Reatividade cruzada entre betalactâmicos: uma abordagem prática / Cross-reactivity among beta-lactams: a practical approach

Os betalactâmicos são a classe de drogas que mais causam reações de hipersensibilidade envolvendo um mecanismo imunológico específico, e são os principais desencadeantes entre os antimicrobianos. São representados pelas penicilinas, cefalosporinas, carbapenêmicos, monobactâmicos e inibidores da betalactamase. A estrutura química básica destes fármacos consiste na presença dos seguintes componentes: anel betalactâmico, anel adjacente e cadeias laterais, sendo todos potenciais epítopos. Os anticorpos da classe IgE e linfócitos T estão frequentemente envolvidos no reconhecimento desses epítopos. A reatividade cruzada depende da estabilidade dos produtos intermediários (determinantes antigênicos) derivados da degradação dos anéis betalactâmicos, anéis adicionais e da semelhança estrutural das cadeias laterais entre as drogas. Classicamente acreditava-se num grande potencial de reatividade cruzada dentro de cada classe e até entre as classes, mas estudos da última década mostraram que indivíduos alérgicos à penicilina (com testes cutâneos positivos) reagiam às cefalosporinas em aproximadamente 3% dos casos, aos carbapenêmicos em cerca de 1%, e praticamente não reagiam aos monobactâmicos. Essa reatividade ou tolerância parece estar vinculada ao grau de similaridade entre as cadeias laterais desses antibióticos. Nesta revisão, ressaltamos a importância da investigação sistematizada na confirmação ou exclusão de alergia aos betalactâmicos, descrevemos a prevalência da reatividade cruzada entre estes fármacos e sugerimos um algoritmo de abordagem desses pacientes baseados em sua estrutura química e nos dados publicados na literatura.

Beta-lactams are the drugs most commonly involved in hypersensitivity reactions mediated by a specific immune mechanism and are the main triggers among antibiotics. They include penicillins, cephalosporins, carbapenems, monobactams and beta-lactam inhibitors. The basic chemical structure of these drugs consist on the presence of the following components: betalactam ring, an adjacent ring and side chains, all of which are potential epitopes. IgE antibodies and T lymphocytes are often involved in recognizing those epitopes. Cross-reactivity depends on the stability of intermediate products (antigenic determinants) derived from the degradation of the beta-lactam ring, on the adjacent rings, and on the structural similarity of the side chains between drugs. Classically, it was believed that there was a great potential for cross-reactivity within each class and even between classes, but studies from the last decade showed that individuals allergic to penicillin (with positive skin tests) reacted to cephalosporins in approximately 3% of cases, to carbapenems in about 1%, and rarely reacted to monobactams. This reactivity or tolerance seems to be linked to the degree of similarity between the side chains of these antibiotics. In this review, we emphasize the importance of systematic investigation to confirm or exclude allergy to beta-lactams, we describe the prevalence of crossreactivity between these drugs and we suggest an algorithm for approaching these patients based on their chemical structure and on data published in the literature.

Differences in Antimicrobial Resistance Phenotypes by the Group of CTX-M Extended-Spectrum β-Lactamase / 대한임상미생물학회지

BACKGROUND: Escherichia coli and Klebsiella pneumoniae clinical isolates producing CTX-M extendedspectrum β-lactamases (ESBLs) were assessed for antimicrobial resistance phenotypes varied by group of enzymes. METHODS: A total of 1,338 blood isolates, including 959 E. coli and 379 K. pneumoniae, were studied. All the strains were collected between January and July 2017 from eight general hospitals in South Korea. The species were identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Antimicrobial susceptibilities were determined by disk diffusion methods and ESBL phenotypes by double-disk synergy tests using disks containing cefotaxime, ceftazidime, cefepime, aztreonam, and clavulanic acid (CA). The genes for β-lactamases were identified by PCR and sequencing. RESULTS: Of total microbes, 31.6% (303/959) E. coli and 24.0% (91/379) K. pneumoniae were resistant to cefotaxime and 28.1% (269/959) E. coli and 20.1% (76/379) K. pneumoniae were CTX-M-type ESBL producers. Among the detected CTX-M ESBLs, 58.0% (156/269) in E. coli and 86.8% (66/76) in K. pneumoniae belonged to group 1, 46.8% (126/269) in E. coli and 14.5% (11/76) in K. pneumoniae were group 9. Ten E. coli and one K. pneumoniae isolates co-produced both groups of CTX-M ESBL. The group 1 CTX-M producers had a higher level of resistance to cefotaxime, ceftazidime, cefepime, and aztreonam and exhibited stronger synergistic activities when combined with CA compared to group 9. CONCLUSION: ESBL phenotypes differ by CTX-M ESBL group and phenotype testing with drugs including 4th generation cephalosporins and monobactams is critical for screening CTX-M-producers with better sensitivity.

effect of amoxicillin on the fetuses of albino mice

Introduction: The present study was carried out to evaluate the effect of the beta-lactam antibiotic amoxicillin on the fetuses of albino mice from the morphological and skeletal points of view

Material and methods: Twenty four adult pregnant mice were used in the present study. They were allocated into 3 groups [8 mice each]. The first group served as a control and were injected intraperitoneally [i.p.] with the solvent of the drug and the second and third groups were treated with 205 and 820 mg/kg body weight of amoxicillin for 8 days [gestation days 7-14], respectively

Results: The morphological examination of the fetuses of treated groups showed growth retardation of mice fetuses as represented by the conspicuous decrease in the average body weight and body length in the two treated groups. No external malformations were recorded among fetuses maternally treated with the low dose of the drug. On the other hand, the fetuses maternally treated with the high dose showed mild external morphological malformations. In addition, the skeleton of the two treated groups exhibited incomplete ossification in most skeletal elements

Conclusion: The beta-lactam antibiotic amoxicillin had exerted mild morphological malformations and skeletal abnormalities in mice fetuses maternally treated during organogenesis period of gestation

Histological and ultrastructural studies on the effect amoxicillin on the stomach of mouse fetuses

Introduction: B-Lactam antibiotics are widely used because of their lack of toxicity in humans. However, during pregnancy, exposure of the fetus is likely to occur due to b-lactam antibiotics cross the placenta. The potential adverse effects of amoxicillin were examined in stomach of mice fetuses

Material and Methods: This study was aimed to evaluate the possible side effects produced by amoxicillin prenatal administration on the stomach of fetuses. Twenty pregnant mice were used in this study; and were divided into two groups: the first group served as a control group and injected by saline solution [the drug solvent]; the second group treated with amoxicillin dose of 205 mg/kg body weight. The treatment was daily administered interperitoneally, from the 7[th] day of gestation till the 14[th] day of gestation [GDs 7-14]. The developing 19-days old fetuses were examined histologically and ultrastructurally to determine any disorders in the stomach

Results: This study illustrated marked deleterious consequences in the gastric wall of 19 day old fetus, following the treatment with amoxicillin, ranging from marked vacuolations and erosions in the epithelial and glandular cells of the gastric mucosa to conspicuous necrosis of glandular [parietal and zymogenic] cells. The electron microscopical examination of the gastric mucosal cells of fetuses maternally treated with amoxicillin, revealed conspicuous alterations, in the cytoplasmic organelles of gastric mucosal cells [surface epithelial, peptic and parietal cells]. The cisternae of RER were dilated and fragmented. The mitochondria displayed gradual devastations

Conclusions: Therefore, the destructive impacts of amoxicillin on the stomach of mice fetuses indicated that it should be used under restricted precautions in the medical fields to protect the pregnant women from its hazardous impact

Epidemiology and Characteristics of Metallo-beta-Lactamase-Producing Pseudomonas aeruginosa

Metallo-beta-lactamase-producing Pseudomonas aeruginosa (MPPA) is an important nosocomial pathogen that shows resistance to all beta-lactam antibiotics except monobactams. There are various types of metallo-beta-lactamases (MBLs) in carbapenem-resistant P. aeruginosa including Imipenemase (IMP), Verona integron-encoded metallo-beta-lactamase (VIM), Sao Paulo metallo-beta-lactamase (SPM), Germany imipenemase (GIM), New Delhi metallo-beta-lactamase (NDM), Florence imipenemase (FIM). Each MBL gene is located on specific genetic elements including integrons, transposons, plasmids, or on the chromosome, in which they carry genes encoding determinants of resistance to carbapenems and other antibiotics, conferring multidrug resistance to P. aeruginosa. In addition, these genetic elements are transferable to other Gram-negative species, increasing the antimicrobial resistance rate and complicating the treatment of infected patients. Therefore, it is essential to understand the epidemiology, resistance mechanism, and molecular characteristics of MPPA for infection control and prevention of a possible global health crisis. Here, we highlight the characteristics of MPPA.

Clinical Significance of Extended-Spectrum beta-Lactamase Producing Escherichia coli in Pediatric Patients with Febrile Urinary Tract Infection

PURPOSE: The incidence of community-acquired urinary tract infection (UTI) due to extended-spectrum beta-lactamase producing Escherichia coli (ESBL(+) E. coli) has increased worldwide. ESBL causes resistance to various types of the newer beta-lactam antibiotics, including the expanded spectrum cephalosporins and monobactams. We aimed to investigate the severity of UTI and associated genitourinary malformations in children with febrile UTI caused by ESBL(+) E. coli. METHODS: We retrospectively reviewed the medical records of 290 patients diagnosed as febrile UTI caused by E. coli between January 2008 and October 2010 at Korea University Medical center. We classified the patients into two groups with ESBL(+) and ESBL(-) E. coli group according to the sensitivity of urine culture. Fever duration, admission period, white blood cell (WBC) counts and C-reactive protein (CRP) in peripheral blood, the presence of hydronephrosis, cortical defects, vesicoureteral reflux (VUR) and renal scar were compared between the two groups. RESULTS: Patients with ESBL(+) E. coli were 32, and those with ESBL(-) E. coli were 258. If we excluded those tested with a sterile urine bag, patients with ESBL(+) E. coli were 22, and those with ESBL(-) E. coli were 212. Whether the results of sterile urine bag tests were included or not, there was no significant difference in all parameters between the two groups statistically. CONCLUSION: Our data shows that ESBL(+) E. coli may not be related to the severity of UTI and associated genitourinary malformations.

A Case Report of Sepsis by Extended-Spectrum beta-Lactamase Producing Escherichia Coli / 가정의학회지

The overall prognosis of acute pyelonephritis is good, but the infections by extended spectrum beta-lactamase (ESBL) producing Escherichia coli (E.coli) cause poor responses to empirical antibiotic treatment, and consequently increase mortality. ESBL can hydrolyze the antibiotics with a beta-lactam ring and confer resistance to oxyimino-cephalosporins and monobactams. If the patient shows poor responses to empirical antibiotics or severe septic conditions, physicians must switch the antibiotics to other antibiotics covering resistant strains without delay. We report a case of acute pyelonephritis by extended-spectrum beta-lactamase producing E.coli in a 29-year-old woman who was empirically treated with oral ciprofloxacin as an initial treatment, but progressed to sepsis.

A Case Report of Sepsis by Extended-Spectrum beta-Lactamase Producing Escherichia Coli / 가정의학회지

The overall prognosis of acute pyelonephritis is good, but the infections by extended spectrum beta-lactamase (ESBL) producing Escherichia coli (E.coli) cause poor responses to empirical antibiotic treatment, and consequently increase mortality. ESBL can hydrolyze the antibiotics with a beta-lactam ring and confer resistance to oxyimino-cephalosporins and monobactams. If the patient shows poor responses to empirical antibiotics or severe septic conditions, physicians must switch the antibiotics to other antibiotics covering resistant strains without delay. We report a case of acute pyelonephritis by extended-spectrum beta-lactamase producing E.coli in a 29-year-old woman who was empirically treated with oral ciprofloxacin as an initial treatment, but progressed to sepsis.

Avaliação do ertapenem frente a bacilos gram negativos produtores de enzima beta lactamase de espectro expandido (ESBL) / Evaluation of the ertapenem front to negative bacilli gram enzyme producers beta lactamase of expanded specter (ESBL)

A resistência bacteriana aos agentes antimicrobianos se tornou uma séria ameaça à saúde pública em todo o mundo, transformando-se em um problema crescente tanto nos ambientes hospitalares quanto na vida diária das comunidades. A busca de novas substâncias capazes de reduzir a atuação e a disseminação dessas bactérias resistentes se tornou um objetivo importante a ser alcançado, notadamente no que diz respeito aos bacilos Gram negativos produtores de enzima β-lactamase de espectro expandido (ESBL), principalmente no caso de Klebsiella e Escherichia coli, que apresentam uma crescente resistência aos agentes β-lactâmicos de amplo espectro. O ertapenem se apresenta hoje como uma das novas alternativas para o tratamento de infecções causadas por estas bactérias. Este trabalho tem como objetivo verificar a eficácia do tratamento antimicrobiano com o Ertapenem, nas infecções causadas por ESBL. Os resultados obtidos apontam para a comprovação de sua eficácia, visto que de 50 amostras testadas, de bacilos Gram negativos, comprovadamente ESBL, 48 se mostraram realmente eficientes, eliminando ou impedindo a proliferação de bactérias. Podemos concluir que o Ertapenem sódico realmente atua de forma eficaz no tratamento das infecções causadas por Bactérias comprovadamente produtoras de ESBL

Antibiotics in older adults

Antibiotics are frequently prescribed in the older person, the dosification needs special care, since the pharmacokinetic parameters changes with aging and the side effects can be different in the older person. The creatinine clearance changes and we must modify the way we prescribe such antibiotics to the elderly, calculating. The variety of antibiotics now available led us to consider this paper in which we have presented the antimicrobial agents that can be considered in the treatment of the older person. We present several groups: the penicillins, cephalosporins, monobactams, carbapenems and betalactamase inhibitors or the great betalactam group. Other trimetroprin-sulfame-thoxazole, the newer macrolides (azithromycin and clarithromycin) as well as the aminoglycosides, vancomycin, clindamycin, metroridazole. The indications and contraindications are presented and reviewed.

Characteristics of Extended-spectrum beta-lactamase of Escherichia coli Strains Isolated from Clinical Specimens / 대한임상병리학회지

BACKGROUND: Recently Escherichia coli isolates with extended-spectrum beta-lactamase(ESBL) have been increased in Korea. ESBLs confer variable levels of resistance to cefotaxime, ceftazidime and other broad-spectrum cephalosporins as well as to monobactams such as aztreonam, but they have no detectable activity against cephamycins and carbapenems. The aim of this study was to characterize the ESBL produced by E. coli strains isolated from clinical specimens. METHODS: From March to July, 1998, a total of 93 clinical isolates of E. coli, which was produced ESBL, were collected from patients of the Asan Medical Center. The isolates flagged as ESBL producers by microbroth dilution antibiotic susceptibility test were confirmed by the double disk synergy test. Minimal inhibitory concentration(MIC) of beta-lactams were determined by agar dilution method. The presence of TEM, SHV or CMY-1 gene was determined by polymerase chain reaction. The types of beta-lactamase gene were determined by isoelectric focusing and nucleotide sequence analysis. RESULTS: Sixty-two strains carried plasmid-mediated TEM-52 gene, which sequence showed the substitution of 3 amino acids compared to that of TEM-1. Seventeen strains produced SHV-12, six strains produced SHV-2a, three strains produced TEM-52 and SHV-12, three strains produced TEM-52 and SHV-2a, and one strain produced SHV-2a and SHV-12. One out of twenty-seven strains of cefoxitin-resistant E. coli was confirmed to have CMY-1 beta-lactamase by PCR and nucleotide sequence analysis. CONCLUSIONS: TEM-52 was the most prevalent in E. coli isolates. The most common SHV-types of ESBL in Korea are SHV-12 and SHV-2a in E. coli isolates. In Korea, widespread use of oxyimino-cephalosporins in the hospitals has dramatically increased the prevalence of ESBL-producers in E. coli. Therefore, more prudent use of antibiotics is necessary to reduce the spread of these resistant organisms.

Carbapenémicos y monobactámicos / Carbapenemics and monobactemics

Se hace una revisión y actualización de los antibióticos del grupo de los carbapenémicos y monobactámicos, se hace énfasis en algunos aspectos como espectro antibacteriano, utilidad clínica, estructura química y otros. Se señalan las diferencias entre los diversos fármacos que conforman estos grupos

Aztreonam no tratamento de infecçöes causadas por bacilos Gram-negativos de múltiplas resistências / Astreonam in the treatment of infections caused by Gram-negative bacilli of multiple resistance

Aztreonam é um composto de uma nova classe de agentes Beta-lactâmicos monocíclicos sintéticos com atividade contra a grande maioria das bactérias Gram-negativas, mas nao contra as bactérias Gram-positivas ou anaeróbias. Aztreonam foi usado para tratar 23 pacientes com importantes infeccçoes por germes Gram-negativos. Neste estudo dos 17 homens e seis mulheres, haviam 11 casos de infecçoes urinárias, três de pneumonia, três de meningite e seis com outros locais de infecçao. Noventa por cento das infecçoes foram curadas tanto por critérios clínicos como microbiológicos sem significantes reaçoes adversas ou toxicidade pela droga.

Nuevos antibióticos: carbapenem y monobactamicos / New antibiotics: carbapenem and monobactamics

Los nuevos betalactámicos representan una valiosa adquisición en el tratamiento de las infecciones graves y moderadas. Estos novedosos antibióticos tienen un amplio espectro antimicrobiano, excelentes propiedades farmacocinéticas y muy baja toxicidad. Los betalactámicos de reciente adquisición incluyen los carbapenem y los monobactámicos. Los monobactámicos están representados fundamentalmente por el aztreonam, y los carbapenem por la combinación de thienamicin más cilastatín. Constituyen una alternativa excelente en la antibioticoterapia futura. En este artículo se revisan estos nuevos antibióticos en su espectro de acción y fundamentalmente su uso clínico