RESUMO
PURPOSE OF REVIEW: To review the most recent literature studying the classifications, immunochemistry, and crossreactivity of allergy reactions to cephalosporins. RECENT FINDINGS: Over the last five years, research interest has focused on three areas related to cephalosporin allergy: cross-reactivity among cephalosporins and with other beta-lactams; the incidence of adverse reactions in penicillin allergy patients or in reported penicillin allergy labels; and new cephalosporins structures involved in the immunological recognition. SUMMARY: Meta-analysis of a substantial number of studies shows that cephalosporins are safer than previously thought. Evidence supports two main conclusions in that regard. First, there is a relatively low percentage of cross-reactivity between cephalosporins and other beta-lactams with penicillins in penicillin allergy patients. Second, there is a very low incidence of allergy reactions in nonselected as well as in selected penicillin allergy patients when cephalosporins are used prior to surgical intervention.On the other hand, few structures have been discovered related to the immune mechanism of cephalosporin allergy reactions, and these are far from being ready to use in clinical practice.
Assuntos
Antibacterianos , Cefalosporinas , Hipersensibilidade a Drogas , Antibacterianos/efeitos adversos , Antibacterianos/classificação , Cefalosporinas/efeitos adversos , Cefalosporinas/classificação , Reações Cruzadas , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/tratamento farmacológico , Hipersensibilidade a Drogas/epidemiologia , Humanos , Penicilinas/efeitos adversos , Penicilinas/classificação , Testes Cutâneos , beta-Lactamas/efeitos adversos , beta-Lactamas/classificaçãoRESUMO
We characterized the impact of removal of the ESBL designation from microbiology reports on inpatient antibiotic prescribing. Definitive prescribing of carbapenems decreased from 48.4% to 16.1% (P = .01) and ß-lactam-ß-lactamase inhibitor combination increased from 19.4% to 61.3% (P = .002). Our findings confirm the importance of collaboration between microbiology and antimicrobial stewardship programs.
Assuntos
Antibacterianos/uso terapêutico , Carbapenêmicos/uso terapêutico , Uso de Medicamentos/estatística & dados numéricos , beta-Lactamas/classificação , beta-Lactamas/uso terapêutico , Centros Médicos Acadêmicos , Enterobacteriaceae , Infecções por Enterobacteriaceae/tratamento farmacológico , Humanos , Philadelphia , Estudos RetrospectivosRESUMO
The increasing incidence of infections caused by extended-spectrum beta-lactamase (ESBL)/AmpC-producing bacteria leads to increasing use of carbapenems and risk of carbapenem resistance. Treatment success of carbapenem-sparing beta-lactams (CSBs) for ESBL infections is unclear. The aim of this study was to appraise the clinical cure rate and estimate the cost-effectiveness of meropenem vs. CSBs (piperacillin-tazobactam, temocillin, ceftazidime-avibactam, and ceftolozane-tazobactam) for urinary tract infections (UTIs) or intra-abdominal infections (IAIs) due to ESBL/AmpC-producing bacteria. A systematic literature search of the Cochrane library, EMBASE, PubMed, and Web of Science was conducted to identify studies assessing the clinical cure rate of the antibiotics. To assess the cost-effectiveness of CSBs vs. meropenem, a combined decision analytic and Markov model was probabilistically analysed over a 5-year period. The main outcome was presented as the incremental cost-effectiveness ratio and evaluated with a threshold of 20 000 per life year gained (LYG). From 656 identified articles, 17 and 14 studies were included in the qualitative synthesis and quantitative synthesis, respectively. A clinical cure of ceftazidime-avibactam and ceftolozane-tazobactam was comparable to meropenem in patients with complicated IAIs (cIAIs) due to ESBL (Risk ratio [RR]=1·04, 95% confidence interval [CI]=0·95-1·13). Both temocillin and ceftolozane-tazobactam were deemed cost-effective compared to meropenem with 157·58 and 13 398·34 per LYG, respectively, in patients with UTIs due to ESBL. However, only ceftazidime-avibactam (plus metronidazole) was cost-effective for the treatment of IAIs, with 16 916·77 per LYG. These results show that several CSBs can be considered as viable candidates for the treatment of UTIs and IAIs caused by ESBL.
Assuntos
Antibacterianos/economia , Antibacterianos/uso terapêutico , Análise Custo-Benefício , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Meropeném/uso terapêutico , beta-Lactamas/uso terapêutico , Antibacterianos/classificação , Humanos , Meropeném/classificação , Meropeném/economia , beta-Lactamas/classificação , beta-Lactamas/economiaAssuntos
Antibacterianos/farmacologia , Complexo Burkholderia cepacia/efeitos dos fármacos , Burkholderia gladioli/efeitos dos fármacos , Fibrose Cística/microbiologia , Bactérias Gram-Negativas/efeitos dos fármacos , beta-Lactamas/farmacologia , Compostos Azabicíclicos/farmacologia , Ceftazidima/farmacologia , Cefalosporinas/farmacologia , Combinação de Medicamentos , Humanos , Testes de Sensibilidade Microbiana , Tazobactam/farmacologia , beta-Lactamas/classificaçãoRESUMO
ß-Lactams represent perhaps the most important class of antibiotics yet discovered. However, despite many years of active research, none of the currently approved drugs in this class combine oral activity with long duration of action. Recent developments suggest that new ß-lactam antibiotics with such a profile would have utility in the treatment of tuberculosis. Consequently, the historical ß-lactam pharmacokinetic data have been compiled and analyzed to identify possible directions and drug discovery strategies aimed toward new ß-lactam antibiotics with this profile.
Assuntos
Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Descoberta de Drogas/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , beta-Lactamas/farmacocinética , beta-Lactamas/uso terapêutico , Administração Oral , Animais , Antibacterianos/administração & dosagem , Antibacterianos/classificação , Disponibilidade Biológica , Permeabilidade da Membrana Celular/efeitos dos fármacos , Meia-Vida , Haplorrinos , Humanos , Ligação Proteica , Estudos Retrospectivos , Solubilidade , Resultado do Tratamento , beta-Lactamas/administração & dosagem , beta-Lactamas/classificaçãoRESUMO
BACKGROUND: Patients with cystic fibrosis (CF) exhibit increased clearance of beta-lactams. The purpose of this study was to predict the probability of beta-lactam target attainment (PTA) against Pseudomonas aeruginosa in adult CF patients based on local microbiological data. METHODS: CF-specific pharmacokinetic parameters were obtained from published data for aztreonam, cefepime, ceftazidime, meropenem and piperacillin-tazobactam. Pharmacodynamic modeling was used to determine the PTA for bolus, prolonged infusion, and continuous infusion regimens. RESULTS: Prolonged infusion of meropenem 2g every 8h performed the best among all regimens tested, with a PTA of 83%. The PTA was increased with both prolonged and continuous infusion; however, no regimen reached the target PTA of >90% against P. aeruginosa in CF patients at our institution. CONCLUSIONS: Prolonged and continuous infusion provided higher PTA than bolus for all regimens. Further investigation of novel regimens in CF patients is needed.
Assuntos
Fibrose Cística , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Infecções Respiratórias/tratamento farmacológico , beta-Lactamas , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/classificação , Antibacterianos/farmacocinética , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Fibrose Cística/microbiologia , Vias de Administração de Medicamentos , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Testes de Sensibilidade Microbiana/métodos , Modelos Teóricos , Infecções por Pseudomonas/diagnóstico , Pseudomonas aeruginosa/isolamento & purificação , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/microbiologia , beta-Lactamas/administração & dosagem , beta-Lactamas/classificação , beta-Lactamas/farmacocinéticaRESUMO
Antibiotic resistance in bacteria is ever changing and adapting, as once-novel ß-lactam antibiotics are losing their efficacy, primarily due to the production of ß-lactamases. Metallo-ß-lactamases (MBLs) efficiently inactivate a broad range of ß-lactam antibiotics, including carbapenems, and are often coexpressed with other antibacterial resistance factors. The rapid dissemination of MBLs and lack of novel antibacterials pose an imminent threat to global health. In an effort to better counter these resistance-conferring ß-lactamases, an investigation of their natural evolution and resulting substrate specificity was employed. In this study, we elucidated the effects of different amino acid substitutions at position 67 in IMP-type MBLs on the ability to hydrolyze and confer resistance to a range of ß-lactam antibiotics. Wild-type ß-lactamases IMP-1 and IMP-10 and mutants IMP-1-V67A and IMP-1-V67I were characterized biophysically and biochemically, and MICs for Escherichia coli cells expressing these enzymes were determined. We found that all variants exhibited catalytic efficiencies (kcat/Km) equal to or higher than that of IMP-1 against all tested ß-lactams except penicillins, against which IMP-1 and IMP-1-V67I showed the highest kcat/Km values. The substrate-specific effects of the different amino acid substitutions at position 67 are discussed in light of their side chain structures and possible interactions with the substrates. Docking calculations were employed to investigate interactions between different side chains and an inhibitor used as a ß-lactam surrogate. The differences in binding affinities determined experimentally and computationally seem to be governed by hydrophobic interactions between residue 67 and the inhibitor and, by inference, the ß-lactam substrates.
Assuntos
Escherichia coli/enzimologia , Mutação , Fenilalanina/química , Valina/química , beta-Lactamases/química , beta-Lactamas/química , Substituição de Aminoácidos , Domínio Catalítico , Escherichia coli/genética , Evolução Molecular , Expressão Gênica , Hidrólise , Cinética , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Fenilalanina/metabolismo , Estrutura Secundária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato , Valina/metabolismo , beta-Lactamases/genética , beta-Lactamases/metabolismo , beta-Lactamas/classificação , beta-Lactamas/metabolismoRESUMO
A emergência e disseminação da resistência aos antimicrobianos são problemas de grande importância mundial, particularmente entre patógenos nosocomiais de importância clínica como os bacilos Gram negativos não fermentadores e membros da família Enterobacteriaceae. O principal mecanismo de resistência desses patógenos é a produção de β-lactamases, que são enzimas que hidrolisam o anel β-lactâmico impedindo assim a ação dos antimicrobianos β-lactâmicos. As β-lactamases foram dividas em quatro classes de acordo com a sua estrutura primária e podem também ser classificadas dentro de dois grupos com base no seu mecanismo catalítico, isto é, serina-β-lactamases (Classes A, C e D) e metalo-β-lactamases (Classe B). As metalo-β-lactamases (MβL) utilizam íons divalentes, comumente zinco, como co-fator para sua atividade catalítica e são atualmente uma das classes que mais merece destaque, devido à sua capacidade de hidrolisar todos os antimicrobianos β-lactâmicos, incluindo os carbapenens. Estes antimicrobianos são utilizados no tratamento de infecções causadas por bactérias Gram-negativas multirresistentes e conseguem se manter estáveis frente às serina-β-lactamases. A detecção de microrganismos produtores de MβL tem por finalidade auxiliar a Comissão de Controle de Infecção Hospitalar (CCIH) na prevenção da disseminação desse mecanismo de resistência no ambiente hospitalar e impedir que ele chegue até a comunidade, bem como enfatizar o uso racional dos antimicrobianos disponíveis para uso clínico, pois, atualmente,há poucos investimentos da indústria farmacêutica na pesquisa de novos agentes antimicrobianos.
The emergence and dissemination of antimicrobial resistance are problems of great importance worldwide, particularly between nosocomial pathogens of clinical importance such as nonfermentative Gram-negative bacilli and members of the family Enterobacteriaceae. The main mechanism of resistance these pathogens is the production of β-lactamases, which are enzymes that hydrolyzing the ring β-lactam hindering the action of antimicrobial β-lactam. The β- lactamases were classified into four classes of according its primary structure and may also be classified in two groups based on their catalytic mechanism, that is, serine-β-lactamases (Classes A, C and D) e metallo-β-lactamases (Class B). The metallo-β-lactamases (MβL) using ions divalentes, commonly zinc, as co-factor for its catalytic activity and currently represent one the most important class of enzymes, due of their ability to hydrolyze all antimicrobial β-lactam, including carbapenens, which are used in the treatment of Gram-negative bacteria multidrug-resistant and to remain stable before the serine-β-lactamases. The detection of samples producing of MβL helps infection control practioners to prevent the dissemination of this mechanism of resistance in the nosocomial environment and to prevent it come to the community, and emphasize the rational use of antimicrobial currently available for clinical use, since there are few investments in the pharmaceutical industry in search of new antimicrobial agents.
Assuntos
Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Farmacorresistência Bacteriana , beta-Lactamas/classificação , Genótipo , Bactérias Gram-NegativasRESUMO
Novel 4-alkylidene-beta-lactams with a polyphenolic side chain were synthesized and evaluated as radical scavengers. We have undertaken a detailed study of the antioxidant activity in vitro with chemical and biological testing of the new beta-lactams and of the corresponding methyl polyhydroxy benzoates. Antioxidant activity of beta-lactams and methyl benzoates was measured with the Briggs-Rauscher oscillating reaction, the TEAC (Trolox( Equivalent Antioxidant Capacity) assay, and as ability to inhibit ROS (=Reactive Oxygen Species) production on myoblast H9c2 cells. The results were discussed with regard to mechanism and correlated with structural parameters.
Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Flavonoides/química , Fenóis/química , beta-Lactamas/química , beta-Lactamas/farmacologia , Antioxidantes/síntese química , Antioxidantes/classificação , Benzoatos/química , Benzoatos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Estrutura Molecular , Polifenóis , Relação Estrutura-Atividade , beta-Lactamas/síntese química , beta-Lactamas/classificaçãoRESUMO
Recent years have seen an explosion in the numbers of extented spectrum class A beta-lactamases (ESBLs). The steady-state kinetic parameters for hydrolysis of beta-lactams by ESBLs is discussed in the light of what is known about the structure of these mutant enzymes.
Assuntos
Bactérias Gram-Negativas/enzimologia , beta-Lactamases/química , beta-Lactamases/metabolismo , beta-Lactamas/metabolismo , Bactérias Gram-Negativas/genética , Humanos , Hidrólise , Cinética , Modelos Moleculares , Mutação , Conformação Proteica , Relação Estrutura-Atividade , Especificidade por Substrato , Inibidores de beta-Lactamases , beta-Lactamases/genética , beta-Lactamas/química , beta-Lactamas/classificaçãoAssuntos
Antibacterianos , beta-Lactamas , Antibacterianos/química , Antibacterianos/classificação , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Farmacorresistência Bacteriana , Humanos , Injeções , Soluções Farmacêuticas , Relação Estrutura-Atividade , beta-Lactamas/química , beta-Lactamas/classificação , beta-Lactamas/farmacologiaAssuntos
Antibacterianos/farmacologia , Infecções Bacterianas/tratamento farmacológico , beta-Lactamas/farmacologia , Antibacterianos/classificação , Antibacterianos/uso terapêutico , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Humanos , Monobactamas/farmacologia , Monobactamas/uso terapêutico , beta-Lactamas/classificação , beta-Lactamas/uso terapêuticoRESUMO
While beta-lactam compounds were discovered in filamentous fungi, actinomycetes and gram-negative bacteria are also known to produce different types of beta-lactams. All beta-lactam compounds contain a four-membered beta-lactam ring. The structure of their second ring allows these compounds to be classified into penicillins, cephalosporins, clavams, carbapenens or monobactams. Most beta-lactams inhibits bacterial cell wall biosynthesis but others behave as beta-lactamase inhibitors (e.g., clavulanic acid) and even as antifungal agents (e.g., some clavams). Due to the nature of the second ring in beta-lactam molecules, the precursors and biosynthetic pathways of clavams, carbapenems and monobactams differ from those of penicillins and cephalosporins. These last two groups, including cephamycins and cephabacins, are formed from three precursor amino acids that are linked into the alpha-aminoadipyl-L-cysteinyl-D-valine tripeptide. The first two steps of their biosynthetic pathways are common. The intermediates of these pathways, the characteristics of the enzymes involved, the lack of introns in the genes and bioinformatic analysis suggest that all of them should have evolved from an ancestral gene cluster of bacterial origin, which was surely transferred horizontally in the soil from producer to non-producer microorganisms. The receptor strains acquired fragments of the original bacterial cluster and occasionally inserted new genes into the clusters, which once modified, acquired new functions and gave rise to the final compounds that we know. When the order of genes in the Streptomyces genome is analyzed, the antibiotic gene clusters are highlighted as gene islands in the genome. Nonetheless, the assemblage of the ancestral beta-lactam gene cluster remains a matter of speculation.
Assuntos
Antibacterianos/metabolismo , Genes Bacterianos , Genes Fúngicos , Família Multigênica , beta-Lactamas/metabolismo , Antibacterianos/classificação , Bactérias/genética , Bactérias/metabolismo , Resistência Microbiana a Medicamentos/genética , Fungos/genética , Fungos/metabolismo , Amplificação de Genes , beta-Lactamas/classificaçãoRESUMO
A method is described to determine the values of the equilibrium (K) and rate (k(2)) constants for enzyme inactivations which occur according to two-step pathways involving a first non-covalent complex and a covalent, irreversibly inactivated adduct. The method rests on a competition between a reference compound [R] for which the k(2) and K values are already known and another inactivator [C]. During the experiments, the disappearance of the reference compound or the appearance of the ER(*) adduct is monitored. The analysis shows that under conditions where the k(2) and K values for the competing substrate can be determined, the measured apparent first-order rate constant for the disappearance of the reference compound is not the sum of the rate constants obtained for each inactivator in the absence of the other. The method can be used to determine the K and k(2) constants when an adequate reference compound is available, in particular, for the interactions between beta-lactam antibiotics and penicillin-binding proteins. The precautions which must be taken to avoid large errors on the estimation of the parameters of the competing inactivator are discussed. Examples found in the literature are discussed where an erroneous simplified equation has been utilised, thus yielding incorrect values for k(2) and K. Interestingly, the correct values can be calculated on the basis of the published results which do not contain the raw experimental data. But some of the values should be considered with a lot of caution since the experiments have not been performed under optimal conditions.
Assuntos
Ligação Competitiva/efeitos dos fármacos , Inibidores Enzimáticos/metabolismo , Enzimas Imobilizadas/efeitos dos fármacos , Métodos , Proteínas de Ligação às Penicilinas/antagonistas & inibidores , Algoritmos , Antibacterianos/química , Antibacterianos/classificação , Antibacterianos/farmacocinética , Interações Medicamentosas , Cinética , Proteínas de Ligação às Penicilinas/química , Proteínas de Ligação às Penicilinas/farmacocinética , beta-Lactamas/química , beta-Lactamas/classificação , beta-Lactamas/farmacocinéticaAssuntos
Antibacterianos , beta-Lactamas , Antibacterianos/efeitos adversos , Antibacterianos/classificação , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Monitoramento de Medicamentos , Farmacorresistência Bacteriana , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , beta-Lactamas/efeitos adversos , beta-Lactamas/classificação , beta-Lactamas/farmacocinética , beta-Lactamas/farmacologiaRESUMO
Many beta-lactam antimicrobials were developed between the 1960s and 1980s, with continuing development driven by the emergence of microbial resistance. Penems form a discrete class of beta-lactams that comprises structural hybrids of penicillins (penams) and cephalosporins (cephems). The chemistry and microbiology of the representative penems MEN 10700, ritipenem, CGP 31608, sulopenem, BRL 42715, and faropenem are reviewed. Particular emphasis is placed on faropenem, which is in late clinical development.
Assuntos
Lactamas , beta-Lactamas/química , beta-Lactamas/classificação , beta-Lactamas/farmacologia , beta-Lactamas/uso terapêutico , Animais , Resistência Microbiana a Medicamentos/fisiologia , HumanosRESUMO
Beta-lactamase production in Pseudomonas aeruginosa was determined in in-vitro models and in rat pouch infection models after exposure to ceftazidime, imipenem, and piperacillin. Exposure of 28 P. aeruginosa strains to 1/4 minimum inhibitory concentration (MIC) of ceftazidime, imipenem, and piperacillin for 24 h enhanced intracellular beta-lactamase activities in 14, 22, and 6 strains, respectively, of the 28 clinical strains tested, and enhanced extracellular beta-lactamase activities which were not detected without exposure to antibiotics, in 7, 23, and 1 of the 28 strains, respectively. Extracellular beta-lactamase activity from P. aeruginosa S-1278, producing an inducible beta-lactamase, scarcely increased after exposure to ceftazidime and piperacillin 24 h after incubation, while the activity increased after exposure to imipenem over the range of 1/8 to 8 MIC. In the rat granuloma pouch models infected with P. aeruginosa S-1278, ceftazidime and piperacillin, after single administration (20 mg/kg) and serial administration (20 mg/kg per day x 3 days), did not enhance extracellular beta-lactamase activities. However, the activities were enhanced with single and serial administrations of imipenem, and levels over 10 mU/ml were detected until the third day. The beta-lactamase activity, similar to the activity found in rat pouches after serial administration of imipenem, inactivated various cephalosporins. In conclusion, extracellular beta-lactamase activity was detected both in vitro and in vivo after exposure to a good inducer, and extracellular beta-lactamase remained at infection site at levels that could inactivate cephalosporins.
Assuntos
Antibacterianos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/enzimologia , beta-Lactamases/metabolismo , beta-Lactamas/farmacologia , Animais , Antibacterianos/classificação , Antibacterianos/uso terapêutico , Células Cultivadas/efeitos dos fármacos , Granuloma/tratamento farmacológico , Masculino , Testes de Sensibilidade Microbiana , Ratos , Ratos Wistar , beta-Lactamases/efeitos dos fármacos , beta-Lactamas/classificação , beta-Lactamas/uso terapêuticoRESUMO
Combinatorial chemistry has became a core technology for the rapid development of novel lead compounds in the pharmaceutical industry and for the optimization of therapeutic efficacy. The effort to prepare libraries of compounds by combinatorial chemistry has led to an unprecedented growth in solid phase organic synthesis (SPOS), particularly for the preparation of non-oligomeric small molecules. In this context, the clinically valuable b-lactam compounds are very attractive targets for research using these new techniques. In recent years, b-lactam compounds have been recognized not only as unique antibacterial agents but also as potent enzyme inhibitors, drug delivery agents, and versatile synthetic intermediates. This review gives a comprehensive up-date for the application of solid-phase and combinatorial synthesis to b-lactam compounds.