Purpose: Pharmacists must ensure the safe and effective use of medication, but often have only the documented patient history to guide assessment of therapy. There is a lack of information on the incidence of claimed drug allergies or the validity of these self-reported drug allergies in the South African population. Mislabelling of patients as being allergic to medication often deprives them of important therapeutic drugs and alternative agents may be more dangerous, less effective and more costly (Hung et al., 1994). The aim of the research was therefore to determine the incidence of drug allergies in patients admitted to a private hospital and to assess the validity of these self-reported drug allergies. Methods: A descriptive, non-experimental study design was used. Data was collected using a concurrent, cross-sectional approach and collected from patients admitted to hospital using Medical Chart Reviews and researcher-led, questionnaire based interviews. During the seven month sampling period, 693 patients were identified with one or more self-reported drug allergies. A subset of 99 patients (14.2%) consented to a researcher-led interview. The allergies were assigned to one of three groups based on the history: (i) High probability: signs and symptoms typical of an immunological reaction. (ii) Low probability: signs and symptoms of the reaction were predictable reactions or side effects of the drug. (iii) Unknown status: no information concerning the reaction history was available. Results: A total of 953 allergies were identified in the 693 patients, with a ratio of drug allergy to patient of 1.4:1. The majority of claimed allergies were to penicillin (39.2%), opioid analgesics (17.6%), other antimicrobials, including co-trimoxazole (13.5%), NSAIDs (9.9%) and unspecified “sulphur” allergy (8.7%). Descriptions of the “allergic” reactions were only recorded on 8.9% (62, n=693) of the reviewed charts. Only 56.5% (35, n=62) of the symptoms recorded as “allergy” were indicative of the event being allergic or immunological in nature. In total, 1.3% (9, n=693) of the patients with a self-reported allergy received the allergen while in hospital. In three cases this was the result of a pharmacist overlooking the recorded allergy, and dispensing the allergen to the patient. A total of 118 allergies were identified in the 99 interviewed patients, with a ratio of drug allergy to patient of 1.2:1. Inaccurate allergy history was found in 9.1% (9, n=99) of the interviewed patients. Overall, the majority of self-reported drug allergies (67.8%) had a “high probability” of being a true drug allergy. Allergies that were assigned into the high probability group were: penicillin (74.1%), co-trimoxazole (91.7%), NSAID‟s (55.6%) and 75.0% of opioids. Conclusion: In summary, the validity of self-reported drug allergies need to be determined before excluding medication from a patient‟s treatment options. Detailed descriptions can assist in the evaluation of self-reported allergies which would be advantageous to both prescribers and patients. Pharmacists need to play a bigger role in ensuring accurate documentation of drug allergy history, with detailed descriptions, in order to ensure safe and effective drug use within the hospital environment.

Adverse drug reactions (ADRs) are known to be a major cause of morbidity and mortality. However, only a small proportion are reported. An increase in the number and quality of reports by improving ADR reporting systems in hospitals, could improve patient outcomes and save healthcare costs. The first part of this project was to review the ADR reporting systems in Australian hospitals and to determine factors contributing to the ADR reporting rate. Data were collected by a postal, self-administered questionnaire. Questionnaires were sent to 299 chief pharmacists of Australian hospitals listed in the Society of Hospital Pharmacists of Australia (SHPA) directory. The response rate was 49.5%. Seventy seven (60%) hospitals had a formal hospital policy for ADR reporting and 110 (85.3%) hospitals targeted all drugs to be reported. ADR reporting rates to ADRAC in 2000 (ADR reports per patient admission) were between zero and 1.09% (median=0.02%) with 7.1% of hospitals having a reporting rate of zero. A centralised ADR system and the existence of an ADR policy was not associated with higher reporting rates. The next part of the project was a survey of 803 Western Australian (WA) doctors and 1323 Australian hospital pharmacists to evaluate involvement in, understanding of and reasons for reporting ADRs. A postal, self-administered, anonymous questionnaire was sent to doctors at two tertiary hospitals in Perth and three regional hospitals in WA. A similar questionnaire was sent to all hospital pharmacists listed in the membership list of SHPA, as well as non-SHPA members in WA. Response rates obtained for the WA doctors survey was 35% (n=277) and 43% (n=574) for hospital pharmacists. Sixty four percent of doctors and 96% of hospital pharmacists knew how to report ADRs within the hospital while 57% and 98% (respectively) knew how to report ADRs to ADRAC. / Factors that would encourage respondents to report ADRs included serious reactions, unusual reactions, reaction to a new product and confidence in the diagnosis of the ADR. More than 70% of respondents agreed that an uncertain association between the ADR and the suspected drug, minor reactions and well known reactions were factors that would deter them from reporting ADRs. From a list of 14 hypothetical ADR questions, it was found that respondents were more likely to report serious and uncommon reactions. Finally, the incidence of cross-sensitivity between penicillin and other β-lactam antibiotics among patients experiencing penicillin allergy in Fremantle Hospital and Health Services (FHHS) was assessed, along with the appropriate documentation of penicillin allergy in the medical records. The study was a retrospective audit and review of medical records in FHHS (1994-2000). All medical records of patients experiencing penicillin allergy during admission, or causing admission to FHHS, (n=85) were reviewed and data on reactions to other β-lactams were recorded. The incidence of definite cross-sensitivity between penicillins and cephalosporins was 6%, consistent with the reported rate of cross-sensitivity. The documentation of penicillin allergy in the medical records was less than optimal, with alerts on 89% of medication charts and only 28% of medical records (front cover). Improvement in the documentation of ADRs in patients' medical records would likely decrease the risk of preventable adverse events.

published_or_final_version / Pathology / Master / Master of Medical Sciences

Benzylpenicilloyl-poly-L-cysteine is prepared by reacting benzylpenicillenic acid with poly-L-cysteine at 370° in water at pH 8.3 or buffer at pH 7.98. The preparations of penicilloyl-cysteine, S-acetamidomethyl-polycysteine, and S-acetamidomethyl-penicilloyl-polycysteine are also described. C14-labeling and penamaldate assays are used to determine penicilloyl content. The iodoacetic acid method is used to ascertain thiol content.The ultraviolet spectra for penicilloyl-polycysteine, pencilloyl-cysteine, poly-L-cysteine, poly-S-carbobenzoxy-L-cysteine, S-acetamidomethyl-polycysteine and S-acetamidomethyl-penicilloyl-polycysteine are reported. The infrared spectra of penicilloyl-polycysteine, penicilloyl-cysteine, poly-S-carbobenzoxy-L-cysteine, S-acetamidomethyl-polycysteine, and S-acetamidomethyl-penicilloyl-polycysteine are reported. The nmr spectra of poly-L-cysteine, penicilloyl-cysteine, S-acetamidomethyl-polycysteine, and S-acetamidomethyl-penicilloyl-polycysteine are discussed.The kinetic rates of reaction of benzylpenicillenic acid at 37.5 ± 0.50 in buffer, cysteine, N, S-di-CBZ L-cysteine, poly-L-cysteine, poly-S-CBZ L-cysteine andβ-mercaptoethylamine are compared.Ball State UniversityMuncie, IN 47306

Benzylpenicillin, a-aminobenzylpenicillin, phenoxymethylpenicillin, and 2,6-dimethoxy-phenylpenicillin were incubated with whole human blood. Migration patterns into human erythrocytes were compared spectrophotometrically.A possible inhibition effect by chloroquine on benzyl-[14C]-penicillin in red blood cells was studied via a Beckman LS-100C Liquid Scintillation Counter.An intraerythrocytic protein, carbonic anhydrase, was investigated as being responsible for the hydrolysis of benzylpenicillin. Three carbonic anhydrases (a, b, and c) were quantitatively measured via a Beckman IR 4250 Spectrophotometer for their effect upon the a-lactam ring of benzylpenicillin.Ball State UniversityMuncie, IN 47306

An estimated 70,000 preventable medication errors occur in Canada annually, causing up to 23,750 deaths. Medication errors increase when the number of medications being administered increases. Therefore, people with multi-morbidity who take several medications at once are more vulnerable to medication errors. Medication errors can be prevented by developing and managing an efficient healthcare system integrated with technology. Near Field Communication (NFC) technology, in particular, has been shown to improve the quality of health care and increase patient safety. NFC has a powerful ability to identify and track objects such as patients and medications; its identification and tracking abilities give it significant potential especially in detecting drug interaction and drug allergy. The main objective of this thesis is to present a novel solution using NFC-enabled smartphone integrated with NFC application to detect and update drug allergies and drug interactions for people with multi-morbidity during medication administration. / The system has been implemented using Samsung Nexus S smartphone with Android 2.3.6 platform, MIFARE Classic 1K tags, and a database populated with 10 patients’ record and 30 medications. The system was validated for the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and computational and communicational cost.

Renny Varghese Impact of an Electronic Medical Record Implementation on Drug Allergy Overrides in a Large Southeastern HMO Setting (Under the direction of Russell Toal, Associate Professor) Electronic medical records (EMRs) have become recognized as an important tool for improving patient safety and quality of care. Decision support tools such as alerting functions for patient medication allergies are a key part of reducing the frequency of serious medication problems. Kaiser Permanente Georgia (KPGA) implemented its EMR system in the primary care departments at Kaiser's twelve facilities in the greater metro Atlanta area over a six month period beginning in June 2005 and ending December 2005. The aim of this study is to analyze the impact of the EMR implementation on the number of drug allergy overrides within this large HMO outpatient setting. Research was conducted by comparing the rate of drug allergy overrides during pre and post EMR implementation. The timeline will be six months pre and post implementation. Observing the impact of the incidence rate of drug allergy alerts after the implementation provided insight into the effectiveness of EMRs in reducing contraindicated drug allergies. Results show that the incidence rate of drug allergy overrides per 1,000 filled prescriptions rose by a statistically significant 5.9% (ñ > 0.0002; 95% CI [-1.531, -0.767]) following the implementation. Although results were unexpected, several factors are discussed as to the reason for the increase. Further research is recommended to explore trends in provider behavior, KPGA specific facilities and departments, and in other KP regions and non-KP healthcare settings. INDEX WORDS: electronic medical records, drug allergy overrides, patient safety, medication errors, decision support tools, outpatient setting, primary care, computerized provider order entry

Tesis por compendio / [EN] About 10 % of all adverse drug reactions are due to allergies, with ß-lactam antibiotics causing the majority of the episodes. Although the actual incidence remains unknown, individuals suspected of being allergic to a drug end up being prescribed with other medications that are less effective, more expensive or harmful. Consequently, a correct diagnosis is key to reduce the derived economic costs and proceed to an adequate 'delabeling' of the population. At present, clinical approaches to diagnose allergies to ß-lactam antibiotics are based on in vivo and in vitro tests. These tests present limited clinical performances since they are invasive, dangerous, and provide false positives and/or negatives. Moreover, the diagnostic sensitivity is far from what is expected, possibly because the epitopes that cause the allergic episodes are still not well detected. In this respect, the preparation of antigens has commonly been determined by the direct attachment of antibiotics to carrier molecules through the formation of an amide bond between amino lysine groups of the carrier molecule and the carboxylate group of the antibiotic. Even so, specific IgE are barely detected with such antigens. This dissertation addresses the synthesis of haptens and the generation of antigens to ß-lactam antibiotics, which develop a more reliable in vitro diagnosis of allergies to these drugs. The evaluation of the antigens has been carried out by means of multiplex in vitro tests based on compact disc technology. This research begins by focusing on the synthesis and preparation of penicillin antigens. To this end, first, the effect of the incorporation of aliphatic spacer arms in the chemical structure of penicillin has been approached, considering the possibility that a better molecular recognition is obtained by moving the hapten away from the carrier protein. Thirteen haptens derived from benzylpenicillin and amoxicillin were synthesized in order to prepare antigens with human serum albumin. The evaluation of the antigens revealed that even though they were immunogenic and were detected by the raised IgG antibodies, they were not detected by specific IgE from allergic patients. Additionally, the next approach considered the cationization of the carrier proteins, human serum albumin and histone. The modification of carboxylate groups of the protein to amino groups allow for an increase of the molar hapten/protein ratio. This strategy led to the generation of five antigens, four of which (only those histone-based antigens), did increase the sensitivity of the assay. Concretely, specific IgE has been determined in sera from allergic patients at low concentrations (LOD = 0.07 IU/mL) with a diagnostic specificity of 100 % and a sensitivity of 60 and 31 % for benzylpenicillin and amoxicillin, respectively. That means a 60 % improvement in the diagnostic sensitivity when compared to the in vitro reference test. Subsequently, the idea of preparing minor antigens based on penicillin metabolites was approached. Penicilloic, penilloic, penicillic, and 6-aminopenicillanic acids, together with penicillamine, were therefore conjugated to the carrier proteins human serum albumin and histone. Except penilloic acid, the rest of antigens were selectively detected when testing a set of serum samples from allergic patients. The diagnostic specificity obtained was 100 %, 94 % in the case of penicillic acid, and the sensitivity was between 67 and 100 %. Another approach was focused on the production of antigens for other families of ß-lactam antibiotics. The generation of antigens for cephalosporins, carbapenems, monobactams or ß-lactam inhibitors is essential, since in vitro tests for the detection of allergies to these antibiotics are not commercially available. Therefore, the results obtained after the preparation of major and minor antigens for the antibiotics cefuroxime, cefotaxime, ceftriaxone, meropenem, and aztreonam were evaluated. / [ES] Alrededor del 10 % de las reacciones adversas a medicamentos son debidas a alergias, siendo los antibióticos ß-lactámicos los que más episodios alérgicos ocasionan. Aunque la incidencia real sigue siendo desconocida, los individuos sospechosos de presentar alergia a algún medicamento acaban siendo prescritos con otros medicamentos, menos efectivos, más caros o perjudiciales. Así pues, un correcto diagnóstico resulta clave para disminuir los costes económicos derivados y proceder a un adecuado 'desetiquetado' de la población. En la actualidad, las pruebas de diagnóstico de alergias a antibióticos ß-lactámicos se basan en ensayos in vivo e in vitro. Estos ensayos muestran bajas prestaciones, ya que son invasivos y peligrosos y proporcionan falsos positivos y/o negativos. Además, la sensibilidad diagnóstica está lejos de ser la esperada, posiblemente porque aún no se ha conseguido reconocer todos los epítopos causantes de los episodios alérgicos. En este sentido, la preparación de antígenos se ha basado hasta el momento, en mayor medida, en la unión directa de los antibióticos a las moléculas portadoras mediante la formación de un enlace amida entre los grupos amino de las lisinas de la molécula portadora y el grupo carboxilato del antibiótico. Aun así, las IgE específicas son vagamente detectadas con estos antígenos. En esta tesis se ha abordado la síntesis de haptenos y la generación de determinantes antigénicos a antibióticos ß-lactámicos con los que poder realizar un diagnóstico in vitro más fiable de alergias a estos fármacos. La evaluación de los mismos se ha llevado a cabo mediante ensayos in vitro multiplex basados en tecnología de disco compacto. Esta investigación comienza centrándose en la síntesis y preparación de antígenos de penicilina. Para ello, en una primera fase se ha estudiado el efecto de la incorporación de brazos espaciadores alifáticos en la generación de antígenos, considerando la posibilidad de que se obtenga un mejor reconocimiento molecular al alejar el hapteno de la proteína portadora. Se sintetizaron trece haptenos derivados de bencilpenicilina y amoxicilina con los que se prepararon antígenos con la proteína albumina de suero humano. La evaluación de los antígenos reveló que a pesar de ser suficientemente inmunogénicos y ser reconocidos por anticuerpos IgG de conejo, éstos no fueron reconocidos por IgE específicas de muestras de pacientes alérgicos. Así bien, por otro lado, la estrategia de cationización de las proteínas albumina de suero humano e histona fue abordada teniendo en cuenta que la modificación de grupos carboxilatos de la proteína a grupos amino aumenta la relación molar hapteno/proteína. Esta estrategia permitió la generación de 5 antígenos, 4 de los cuales (los antígenos de histona), esta vez sí, incrementaron la especificidad de la respuesta inmunológica obtenida, reconociendo IgE específicas. Concretamente, se han determinado IgE específicas en suero de pacientes alérgicos a bajas concentraciones (LOD = 0.07 IU/mL) con una especificidad diagnóstica del 100 % y una sensibilidad del 60 y 31 % para bencilpenicilina y amoxicilina, respectivamente, mejorando la sensibilidad un 60 % en comparación con el ensayo in vitro de referencia. A pesar de las mejoras obtenidas con las estrategias llevadas a cabo, se estudiaron otras vías no clásicas para la síntesis de nuevos haptenos con mayor diversidad química. Este enfoque se basa en la generación de antígenos en librerías químicas de compuestos con diversidad estructural para encontrar nuevos haptenos biológicamente activos. Dichas estrategias, hasta el momento, no han sido empleadas para la generación de antígenos y el análisis de muestras de suero de pacientes alérgicos. Con el fin de incorporar diversidad estructural, se sintetizaron, mediante la técnica combinatoria diversity-oriented synthesis, 22 compuestos de los precursores de las penicilinas y cefalosporinas, ácido 6-aminopenicilánico y ácido 7-amino-desacetoxicefalosporánico, respectivamente, y de los antibióticos amoxicilina y ampicilina. Su evaluación con el inmunoensayo in vitro basado en disco compacto ha demostrado que la incorporación de diversidad permite el reconocimiento de epítopos causantes de episodios alérgicos. Concretamente, se observó que estos antígenos eran capaces de detectar anticuerpos tipo IgG e IgE específicos procedentes de suero de conejos inmunizados y de suero humano de pacientes alérgicos, siendo especialmente selectivos los determinantes de amoxicilina y ampicilina. Concretamente, se obtuvo una sensibilidad diagnóstica del 79 % y una especificidad diagnóstica del 100 % / [CA] Al voltant del 10% de les reaccions adverses a medicaments són degudes a al·lèrgies, sent els antibiòtics ß-lactàmics aquells que més episodis al·lèrgics ocasionen. Encara que la incidència real continua sent desconeguda, els individus sospitosos de presentar al·lèrgia a algun medicament acaben sent prescrits amb altres medicaments, menys efectius, més cars o perjudicials. Així doncs, un correcte diagnòstic resulta clau per a disminuir els costos econòmics derivats i procedir a un adequat 'desetiquetatge' de la població. En l'actualitat, les proves de diagnòstic d'al·lèrgies a antibiòtics ß-lactàmics es basen en assaigs in vivo i in vitro. Aquests assaigs mostren baixes prestacions, ja que són invasius i perillosos i proporcionen falsos positius i/o negatius. A més a més, la sensibilitat diagnòstica està lluny de ser l'esperada, possiblement perquè encara no s'ha aconseguit reconéixer tots els epítopes causants dels episodis al·lèrgics. En aquest sentit, la preparació d'antígens s'ha basat fins al moment, en major mesura, en la unió directa dels antibiòtics a les molècules portadores mitjançant la formació d'un enllaç amida entre els grups amino de les lisines de la molècula portadora i el grup carboxilat de l'antibiòtic. Així i tot, les IgE específiques són vagament detectades amb aquests antígens. En aquesta tesi s'ha abordat la síntesi d'haptens i la generació de determinants antigènics a antibiòtics ß-lactàmics amb els quals poder realitzar un diagnòstic in vitro més fiable d'al·lèrgies a aquests fàrmacs. La seua avaluació s'ha dut a terme mitjançant assaigs in vitro multiplex basats en tecnologia de disc compacte. Aquesta investigació comença centrant-se en la síntesi i preparació d'antígens de penicil·lina. Per a això, en una primera fase s'ha estudiat l'efecte de la incorporació de braços espaiadors alifàtics en la generació d'antígens, considerant la possibilitat que s'obtinga un millor reconeixement molecular en allunyar l'haptè de la proteïna portadora. Es van sintetitzar tretze haptens derivats de bencilpenicil·lina i amoxicil·lina amb els quals es van preparar antígens amb la proteïna albúmina de sèrum humà. L'avaluació dels antígens va revelar que malgrat ser prou immunogènics i ser reconeguts per anticossos IgG de conill, aquests no van ser reconeguts per IgE específiques de mostres de pacients al·lèrgics. Així bé, d'altra banda, l'estratègia de cationització de les proteïnes albúmina de sèrum humà i histona va ser abordada tenint en compte que la modificació dels grups carboxilats de la proteïna a grups amino augmenta la relació molar hapten/proteïna. Aquesta estratègia va permetre la generació de 5 antígens, 4 dels quals (els antígens d'histona), aquesta vegada sí, van incrementar l'especificitat de la resposta immunològica obtinguda, reconeixent IgE específiques. Concretament, s'han determinat IgE específiques en sèrum de pacients al·lèrgics a baixes concentracions (LOD = 0.07 IU/mL) amb una especificitat diagnòstica del 100 % i una sensibilitat del 60 i 31 % per a bencilpenicil·lina i amoxicil·lina, respectivament, millorant la sensibilitat un 60 % en comparació amb l'assaig in vitro de referència. Malgrat les millores obtingudes amb les estratègies dutes a terme, es van estudiar altres vies no clàssiques per a la síntesi de nous haptens amb major diversitat química. Aquest enfocament es basa en la generació d'antígens en llibreries químiques de compostos amb diversitat estructural per a trobar nous haptens biològicament actius. Aquestes estratègies, fins al moment, no han sigut emprades per a la generació d'antígens i l'anàlisi de mostres de sèrum de pacients al·lèrgics. Amb la finalitat d'incorporar diversitat estructural, es van sintetitzar, mitjançant la tècnica combinatòria diversity- oriented synthesis, 22 compostos dels precursors de les penicil·lines i cefalosporines, àcid 6-aminopenicilànic i àcid 7-amino-desacetoxicefalosporànic, respectivament, i dels antibiòtics amoxicil·ina i ampicil·lina. La seua avaluació amb l'immunoassaig in vitro basat en disc compacte ha demostrat que la incorporació de diversitat permet el reconeixement d’epítops causants d'episodis al·lèrgics. Concretament, es va observar que aquests antígens eren capaços de detectar anticossos tipus IgG i IgE específics procedents de sèrum de conills immunitzats i de sèrum humà de pacients al·lèrgics, sent especialment selectius els determinants d’amoxicil·lina i ampicil·lina. Concretament, es va obtindre una sensibilitat diagnòstica del 79 % i una especificitat diagnòstica del 100 %. / This work was supported by the H2020 program (project COBIOPHAD, grant agreement No. 688448 awarded to A.M.), being an initiative of the Photonics Public Private Partnership; Agencia Estatal de Investigación Agencia Estatal de Investigación (CTQ2016-75749-R, FEDER) (PID2019-110713RB-I00, FEDER) awarded to S.M.; Generalitat Valenciana (PROMETEO/2020/094 awarded to A.M. & S.M.); program UPV-La FE 2019 (P105 VALBIOAL awarded to S.M & E. I-E.); and the National Institute of General Medical Sciences (GM-1R35GM127045 awarded to S.L.S.). E.P.M. was supported by a FPU fellowship from the Ministerio de Educación, Cultura y Deporte (FPU15/01738 and EST18/00360). B.K.H. was supported by a fellowship from the National Science Foundation (DGE1144152 and DGE1745303). The authors acknowledge the Instituto de Investigación Sanitaria La Fe, Valencia, Spain, which provided the samples from both allergic patients and controls. / Peña Mendizabal, E. (2022). Synthesis and Evaluation of Antigenic Determinants for ß-lactam Allergy Diagnosis [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/182979 / TESIS / Compendio