Neo-antigens for the serological diagnosis of IgE-mediated drug allergic reactions to antibiotics cephalosporin, carbapenem and monobactam.

New antigens deriving from -lloyl and -llanyl, major and minor determinants, respectively, were produced for ß-lactam antibiotics cefuroxime, cefotaxime, ceftriaxone, meropenem and aztreonam. Twenty ß-lactam antigens were produced using human serum albumin and histone H1 as carrier proteins. Antigens were tested by multiplex in vitro immunoassays and evaluated based on the detection of specific IgG and IgE in the serum samples. Both major and minor determinants were appropriate antigens for detecting specific anti-ß-lactam IgG in immunised rabbit sera. In a cohort of 37 allergic patients, we observed that only the minor determinants (-llanyl antigens) were suitable for determining specific anti-ß-lactam IgE antibodies with high sensitivity (< 0.01 IU/mL; 24 ng/L) and specificity (100%). These findings reveal that not only the haptenisation of ß-lactam antibiotics renders improved molecular recognition events when the 4-member ß-lactam ring remains unmodified, but also may contribute to develop promising minor antigens suitable for detecting specific IgE-mediated allergic reactions. This will facilitate the development of sensitive and selective multiplexed in vitro tests for drug-allergy diagnoses to antibiotics cephalosporin, carbapenem and monobactam.

Unusual serological findings associated with ceftriaxone-induced immune hemolytic anemia in a child with disseminated low-grade glioma.

Ceftriaxone-induced immune hemolytic anemia (CIHA) is the second most common cause of drug-induced hemolytic anemia. Prompt recognition of this drug reaction is essential because brisk hemolysis can be deadly. The extent to which ceftriaxone antibodies persist after CIHA is unknown; rechallenging patients who have experienced CIHA is not recommended. We report a case of CIHA in a neurooncology patient, which is the first to show anticeftriaxone antibodies with Rh specificity and persisted for 8 months after the drug reaction. These findings have implications for understanding the mechanism of CIHA.

Fatal Anaphylactic Shock Ceftriaxone-Induced in a 4-Year-Old Child.

One of the most used cephalosporin in clinical practice is ceftriaxone. Anaphylaxis due to the administration of ceftriaxone is considered a rare event. Here, we report a case of fatal anaphylactic shock after the administration of ceftriaxone in a child who had tolerated the drug in past exposures. The allergic pathogenesis is sustained by the clinical data (short time between the inoculation of the drug and the onset of the symptoms; past exposure to the same molecule and probable sensitization) and the postmortem examination findings (polivisceral congestion and intense eosinophilia found in the histological examination).

An unusual case of delayed-type hypersensitivity to ceftriaxone and meropenem.

Recent studies have demonstrated a low cross-reactivity between ß-lactam antibiotics and carbapenems in IgE-mediated reactions. There are no studies on cross-reactivity of meropenem in patients with non-immediate hypersensitivity to cephalosporins. We describe a case of a 13-year-old male, admitted in Neurosurgery with a severe extradural empyema complicating frontal sinusitis, submitted to an emergent bifrontal craniotomy. A generalized maculopapular exanthema, fever and malaise, appeared by the 7th day of meningeal doses of ceftriaxone, clindamycin and vancomycin. Those were replaced by meropenem, with posterior worsening of the reaction and mucosal involvement. A new scheme with amikacin, metronidazole and linezolid was done with improvement. Skin prick, intradermal and patch tests to penicillins, ceftriaxone and meropenem were negative. Lymphocyte transformation test was positive to ceftriaxone and negative to meropenem.Non-immediate T cell mechanism seems to be involved. Diagnosis work-up couldn't exclude cross-reactivity between ceftriaxone and meropenem.

Ceftriaxone-induced immune hemolytic anemia.

OBJECTIVES: To describe a case of ceftriaxone-induced immune hemolytic anemia (CIIHA) in a 6 year-old boy with sickle cell disease (SCD) and perform a systematic literature review to delineate the clinical and laboratory features of this condition. DATA SOURCES: EMBASE (1947-January 2014), MEDLINE (1946-January 2014), and databases from the US Food and Drug Administration and Health Canada were searched, using anemia, hemolytic anemia, hemolysis, and ceftriaxone as search terms. Additional references were identified from a review of literature citations. STUDY SELECTION AND DATA EXTRACTION: All case reports and observational studies describing clinical and laboratory features of CIIHA were included. DATA SYNTHESIS: A total of 37 eligible reports of CIIHA were identified, including our index case, and 70% were children. Mortality was 30% in all age groups and 64% in children. The majority of patients had underlying conditions (70%), of which SCD was most commonly reported. Previous ceftriaxone exposure was reported in 65%. Common features included elevated lactate dehydrogenase (70%); early, new-onset hemoglobinuria (59%); acute renal failure (46%); positive direct antibody testing (70%); and anticeftriaxone antibodies (68%). Also, 32% had a preceding, unrecognized, hemolytic episode associated with ceftriaxone. SUMMARY: Given the common use of ceftriaxone worldwide, knowledge of CIIHA, which often goes undiagnosed until late in the course, is essential for clinicians. Based on the findings of this review, we suggest obtaining past history of ceftriaxone exposures and screening for new-onset hemoglobinuria during ceftriaxone therapy in selected patients as potential methods for early diagnosis of this rare but potentially fatal condition.

Adverse events induced by ceftriaxone: a 10-year review of reported cases to Iranian Pharmacovigilance Centre.

WHAT IS KNOWN AND OBJECTIVES: Ceftriaxone, a third-generation cephalosporin antibiotic, is used for a vast variety of infectious diseases. Different types of adverse reactions are reported to be induced by ceftriaxone; however, there is limited published information on spontaneous adverse reactions collected by a national pharmacovigilance centre. This study was conducted to evaluate ceftriaxone-induced adverse drug events, registered in the Iranian pharmacovigilance database during a 10-year period, and to identify preventive measures for reducing ceftriaxone-induced adverse events. METHOD: All adverse events registered in the Iranian pharmacovigilance database from 1998 through 2009 were screened for ceftriaxone-related adverse events. The extracted data were categorized based on patients' demographics and previous history of allergic reactions to antibiotics. Assessment of system-organ classes, seriousness and causality of reactions was performed according to World Health Organization scale. The preventability was analysed based on Schumock questionnaire. RESULTS AND DISCUSSION: Ceftriaxone was responsible for the highest number of deaths in our database (49 cases). Of 20,877 reports, 1205 (5·8%) were related to ceftriaxone; 357 reports (30%) are categorized as serious including cardiac arrest, anaphylactic and anaphylactoid reactions. The high number of serious cases makes it necessary to develop preventive measures for reducing those adverse events. Unlabelled use of the drug (2·9%) is identified as one of the risk factors for adverse events. Evaluation of the 1030 intravenous injections of the drug shows that rapid intravenous injection of ceftriaxone is another risk factor. One hundred and sixteen patients (9·6%) had a previous history of allergic reaction to ceftriaxone, penicillin or both. We recommend an alternative antibiotic, if possible, in the case of a positive history of allergic reaction to cephalosporins, penicillins and/or other beta-lactam antibiotics. WHAT IS NEW AND CONCLUSION: Severe and life-threatening adverse reactions induced by ceftriaxone are of great concern. Rapid intravenous injection, unlabelled use and previous patient history of allergic reactions to cephalosporins or penicillins are risk factors that should be guarded against.

Serologic characteristics of ceftriaxone antibodies in 25 patients with drug-induced immune hemolytic anemia.

BACKGROUND: Ceftriaxone, a third-generation cephalosporin, is commonly used to prevent and treat infections. Since 1987, it has been the second most common cause of drug-induced immune hemolytic anemia (DIIHA) investigated in our laboratory. STUDY DESIGN AND METHODS: Samples from 79 patients (1987-2010), suspected of having DIIHA caused by ceftriaxone, were studied for the presence of ceftriaxone antibodies. Direct antiglobulin tests (DATs) and tests with ceftriaxone-treated red blood cells (RBCs) or untreated and enzyme-treated RBCs in the presence of ceftriaxone were performed. RESULTS: Twenty-five (32%) of the 79 patients had antibodies to ceftriaxone detected. Seventeen (68%) of the 25 patients were children; reactions in children were usually dramatic and severe. Nine (36%) of the 25 patients had fatal DIIHA. Nineteen of the 25 samples had DATs performed by our laboratory; 100% of samples were reactive with anti-C3 and 47% were reactive with anti-IgG. All 25 sera had ceftriaxone antibodies detected when testing untreated or ficin-treated RBCs in the presence of ceftriaxone (resulting in agglutination, hemolysis or sensitization of test RBCs). These antibodies were primarily IgM and reactivity was enhanced by testing ficin-treated RBCs. Sixteen (64%) of the 25 sera reacted with test RBCs when no ceftriaxone was added in vitro; this was most likely due to the transient presence of drug or drug-immune complexes in the patient's circulation at the time that the blood samples were drawn. CONCLUSION: Ceftriaxone antibodies can cause severe intravascular hemolysis. Complement can usually be detected on the patient's RBCs and IgM antibodies are usually detected in the patient's serum.

Severe ceftriaxone-induced hemolysis complicated by diffuse cerebral ischemia in a child with sickle cell disease.

Ceftriaxone-induced hemolytic anemia is a rare and often fatal phenomenon. We report here the case of a 6-year-old female with sickle cell disease who survived a brisk and profound hemolytic reaction, resulting in hemoglobin of 0.4 g/dL, after ceftriaxone infusion. Ongoing hemolysis was abrogated with aggressive supportive care, but the patient suffered extensive neurologic sequelae as a result of the event. Serologic testing confirmed the presence of ceftriaxone antibodies.

Phenobarbital-induced DiHS and ceftriaxone hypersensitivity reaction: a case of multiple drug allergy.

Patients with DiHS show an increased risk of sensitization to multiple drugs. We report a case of a young woman who developed cutaneous rash, lymphoadenopathy, malaise and fever after the introduction of phenobarbitale. Because of these symptoms, she was treated with ceftriaxone and she experienced a severe flare-up of the cutaneous and general reaction. Allergological work-up, by cutaneous and lymphocyte transformation test, confirmed a double sensitization to phenobarbital and ceftriaxone. In conclusion, the high risk of DiHS during anticonvulsive therapy should suggest caution in using additional drugs, because of an increased risk of multiple reactions.

Intravascular haemolysis in a patient on ceftriaxone with demonstration of anticeftriaxone antibodies.

Drug-induced haemolytic anaemia can be life threatening. We report a case of ceftriaxone-induced severe haemolytic anaemia in a previously healthy 68-year-old woman. The patient had a positive direct antiglobulin test (anti-C3d positive, anti-immunoglobulin G negative). Serological tests showed ceftriaxone-specific antibodies. The patient recovered after cessation of the drug. This complication may cause milder anaemia and thus be poorly recognized.

Prevalence of ceftriaxone-induced red blood cell antibodies in pediatric patients with sickle cell disease and human immunodeficiency virus infection.

Ceftriaxone can be associated with catastrophic immune hemolysis in pediatric patients, particularly those with underlying diseases such as sickle cell disease and human immunodeficiency virus infection. We designed a study to screen for ceftriaxone-induced RBC antibodies in these 2 pediatric populations. The prevalence of anticeftriaxone antibody was 12.5% (8 of 64). Two of these 8 patients with the antibody experienced hemolysis; 1 case was fatal.

Resistência da Neisseria gonorrhoeae a antimincrobianos em Manaus: período 2005-2006 / Neisseria gonorrhoeae antimicrobial resistance in Manaus: 2005-2006 period

Introdução: em 1998, a Fundação Alfredo da Matta, de Manaus, iniciou estudos para avaliar a resistência de isolados de N. gonorrhoeae aos antibióticos recomendados para o tratamento das uretrites e cervicites gonocócicas. Objetivo: verificar a resistência de isolados de Neisseria gonorrhoeae aos antibióticos penicilina, tetraciclina, azitromicina, ceftriaxona e ciprofloxacino no Laboratório de Bacteriologia Clínica da Fundação Alfredo da Matta, Manaus - Amazonas - Brasil. Métodos: neste estudo, avaliou-se a resistência de 110 gonococos à penicilina, à tetraciclina, à azitromicina, à ceftriaxona e ao ciprofloxacino pelo método de difusão com discos. Resultados: após os testes, verificou-se que 14,5% foram betalactamase positivos (PPNG) e a resistência à penicilina foi de 21,8%. Para a tetraciclina, 80,0% foram resistentes com 12,7% TRNG. Em relação à azitromicina, 8,2% dos isolados foram resistentes e não se detectou resistência ao ciprofloxacino e à ceftriaxona, porém 6,4% apresentaram sensibilidade reduzida ao primeiro e 5,5% diâmetro inferior a 33mm ao segundo. Conclusão: ao final, conclui-se que os altos percentuais de resistência à penicilina e tetraciclina são semelhantes aos observados em outros estudos realizados com cepas da região e sugerem que ainda há elevada pressão seletiva desses antibióticos sobre os gonococos. Os índices de resistência à azitromicina inviabilizam sua utilização como opção terapêutica. Tanto o ciprofloxacino quanto a ceftriaxona foram eficazes "in vitro", mas as taxas de sensibilidade reduzida de ciprofloxacino e os valores abaixo de 35 mm de diâmetro no antibiograma para a ceftriaxona, são indicativos da necessidade do monitoramento clínico e laboratorial constante desses medicamentos.

A case of acute hemolysis after ceftriaxone: immune complex mechanism demonstrated by flow cytometry.

An immune complex mechanism for ceftriaxone sodium- induced severe autoimmune hemolytic anemia has previously been demonstrated using routine blood bank techniques. We describe herein a patient with severe hemolysis that subsided once the drug was discontinued. Serologic techniques demonstrated immune complex-mediated ceftriaxone-dependent red cell antibodies. These findings were further supported by the results of flow cytometry, in which a change in basal red cell autofluorescence was seen in the presence of the antibody and the drug. Our case illustrates the adjunctive value of flow cytometry in the diagnosis of ceftriaxone-dependent red cell antibody.

Cross-reactivity of cefotetan and ceftriaxone antibodies, associated with hemolytic anemia, with other: cephalosporins and penicillin.

Most drug-induced immune hemolytic anemias since the late 1980s have been caused by the second- and third-generation cephalosporins, cefotetan and ceftriaxone, respectively. Cross-reactivity of cefotetan and ceftriaxone antibodies with other cephalosporins or penicillin has been studied only minimally. We tested 7 serum samples previously identified to contain cefotetan antibodies and one serum sample previously identified to contain ceftriaxone antibodies against 9 other cephalosporins, penicillin, and 7-aminocephalosporanic acid in the presence of RBCs and also used hapten inhibition to indicate cross-reactivity. Serum samples containing cefotetan antibodies showed some cross-reactivity with cephalothin and cefoxitin (and to a much lesser extent with penicillin and ceftazidime). The ceftriaxone antibodies showed very weak cross-reactivity with cefotaxime, cefamandole, and cefoperazone. There was very little cross-reactivity between cefotetan antibodies and the drugs tested in the present study. We have no data to determine whether the in vitro data relate to in vivo reactivity.

Serology of antibodies to second- and third-generation cephalosporins associated with immune hemolytic anemia and/or positive direct antiglobulin tests.

BACKGROUND: First-generation cephalosporins rarely caused immune hemolytic anemia (IHA). Second- and third-generation cephalosporins, especially cefotetan and ceftriaxone, are increasingly associated with severe, sometimes fatal IHA. STUDY DESIGN AND METHODS: Samples from 53 patients with drug-induced IHA and/or positive direct antiglobulin test (DAT) were tested. Patients' sera were tested against drug-treated red cells (RBCs) and untreated or enzyme-treated RBCs, with and without the addition of drug solution. Eluates from patients' RBCs were tested against drug-treated and untreated RBCs. RESULTS: Forty-three patients had antibodies to cefotetan, 8 to ceftriaxone, 1 to cefoxitin, and 1 to cefotaxime. All patients had a positive DAT; only anticefoxitin and anti-cefotetan were demonstrable in RBC eluates. Sera containing anti-cefoxitin, anti-cefotaxime, and anti-cefotetan reacted with drug-treated RBCs (100%) and untreated or enzyme-treated RBCs in the presence of drug (98% or 100%, respectively). All of the ceftriaxone antibodies reacted with untreated or enzyme-treated RBCs in the presence of drug, but those tested did not react with ceftriaxone-treated RBCs. In addition to cefotetan-dependent antibodies, 19 (44%) and 14 (33%) of 43 sera contained drug-independent antibodies when tested with and without the presence of a polyethylene glycol potentiator, respectively. CONCLUSION: Cefotetan is by far the most common cause of drug-induced IHA. All cefotetan antibodies and the single examples of cefoxitin and cefotaxime antibodies reacted with drug-coated RBCs, and most, in contrast to the reactions of antibodies to first-generation cephalosporins (e.g., cephalothin), also reacted with RBCs (not treated with drug) in the presence of the drug. Ceftriaxone antibodies reacted only by the latter mechanism. Drug-independent antibodies (i.e., those reacting without any drug being present) were detected in 33 to 44 percent of patients' sera containing cefotetan antibodies, depending on the sensitivity of the method used.