The negative predictive value of 5-day drug provocation test in nonimmediate beta-lactam allergy in children.

BACKGROUND: Extending the drug provocation test (DPT) period is recommended for patients with suspected nonimmediate beta-lactam antibiotic (BLA) allergy and negative DPT. No consensus has been reached regarding the duration of prolonged provocation. OBJECTIVE: We aimed to determine the negative predictive value (NPV) of the 5-day extended DPT. METHODS: Parents of patients with suspected nonimmediate mild cutaneous reactions with BLAs who had been subjected to 5-day DPT with culprit drugs were questioned by telephone interview about reexposure to the tested drug. Patients with reported reaction during reexposure were reevaluated. Skin tests and serum-specific immunoglobulin E (IgE) analysis were not performed before first DPT. RESULTS: A total of 355 patients had negative results in 5-day DPT. The median age at DPT was 4.2 years, and 52.9% were male. The families of 255 patients (72%) could be contacted. Of these 255 patients, 179 (70%) had used the same drug, and reactions were reported for 6 (3.4%) of those patients, who were subsequently reevaluated. Five of the 6 patients had DPT with amoxicillin-clavulanate and 1 with cefixime. When detailed history was taken, 2 of the 5 patients with amoxicillin-clavulanate reaction were found to have used the drug unintentionally after their reaction to reexposure and did not have any symptoms. One of the patients underwent allergy workup and tested negative, and the other 2 refused the test. The patient with reported cefixime reaction underwent repeated allergy workup and tested negative. Therefore, the NPV of 5-day prolonged DPT was 98.9%. CONCLUSION: The 5-day prolonged DPT has high NPV and seems appropriate in duration for children with suspected nonimmediate-BLA allergy.

The utility of the basophil activation test in the diagnosis of immediate amoxicillin or amoxicillin-clavulanate hypersensitivity in children and adults.

BACKGROUND: The basophil activation test (BAT), has been proposed as a possible assay for the diagnosis of immediate-type allergy to beta-lactams (BLs). The aim of this study was to assess the utility of BAT in the diagnosis of amoxicillin (AMX) or AMX-clavulanate (AMX-C) IgE-mediated hypersensitivity in children and adults. MATERIAL AND METHODS: Eighteen children and 21 adults, with clinical history of immediate reactions to AMX or AMX-C, were referred to Anna Meyer Children's Hospital and San Giovanni di Dio Hospital, respectively. They underwent in vivo tests (skin prick test and intradermal test). Moreover, BAT with AMX or AMX-C was performed within 6 months from the reaction. RESULTS: In the pediatric group, the concordance between the skin tests (ST) and BAT results was 83.3%. Upon comparing the symptom grades and ST results to the BAT results, we found that the reaction severity and ST positivity did not correlate with BAT results in children. In the adult group, the concordance between the ST and BAT results was 61.9%. Upon comparing patients with severe reactions and patients with mild reactions in terms of BAT results, we found a BAT sensitivity of 38.5% and a specificity of 100%. When comparing the symptom grades to the BAT results, we found that no patients with mild symptoms had a positive BAT result, whereas 38.5% of patients with severe symptoms had a positive BAT result. CONCLUSIONS: BAT does not seem to be a useful tool to increase the sensitivity of an allergy work-up to diagnose immediate hypersensitivity to AMX or AMX-C.

Amoxicillin and Clavulanate Form Chemically and Immunologically Distinct Multiple Haptenic Structures in Patients.

Amoxicillin-clavulanate (AC) is one of the most common causes of drug induced liver injury (DILI). The association between AC-DILI and HLA alleles and the detection of drug-specific T cells in patients with AC-DILI indicate that the adaptive immune system is involved in the disease pathogenesis. In this study, mass spectrometric methods were employed to characterize the antigen formed by AC in exposed patients and the antigenic determinants that stimulate T cells. Amoxicillin formed penicilloyl adducts with lysine residues on human serum albumin (HSA) in vitro, with K190 and K199 being the most reactive sites. Amoxicillin-modified K190 and K199 have also been detected in all patients, and more extensive modification was observed in patients exposed to higher doses of amoxicillin. In contrast, the binding of clavulanic acid to HSA was more complicated. Multiple adducts were identified at high concentrations in vitro, including those formed by direct binding of clavulanic acid to lysine residues, novel pyrazine adducts derived from binding to the degradation products of clavulanic acid, and a cross-linking adduct. Stable adducts derived from formylacetic acid were detected in all patients exposed to the drug. Importantly, analysis of hapten-protein adducts formed in the cell culture medium revealed that the highly drug-specific T-cell responses were likely driven by the markedly different haptenic structures formed by these two drugs. In this study, the unique haptenic structures on albumin in patients formed by amoxicillin and clavulanic acid have been characterized and shown to function as chemically distinct antigens which can stimulate separate, specific T-cell clones.

The Importance of Amoxicillin and Amoxicillin-Clavulanate Determinants in the Diagnosis of Immediate Allergic Reactions to ß-Lactams.

BACKGROUND: Immediate allergic reactions to ß-lactam antibiotics are considered to be one of the most important drug hypersensitivities. A positive skin test (ST) with a combination of major and minor penicillin determinants is usually sufficient to recommend avoidance of the culprit drug, whereas a negative ST is usually followed by an oral challenge test (OCT). Recently, concern has been raised regarding the role of amoxicillin (AMX) ST in the diagnosis of AMX allergy. OBJECTIVE: The aim of this study was to examine the additive value of AMX determinants in STs of patients with immediate hypersensitivity reactions to AMX or AMX-clavulanate (AMX-C). METHODS: Patients with a history of immediate AMX or AMX-C allergy underwent an ST using a combination of penicilloyl-polylysine (PPL) and minor determinants as well as AMX. An ST with AMX-C was added when appropriate. RESULTS: Thirty-one patients were evaluated. Eight patients, all of them with a history of AMX allergy, had positive reactions only to the AMX component. Two patients with AMX-C allergy had a positive ST reaction only to the AMX-C component. Moreover, only 14 patients (13 with AMX and 1 with AMX-C allergy) had a positive reaction to PPL, whereas most patients (54.8%) had positive reactions to other determinants. One patient, who was positive for AMX, developed several urticarial lesions after the test. CONCLUSIONS: Skin testing with AMX and AMX-C is mandatory in patients with immediate allergy to these drugs. Failure to perform it may result in a false-negative ST jeopardizing these patients with anaphylactic reactions during a hazardous OCT.

Selective sensitization to clavulanic acid and penicillin V.

Allergic reactions to beta-lactam antibiotics have been reported frequently and may occur because of sensitization to unique haptens or to determinants shared with other drugs. A woman who received 1 tablet of amoxicillin-clavulanic acid developed wheals and flares although she had previously tolerated the same preparation well. Levels of specific immunoglobulin (Ig) E to penicillin V, penicillin G, amoxicillin, and ampicillin were undetectable. Skin tests to amoxicillin, penicillin major determinant and minor determinant mixture were negative. The patient tolerated oral challenge with 500 mg of amoxicillin but developed wheals and flares when challenged with amoxicillin-clavulanic acid 500/125 mg. A histamine release test was negative with amoxicillin but positive with the amoxicillin-clavulanic acid and clavulanic acid. A prick test to the combination was positive. Specific IgE to penicillin V later became positive while remaining negative to other beta-lactams. No inhibition was obtained using penicillin V against clavulanic acid and amoxicillin but was complete when penicillin V was used in the solid-phase and as the inhibitor. No cross-reactivity was proven between these sensitizations.

Myocardial ischemia due to severe amoxicillin allergy.

A patient suffered a myocardial injury as a manifestation of anaphylactic reaction to amoxicillin-clavulanic acid administration. A cardiologic study (ergometry and catheterization) showed no obstructive coronary disease and prick test to amoxicillin was positive. Anaphylaxis may cause myocardial injury and the mechanism is likely to be vasospasm induced by mast cells and basophil mediators.

Prevalence of Bacterial Pathogens and Susceptibility Patterns from clinical sources in Trinidad

During a 12-month period (January-December, 1997), bacterial isolates of specimens from in-patients and out-patients of the Eric Wiliams Sciences Complex (EWMSC) were reviewed. A total of 3,513 specimens were processed, 43.1 percent from in-patients and 56.9 percent from out-patients. Of the 3,513 specimens, 1,129 (32.1 percent) yielded positive cultures. Micro-organisms from wounds, sputum and genital tract accounted for 90.2 percent, 51.5 percent and 31.8 percent, respectively, of all isolates. E coli (17.4 percent) and Enterococci (12.2percent) were the predominant isolates and were also the major pathogens from blood stream infections, 25.8 percent and 18.2 percent, respectively, followed by P aeruginosa, 15.2 percent. High levels of resistance were seen to ampicillin, augmentin (amoxicillin-clavulanic acid) and tetracycline. The most effective antibiotics were ceftazidime (no resistance in E coli Citrobacter spp, non-typhoidal Salmonella and Group B streptococci, 63.2 percent resistance in Acinetobacter spp, 15.2 percent in Enterobacter spp, 17.4 percent in Klebsiella spp.], erythromycin (no resistance in Enterobacter and Citrobacter spp, and 89.5 percent in Acinetobacter (spp), erythromycin (no resistance in Groups A and B streptococci, 85.1 percent in S aurens and S pneumoniae). The spectrum of isolates will provide clinicians with data on which to base their "best guess" aetiologic agent and choice of antibiotics when faced with infectious diseases in areas where laboratory assistance is not readily available.(Au)

Prevalence of Bacterial Pathogens and Susceptibility Patterns from clinical sources in Trinidad

During a 12-month period (January-December, 1997), bacterial isolates of specimens from in-patients and out-patients of the Eric Wiliams Sciences Complex (EWMSC) were reviewed. A total of 3,513 specimens were processed, 43.1 percent from in-patients and 56.9 percent from out-patients. Of the 3,513 specimens, 1,129 (32.1 percent) yielded positive cultures. Micro-organisms from wounds, sputum and genital tract accounted for 90.2 percent, 51.5 percent and 31.8 percent, respectively, of all isolates. E coli (17.4 percent) and Enterococci (12.2percent) were the predominant isolates and were also the major pathogens from blood stream infections, 25.8 percent and 18.2 percent, respectively, followed by P aeruginosa, 15.2 percent. High levels of resistance were seen to ampicillin, augmentin (amoxicillin-clavulanic acid) and tetracycline. The most effective antibiotics were ceftazidime (no resistance in E coli Citrobacter spp, non-typhoidal Salmonella and Group B streptococci, 63.2 percent resistance in Acinetobacter spp, 15.2 percent in Enterobacter spp, 17.4 percent in Klebsiella spp.], erythromycin (no resistance in Enterobacter and Citrobacter spp, and 89.5 percent in Acinetobacter (spp), erythromycin (no resistance in Groups A and B streptococci, 85.1 percent in S aurens and S pneumoniae). The spectrum of isolates will provide clinicians with data on which to base their "best guess" aetiologic agent and choice of antibiotics when faced with infectious diseases in areas where laboratory assistance is not readily available.