Allergy to penicillin and betalactam antibiotics / Alergia a penicilina e antibióticos beta-lactâmicos

ABSTRACT Betalactams are the most frequent cause of hypersensitivity reactions to drugs mediated by a specific immune mechanism. Immediate reactions occur within 1 to 6 hours after betalactam administration, and are generally IgE-mediated. They clinically translate into urticaria, angioedema and anaphylaxis. Non-immediate or delayed reactions occur after 1 hour of administration. These are the most common reactions and are usually mediated by T cells. The most frequent type is the maculopapular or morbilliform exanthematous eruption. Most individuals who report allergies to penicillin and betalactams can tolerate this group of antibiotics. To make diagnosis, a detailed medical history is essential to verify whether it was an immediate or non-immediate reaction. Thereafter, in vivo and/or in vitro tests for investigation may be performed. The challenging test is considered the gold standard method for diagnosis of betalactam hypersensitivity. The first approach when suspecting a reaction to betalactam is to discontinue exposure to the drug, and the only specific treatment is desensitization, which has very precise indications. The misdiagnosis of penicillin allergy affects the health system, since the "penicillin allergy" label is associated with increased bacterial resistance, higher rate of therapeutic failure, prolonged hospitalizations, readmissions, and increased costs. Thus, it is essential to develop strategies to assist the prescription of antibiotics in patients identified with a label of "betalactam allergy" at hospitals, and to enhance education of patients and their caregivers, as well as of non-specialist physicians.

RESUMO Os beta-lactâmicos constituem a causa mais frequente de reações de hipersensibilidade a fármacos mediadas por mecanismo imunológico específico. As reações imediatas ocorrem em 1 até 6 horas após a administração do beta-lactâmico, sendo geralmente IgE-mediadas. Elas se traduzem clinicamente por urticária, angioedema e anafilaxia. As reações não imediatas ou tardias ocorrem após 1 hora da administração. São as reações mais comuns, sendo geralmente mediadas por células T. O tipo mais frequente é o exantema maculopapular ou morbiliforme. A maioria dos indivíduos que refere alergia aos beta-lactâmicos pode tolerar esse grupo de antibióticos. No diagnóstico, uma história clínica detalhada é fundamental para verificar se a reação foi do tipo imediato ou não imediato. A partir daí, podem ser realizados testes in vivo e/ou in vitro para investigação. O teste de provocação é considerado o método padrão-ouro no diagnóstico de hipersensibilidade aos beta-lactâmicos. A primeira conduta diante da suspeita de uma reação ao beta-lactâmico é suspender a exposição ao medicamento, e o único tratamento específico é a dessensibilização, que possui indicações bem precisas. O diagnóstico equivocado de alergia à penicilina afeta o sistema de saúde, pois o rótulo de "alergia à penicilina" está associado a aumento da resistência bacteriana, maior índice de falha terapêutica, hospitalizações prolongadas, readmissões e aumento dos custos. Assim, torna-se fundamental elaborar estratégias com o objetivo de auxiliar na prescrição de antibióticos em pacientes com rótulo de "alergia aos beta-lactâmicos" nos hospitais e melhorar a educação dos pacientes e seus responsáveis, além de médicos não especialistas.

¿Cumplimos el objetivo de farmacocinética y farmacodinamia en pacientes críticos que reciben antibióticos betalactámicos? / Do we meet the goal of pharmacokinetics and pharmacodynamics in critically ill patients receiving beta-lactam antibiotics?

Introducción: Los pacientes críticamente enfermos presentan cambios fisiopatológicos que alteran las concentraciones de antibióticos betalactámicos. El objetivo fue determinar si las dosis de uso habitual en pacientes críticos alcanzan las concentraciones asociadas con mayor actividad y establecer las variables de PK/PD que se asocian con concentraciones subóptimas de antibiótico.Métodos: Estudio prospectivo realizado en una terapia intensiva de adultos en un periodo de 13 meses. Se incluyeron pacientes que recibieron cefazolina, ceftriaxona, ceftazidima o meropenem. Se realizó dosaje de concentración de antibiótico en plasma en el 50% del intervalo de dosis. Se calculó la concentración de antibiótico libre y se comparó con el objetivo 50% fT>CIM y el objetivo 50% fT>CIM x 4 para los microorganismos susceptibles definidos, según criterios del CLSI. Se comparó el grupo de pacientes que cumplió el objetivo 50% fT>CIM x 4 con el que no, en términos de variables de PK/PD.Resultados: Se incluyeron 29 determinaciones y 55 comparaciones. En el 92,7% de los casos se alcanzó el objetivo 50% fT>CIM y en el 61,8% el objetivo 50% fT>CIM x 4. En el peor escenario, es decir considerando el germen susceptible con CIM más alta, solo el 48,3% de los pacientes cumplieron el objetivo 50% fT>CIM x 4. Los pacientes que no llegaron al objetivo 50% fT>CIM x 4 tuvieron mayor RESUMENARTÍCULO ORIGINALaclaramiento renal que los que sí lo hicieron (160 vs 108,5 ml/min/1,73m2, p= 0,01). Conclusiones: un gran porcentaje de pacientes críticos que recibe betalactámicos no alcanza las metas de PK/PD recomendadas en la actualidad

Introduction: critically ill patients have physiopathological changes that upset the concentrations of beta-lactam antibiotics. The aim was to determine if the doses of usual use in critically ill patients reach the concentrations associated with maximal activity and to establish the variables of PK/PD that are associated with suboptimal concentrations of antibiotic. Methods: prospective study conducted in an intensive therapy of adults in a period of 13 months. Patients who received cefazolin, ceftriaxone, ceftazidime or meropenem were included. Dosage of antibiotic concentration in plasma was performed at 50% of the dose interval. The concentration of free antibiotic was calculated and compared with the objective 50% fT>MIC and the objective 50% fT>MIC x 4 for susceptible microorganisms, according to CLSI criteria. The group of patients who met the 50% objective fT>MIC x 4 was compared with the one who did not, in terms of PK/PD variables. Results: 29 determinations and 55 comparisons were included. The objective 50% fT>MIC was reached in 92.7% of the cases and the target 50% fT>MIC x 4 was achieved in 61.8%. In the worst scenario, that is, considering the germ susceptible with MIC higher, only 48.3% of patients met the objective 50% fT>MIC x 4. Patients who did not reach the goal 50% fT>MIC x 4 had greater renal clearance than those who reached the goal (160 vs 108.5 ml/min/1.73m2, p=0.01). Conclusions: a large percentage of critically ill patients receiving beta-lactams do not reach the PK/PD goals recommended nowadays

Clonal relation and antimicrobial resistance pattern of extended-spectrum ß-lactamase- and AmpC ß-lactamase-producing Enterobacter spp. isolated from different clinical samples in Tehran, Iran

Abstract INTRODUCTION: Here, we determined the genes encoding antibiotic resistance enzymes and virulence factors and evaluated the genetic relationship between Enterobacter spp. isolated from different clinical samples. METHODS: A total of 57 clinical isolates of Enterobacter spp. were tested for the production of extended-spectrum β-lactamases (ESBLs), carbapenemase, and AmpC using phenotypic and genotypic methods. RESULTS: The most common ESBLs and AmpC β-lactamases were bla TEM (63.3%) and bla EBC (57.7%), respectively. The most prevalent virulence gene was rpos (87.7%). The random amplified polymorphic DNA (RAPD) patterns of strains were genetically unrelated. CONCLUSIONS: RAPD polymerase chain reaction analysis revealed high genetic diversity among isolates.

Interacciones farmacológicas relacionadas con la administración de antibióticos betalactámicos / Drug interactions related to the administration of beta-lactam antibiotics

Los antibióticos betalactámicos son los que más se usan en el tratamientoy profilaxis de las infecciones odontogénicas. Con frecuenciaes necesario prescribir un segundo antibiótico que incremente el efectodel primero. Debido a ello se hizo una revisión de los antibióticos y otros medicamentos que administrados simultáneamente o en forma secuencial con betalactámicos producen efectos deseados (sinergismo, potenciación) o indeseados (antagonismo) o provocan efectos adversos en el organismo.

Beta-lactams are the most commonly used antibiotics in the treatmentand prophylaxis of odontogenic infections. It is often necessary toprescribe a second antibiotic to increase the eff ect of the fi rst. For thisreason, we performed a review of antibiotics and other medicationswhich, when administered simultaneously or sequentially with betalactams,produce desirable (synergism, potentiation) or undesirable(antagonism) eff ects or provoke adverse eff ects in the organism.

Aspectos práticos no diagnóstico e manejo das reações de hipersensibilidade a fármacos / Practical aspects in the diagnosis and management of drug hypersensitivity reactions

As reações de hipersensibilidade a fármacos (RHF) podem ser de natureza alérgica ou não alérgica, e correspondem a aproximadamente 15% de todas as reações adversas a fármacos (RAF). As reações alérgicas são mediadas por mecanismo imune, não previsíveis, podendo ser grave se até mesmo fatais, ou requererem internações hospitalares prolongadas. Erros na classificação das RHF ocorrem com frequência, principalmente quando o diagnóstico é baseado apenas na história clínica (superdiagnóstico) ou quando as reações não são documentadas de maneira apropriada (subdiagnóstico). O diagnóstico inadequado pode levar à exclusão desnecessária, com diminuição das opções terapêuticas, e ao uso de fármacos alternativos ineficazes e/ou de custo elevado. Os grupos de fármacos mais comumente envolvidos em reações de hipersensibilidade são os betalactâmicos e os anti-inflamatórios não esteroidais (AINEs). Consensos atuais preconizam uma investigação diagnóstica sistematizada das RHF através da realização de testes cutâneos, laboratoriais e testes de provocação, direcionados por uma história clínica detalhada. O objetivo do presente estudo é abordar aspectos práticos do diagnóstico e manejo das reações de hipersensibilidade a fármacos, com ênfase aos betalactâmicos e AINEs, de acordo com os estudos e consensos atuais...

Drug hypersensitivity reactions (DHRs) may be classified as allergic or non-allergic, and they correspond to approximately 15% of all adverse drug reactions (ADRs). Allergic reactions are non-predictable and mediated by immune mechanisms; they may be severe and even life threatening, or may require prolonged hospitalization. Misclassification of DHRs is frequent, especially when diagnosis is based only on medical history (overdiagnosis), or when reactions are not properly documented (underdiagnosis). An incorrect diagnosis may lead to unnecessary exclusion of drugs, reducing treatment options, as well as to the use of alternative ineffective and/or expensive medications. Beta-lactam and non-steroidal anti-inflammatory drugs are the groups most commonly involved in DHRs. Current guidelines recommend a systematic diagnostic investigation of DHRs using skin, laboratory, and provocations tests, guided by a detailed medical history. The aim of this study was to address practical aspects of the diagnosis and management of DHRs, with a focus on beta-lactam and non-steroidal anti-inflammatory drugs, according to current studies and consensuses...

Penicillin allergy and cross-reactivity with other beta-lactams

Beta-lactams are a group of antibiotics with a broad spectrum of both Gram-negative and Gram-positive coverage. The goal of this study is to evaluate the results from studies regarding Ig-E mediated hypersensitivity to Penicillin and cross-reactivity with other beta-lactams. Review was conducted of both retrospective and prospective studies by searching in PubMed and Medline for the original and systematic review articles by using the keywords: penicillin allergy, beta-lactams and cross-reactivity. The rate of true Penicillin allergy is about 10% of reported cases by the patients. The rate of Ig-E mediated cross-reactivity between Penicillin and Cephalosporins is less than 10% for the first and second generations and less than 5% for the third and fourth generations. According to the reviewed studies, Imipenem has between 9.2% to 25.6% cross-reactivity with Penicillin. Recent studies have shown safe use of Meropenem in patients with penicillin allergy even with positive skin test. The only member of Monobactam family, Aztreonam, has no cross-reactivity with any of Penicillins, Cephalosporins [with the exception of Ceftazidime] and Carbapenems. Due to the low rate of true Penicillin allergy, the patient's self report of this adverse reaction must be justified carefully before avoiding beta-lactams. Even in the cases of true penicillin allergy, Meropenem appears to be safe, if indicated. There are also a few case reports regarding hypersensitivities to Clavulanate itself and also its cross-reactivity with Penicillin.

Type 1 Ig-E mediated allergy to human insulin, insulin analogues and beta-lactam antibiotics / Hipersensibilidade imediata a insulina humana, análogos de insulina e a antibióticos beta-lactâmicos

Insulin, a crucial therapeutic agent for diabetes mellitus, has been rarely associated with hypersensitivity events. We present a 69-year-old type-2 diabetic patient with urticariform lesions on the sites of subcutaneous injection of insulin. The patient denied any known allergies, except for an unspecific cutaneous reaction after intramuscular penicillin administration in childhood. Prick tests revealed positive reactions to all tested human insulins and insulin analogues. Serum IgE levels were above normal range and RAST tests were positive for human, bovine and porcine insulins, as well as beta-lactams. Type 1 IgEmediated allergy to insulin analogues demands a prompt diagnosis and represents a significant therapeutic challenge in diabetic patients.

A insulina é um agente indispensável para o controlo da diabetes mellitus. Os efeitos adversos da sua administração, em particular fenómenos de hipersensibilidade, são raros. Apresentamos um doente de 69 anos, diabético do tipo 2, com episódios recorrentes de lesões urticariformes nos locais de administração subcutânea de insulina. Negava alergias medicamentosas, à excepção de reacção não especificada na infância após penicilina intramuscular. Foram realizados testes cutâneos por puntura (prick tests) com diversos tipos de insulina humana e análogos, todos com reacções positivas, associando elevação dos níveis de IgE sérica e provas RAST positivas para as insulinas humana, bovina e porcina e para os antibióticos beta-lactâmicos. A alergia a análogos de insulina exige um diagnóstico precoce, originando um desafio terapêutico importante no doente diabético.

Farmacodermia em um cão após administração de antibióticos do grupo betalactâmico: relato de caso / Pharmacodermia in a dog after administration of beta-lactam antibiotics: case report

A severe cutaneous reaction in a female dog after administration of penicillin and cephalexin is described, in which the main signs presented by the patient were fever, lack of appetite, and detachment of epidermis in the dorsal region of body.The established treatment was surgical debridement of the region, topical application of Aloe Vera with sugar, and systemic antibiotic therapy with ciprofloxacin, resulting in the recovery and wound closure in approximately 45 days.

Drug hypersensitivity in students from São Paulo, Brazil

BACKGROUND: Drug hypersensitivity is responsible for substantial mortality and morbidity, and increased health costs. However, epidemiological data on drug hypersensitivity in general or specific populations are scarce. METHODS: We performed a cross-sectional survey of 1015 university students, using a self-reported questionnaire. RESULTS: The prevalence of self-reported drug hypersensitivity was 12,11 percent (123/1015). The most frequently implicated drugs were non-steroidal anti-inflammatory drugs (45,9 percent) and beta-lactam and sulfonamide antibiotics (25,40 percent). The majority of the patients reported dermatological manifestations (99), followed by respiratory (40), digestive (23) and other (19). Forty-five patients had an immediate type reaction, and 76,72 percent (89) had the drug by oral route. CONCLUSION: The results showed that drug hypersensitivity is highly prevalent in university students, and that nonsteroidal anti-inflammatory drug and antibiotics (beta-lactams and sulfonamide) are the most frequently concerned drugs.