can be used to diagnose immediate and delayed hypersensitivity (HS) reactions to beta-lactam antibiotics. Very few studies have been performed with children with suspected beta-lactam allergy. In these studies, immediate HS to beta-lactams was diagnosed by skin tests in 4.9% to 40% of children. The diagnostic and predictive values of immediate responses in skin tests are good, because very few children with negative skin test results have positive oral challenge (OC) test results. Delayed responses in skin tests (intradermal and patch tests) have been reported in adult patients and children suffering with urticaria, angioedema, and maculopapular rashes during treatments with beta-lactam antibiotics. However, the diagnostic and predictive values of late responses are unknown. Semi-late responses in skin tests with beta-lactams have never been studied in adults or children. OBJECTIVES: The aims of this study were to confirm or rule out the diagnosis of allergy to beta-lactams in children with histories of adverse reactions to these antibiotics, to determine whether allergic children were sensitized to one or several classes of beta-lactams, and to evaluate the frequency and diagnostic value of immediate, accelerated, and delayed responses in skin tests with beta-lactam antibiotics in children. METHODS: We studied 325 children with suspected beta-lactam allergy. Skin tests (prick and intradermal) were performed with soluble forms of the suspected (or very similar) beta-lactams and with one or several beta-lactams from other classes. The reaction was assessed after 20 minutes (immediate), 8 hours (accelerated), and 48 to 72 hours (delayed). OCs with the suspected beta-lactams were performed in patients with negative skin test results, except those with severe serum sickness-like reactions and potentially harmful toxidermias. RESULTS: Skin tests and OCs led to the diagnosis of beta-lactam allergy in 24 (7.4%) and 15 (4.6%) of the children, respectively. Thus, only 12% of the children were diagnosed as allergic to beta-lactams by means of skin tests and OC. HS to beta-lactams was suspected from clinical history in 30 (9.2%) children reporting serum sickness-like reactions and potentially harmful toxidermias. In a few children, we diagnosed food allergy and intolerance to excipients or nonsteroidal antiinflammatory drugs. No cause was found in the other children. Based on skin tests and OC, the prevalences of immunoglobulin E-dependent and of semi-late or delayed sensitizations to beta-lactam assessed were similar (6.8% vs 5.2%, respectively). Most immunoglobulin E-dependent sensitizations were diagnosed by means of skin tests (86.4%). In contrast, most semi-late and delayed sensitizations were diagnosed by OC (70.6%). The likelihood of beta-lactam allergy was significantly higher for anaphylaxis (42.9% vs 8.3% in other reactions) and immediate reactions (25% vs 10% in accelerated and delayed reactions). Of the children diagnosed as allergic to beta-lactam by means of skin tests, OC, and clinical history, 11.7% were sensitized to several classes of beta-lactams. The risk was significantly higher in children with anaphylaxis (26. 7% vs 7.5% of the children with other reactions) and in children reporting immediate reactions (33.3% vs 8.5% of the children with accelerated and delayed reactions). Finally, age, sex, personal history of atopy, number of reactions to beta-lactams, and number of reactions to other drugs were not significant risk factors for beta-lactam allergy. CONCLUSION: The skin tests were safe, and the immediate reaction to skin tests successfully diagnosed allergy to beta-lactam antibiotics in children reporting reactions suggestive of immediate HS. In contrast, most accelerated and delayed reactions were diagnosed by OC. Thus, our results suggest that the diagnostic and predictive values of skin tests for nonimmediate HS to beta-lactams in children are low. (ABSTRACT TRU

Administration, Oral↗
PubMed2006

Gabapentin-lactam induces dendritic filopodia and motility in cultured hippocampal neurons.

Gabapentin is currently used as a therapeutic agent against epilepsy as well as neuropathic pain. In contrast to gabapentin, its derivative gabapentin-lactam has a pronounced neuroprotective activity. We have studied in cultured hippocampal neurons whether gabapentin-lactam has also neurotrophic effects. Gabapentin-lactam enhanced the formation of dendritic filopodia, which are necessary for synapse formation. It also induced a network of F-actin-containing neurites. In studies with time lapse microscopy, gabapentin-lactam increased the addition but also the elimination of new branches. Affinity precipitation assays showed that gabapentin-lactam increased the GTP binding of the small GTPases Rac and Cdc42, which facilitate branch addition. Gabapentin-lactam also activated RhoA and phosphatidylinositol 3-kinases. In neurons transfected with dominant-negative RhoA or treated with the RhoA-inactivating C3 toxin, gabapentin-lactam increased the number of dendrites and branches. In the presence of Y-27632, which inhibits Rho kinase, newly added branches induced by gabapentin-lactam were no longer eliminated so that gabapentin-lactam increased the number of branches. Y-27632 [(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide] also prevented the gabapentin-lactam induced activation of phosphatidylinositol 3-kinases. The phosphatidylinositol 3-kinase inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride] reduced the elimination of newly added branches caused by gabapentin-lactam and thus facilitated branch formation. In contrast to gabapentin-lactam, gabapentin had no effect on dendritic filopodia or motility. The effects exerted by gabapentin-lactam on dendritic arborization may be of potential therapeutic interest.

Amides↗
PubMedDate not supplied

Lactam bridge stabilization of alpha-helical peptides: ring size, orientation and positional effects.

A series of 14 residue amphipathic alpha-helical peptides, in which the sidechains of glutamic acid and lysine have been covalently joined, was synthesized in order to determine the effect of spacing, position and orientation of these lactam bridges. It was found that although an (i, i+3) spacing would position the lactam bridge on the same face of the helix, these lactams with 18-member rings were actually helix-destabilizing regardless of position or location. On the other hand, (i, i+4) lactams with 21-member rings were helix-stabilizing but this was dependent on orientation. Glutamic acid-lysine lactams increased the helical content of the peptide when compared with their linear homologue in benign conditions (50 mM KH2PO4, 100 mM KCl, pH 7). Two Glu-Lys (i, i+4) lactams located at the N- and C-termini gave rise to a peptide with greater than 99% helical content in benign conditions. Peptides with Lys-Glu oriented lactams were random structures in benign conditions but in the presence of 50% TFE could be induced into a helical conformation. The stability of the single-stranded alpha-helices, as measured by thermal denaturations in 25% TFE indicated that Glu-Lys oriented lactam bridges stabilized the helical conformation relative to the linear unbridged peptide. One Glu-Lys lactam in the middle of the peptide was more effective at stabilizing helical structure than two Glu-Lys lactams positioned one at each end of the molecule. The lactams with the Lys-Glu orientation were destabilizing relative to the unbridged peptide. This study demonstrates that correct orientation and position of a lactam bridge is critical in order to design peptides with high helical content in aqueous media.

Amino Acid Sequence↗
PubMed2000

The biotransformation of nitrogen containing xenobiotics to lactams.

The metabolism of nitrogen heterocyclics may lead to lactam formation. In early studies on xenobiotic metabolism lactams were identified as metabolites of nicotine, cyproheptadine, tremorine and prolintane. Now, because of the increasing availability of powerful analytical techniques, there are many instances of lactams being identified as metabolites. Lactam metabolites are formed from either iminium ions or carbinolamines. These two intermediates may have distinct mechanisms of formation but they can interconvert. There is evidence that the iminium ions are oxidized to lactams by aldehyde oxidases (cytosolic molybdenum hydroxylases). The tissue distribution and enzyme activities of aldehyde oxidase have been studied in several animal species. However, it is also known that iminium ions can undergo spontaneous hydrolysis to the corresponding carbinolamine. If the latter is stable it may undergo oxidation by cytochrome P-450 to form the lactam. Thus, species differences in lactam formation might be caused by differences in the concentrations of either cytochrome P450 isozymes or aldehyde oxidases. It appears that lactam formation is an end stage in the metabolism of N-heterocycles in that it is unlikely that the lactam will undergo hydrolysis to the corresponding amino acid. Such amino acids probably arise from the amino aldehydes that may be produced from ring opening of unstable carbinolamine intermediates. When microsomal preparations are incubated with the appropriate substrate in the presence of sodium cyanide the iminium ion may be trapped to produce a cyano compound. Such reactions have led to the proposal that iminium ions might react with nucleophilic sites of cellular macromolecules and so contribute to both the pharmacology and toxicology of N-heterocyclic compounds. Other pathways for the formation of lactam metabolites involve the internal cyclization of precursor metabolites, e.g. the self-condensation of an aldehyde group (formed during metabolism) with a neighboring amide group. However, spontaneous ring closures of amino acids to form lactams seem unlikely since it would be anticipated that the amino acid residue would exist as a stable zwitterion under physiological conditions. Thus, it is unlikely that lactams will undergo futile metabolism via hydrolytic ring opening followed by ring closure. Under extreme conditions such unanticipated ring closures may occur and the conditions of metabolite isolation may contribute to the occurrence of artifacts.

Animals↗
PubMed2006

The role of aminoglycosides in combination with a beta-lactam for the treatment of bacterial endocarditis: a meta-analysis of comparative trials.

BACKGROUND: The addition of an aminoglycoside to a beta-lactam for the treatment of patients with infective endocarditis has been supported by data from laboratory and animal studies. PURPOSE: We sought to review the evidence from the available comparative clinical trials regarding the role of aminoglycosides in combination with a beta-lactam for the treatment of bacterial endocarditis caused by Gram-positive cocci. DATA SOURCES: The studies for our meta-analysis were retrieved from searches of the PubMed and Cochrane Central Register of Controlled Trials databases, as well as from the references cited in relevant articles. No limits were set regarding the language and date of publication of the studies. STUDY SELECTION: Included studies were prospective studies that provided comparative data regarding the effectiveness of the treatment and/or mortality in patients receiving monotherapy with a beta-lactam or beta-lactam/aminoglycoside combination therapy. DATA EXTRACTION: Two independent reviewers performed the literature search, study selection and extraction of data from relevant studies. DATA SYNTHESIS: No clinical trial comparing beta-lactam monotherapy with beta-lactam/aminoglycoside combination therapy for the treatment of enterococcal endocarditis was found. We performed a meta-analysis of five available comparative trials [four randomized controlled trials (RCTs) and one comparative prospective trial], which included 261 patients with bacterial endocarditis in native valves due to Staphylococcus aureus (four studies) or streptococci of the viridans group (one study). There was no statistically significant difference between beta-lactam monotherapy and beta-lactam/aminoglycoside combination therapy regarding mortality [odds ratio (OR) = 0.59, 95% confidence interval (95% CI) = 0.21-1.66], treatment success (OR = 1.25, 95% CI = 0.49-3.05), treatment success without surgery (OR = 1.66, 95% CI = 0.64-4.30) or relapse of endocarditis (OR = 0.79, 95% CI = 0.15-4.29). Nephrotoxicity was less common in the beta-lactam monotherapy arm than in the beta-lactam/aminoglycoside combination therapy arm (OR = 0.38, 95% CI = 0.16-0.88, P = 0.024). No difference between the two treatment arms was found in subanalyses of the four studies that included only patients with staphylococcal infections in terms of mortality (OR = 0.69, 95% CI = 0.26-1.86, fixed effects model), treatment success (OR = 1.27, 95% CI = 0.47-3.43, fixed effects model) or relapse (OR = 0.76, 95% CI = 0.12-4.92, fixed effects model). LIMITATIONS: The relatively small number of available comparative trials was the major limitation of this meta-analysis. CONCLUSIONS: The limited evidence from the available prospective comparative studies does not offer support for the addition of an aminoglycoside to beta-lactam treatment of patients with endocarditis caused by Gram-positive cocci. A large multicentre RCT is necessary to reach a definitive conclusion on this issue.

Aminoglycosides↗
PubMed2004

Beta-lactams as versatile synthetic intermediates for the preparation of heterocycles of biological interest.

Since the advent of penicillin, the beta-lactam antibiotics have been the subject of much discussion and investigation, within both the scientific and public sectors. The primary biological targets of the beta-lactam antibacterial drugs are the penicillin binding proteins, a group of transpeptidases anchored within the bacterial cellular membrane, which mediate the final step of cell wall biosynthesis. The extensive use of common beta-lactam antibiotics such as penicillins and cephalosporins in medicine has resulted in an increasing number of resistant strains of bacteria through mutation and beta-lactamase gene transfer. Thus, a handful of nonconventional fused polycyclic beta-lactams have been described in the literature in order to overcome the defence mechanisms of the bacteria. In fact, tricyclic beta-lactam antibiotics, generally referred to as trinems, are a new class of synthetic antibacterial agents featuring good resistance to beta-lactamases and dehydropeptidases. In addition, recent discoveries have shown other biological properties of these compounds apart from their antibacterial action. In this sense, beta-lactams can serve as inhibitors of serine proteases, such as human leukocyte elastase (HLE) or thrombin, acyl-CoA cholesterol acyltransferase inhibitors and inhibitors of human cytomegalovirus. Additional impetus for research efforts on beta-lactam chemistry has been provided by the introduction of the beta-lactam synthon method, a term coined by Ojima 20 years ago, according to which 2-azetidinones can be employed as useful intermediates in organic synthesis. The usefulness of beta-lactams in the stereocontrolled synthesis of heterocycles of biological significance is based on the impressive variety of transformations, which can be derived from this system, due inter alia to a high chirality content that can be transferred into a variety of products. The cyclic 2-azetidinone skeleton has been extensively used as a template on which to build the heterocyclic structure fused to the four-membered ring, using the chirality and functionalisation of the beta-lactam nucleus as a stereocontrolling element. Alternatively, the direct one-pot generation of fused nitrogen heterocyclic systems from the nitrogen framework of 2-azetidinone derivatives has been achieved by selective bond breakage and rearrangement. It is our aim in this Review to highlight the state of the art in this endeavour, consisting either of the stereocontrolled synthesis of fused polycyclic beta-lactams of antibacterial interest, or stereoselective synthesis of different sized heterocycles of biological significance. Representative examples of the latter include indolizidines, pyrrolizidines, pirrolidines, pyrroles, taxoids and macrolide natural products.

Heterocyclic Compounds↗