Comprehensive stability analysis of 13 ß-lactams and ß-lactamase inhibitors in in vitro media, and novel supplement dosing strategy to mitigate thermal drug degradation.

Non-clinical antibiotic development relies on in vitro susceptibility and infection model studies. Validating the achievement of the targeted drug concentrations is essential to avoid under-estimation of drug effects and over-estimation of resistance emergence. While certain ß-lactams (e.g., imipenem) and ß-lactamase inhibitors (BLIs; clavulanic acid) are believed to be relatively unstable, limited tangible data on their stability in commonly used in vitro media are known. We aimed to determine the thermal stability of 10 ß-lactams and 3 BLIs via LC-MS/MS in cation-adjusted Mueller Hinton broth at 25 and 36°C as well as agar at 4 and 37°C, and in water at -20, 4, and 25°C. Supplement dosing algorithms were developed to achieve broth concentrations close to their target over 24 h. During incubation in broth (pH 7.25)/agar, degradation half-lives were 16.9/21.8 h for imipenem, 20.7/31.6 h for biapenem, 29.0 h for clavulanic acid (studied in broth only), 23.1/71.6 h for cefsulodin, 40.6/57.9 h for doripenem, 46.5/64.6 h for meropenem, 50.8/97.7 h for cefepime, 61.5/99.5 h for piperacillin, and >120 h for all other compounds. Broth stability decreased at higher pH. All drugs were ≥90% stable for 72 h in agar at 4°C. Degradation half-lives in water at 25°C were >200 h for all drugs except imipenem (14.7 h, at 1,000 mg/L) and doripenem (59.5 h). One imipenem supplement dose allowed concentrations to stay within ±31% of their target concentration. This study provides comprehensive stability data on ß-lactams and BLIs in relevant in vitro media using LC-MS/MS. Future studies are warranted applying these data to antimicrobial susceptibility testing and assessing the impact of ß-lactamase-related degradation.

Hoigné's syndrome, an uncommon mimicker of anaphylaxis: Systematic literature review.

The term Hoigné's syndrome denotes a mimicker of anaphylaxis, which occurs immediately after the parenteral administration of a drug and is likely caused by non-thrombotic pulmonary and systemic drug micro-embolization. It has so far been documented uniquely in case reports and small case series. Because this condition has never been systematically evaluated, we performed a structured literature review (pre-registered as CRD42023392962). The search was carried out in Excerpta Medica, National Library of Medicine, and Google Scholar. Cases with features consistent with anaphylaxis, urticaria, angioedema, asthma, syncope, anxiety, or panic attack triggered by needle phobia, and local anesthetic systemic toxicity were excluded. For the final analysis, we retained reports published between 1951 and 2021, which presented 247 patients with Hoigné's syndrome: 37 children and 211 adults with a male: female ratio of 2.1 : 1.0. The patients presented within 1 min after parenteral administration of a drug (intramuscular penicillin in 90 % of the cases) with chest discomfort, shortness of breath, fear of death, psychomotor agitation, and auditory or visual hallucinations and impairment. Recovery occurred within 30 min. The diagnosis of Hoigné's syndrome was also established in five patients 66-91 years of age with pre-existing cardiovascular or pulmonary diseases, who suddenly died after the administration of penicillin despite not exhibiting the aforementioned symptoms. It was therefore speculated that pulmonary drug micro-embolization induced a lethal cardiovascular compromise in these individuals. Histologic investigations supporting this hypothesis were performed in only one case. The diagnosis of Hoigné's pulmonary drug micro-embolization was established also in five patients with pre-existing cardiovascular or pulmonary diseases, who suddenly died after the administration of penicillin despite not exhibiting the afore mentioned symptoms. Histologic investigations supporting this hypothesis were performed in only one case. In conclusion, Hoigné's syndrome is an uncommon non-immune-mediated reaction. This report seeks to promote broader awareness and knowledge regarding this alarming mimicker of anaphylaxis. Diagnosis relies solely on clinical evaluation.

Flucloxacillin and cefazolin for treatment of Staphylococcus aureus bloodstream infection.

PURPOSE: Antistaphylococcal penicillins and cefazolin have been used as first line therapy in Methicillin-susceptible Staphylococcus aureus bloodstream infection. While efficacy of both regimens seems to be similar, the compounds may differ with regard to tolerability. This study aims to describe the clinical use of cefazolin and flucloxacillin, focussing on discontinuation or change of anti-infective agent due to adverse events. METHODS: This observational prospective study was conducted at two German tertiary care centres with an internal recommendation of flucloxacillin for MSSA-BSI in one, and of cefazolin in the other centre. Adverse events were registered weekly under treatment and at a 90-day follow-up. Descriptive analysis was complemented by a propensity score analysis comparing adverse events (stratified rank-based test applied to the sum of Common Terminology Criteria for adverse events ratings per patient). RESULTS: Of 71 patients included, therapy was initiated with flucloxacillin in 56 (79%), and with cefazolin in 15 (21%). The propensity score analysis indicates a statistically significant difference concerning the severity of adverse events between the treatment groups in favour of cefazolin (p = 0.019). Adverse events led to discontinuation of flucloxacillin in 7 individuals (13% of all patients receiving flucloxacillin). Clinical outcome was not different among treatment groups. CONCLUSION: Using cefazolin rather than flucloxacillin as a first line agent for treatment of MSSA-BSI is supported by these clinical data.

Resensitization in suspected penicillin allergy.

BACKGROUND: The diagnosis of allergic reactions to penicillins (AR-PEN) is very complex as there is a loss of sensitization over time, which leads to negative skin tests (STs) and specific IgE in serum, and even to tolerance to the drug involved. However, STs may become positive after subsequent exposure to the culprit drug (resensitization), with the risk of inducing potentially severe reactions. The exact rate of resensitization to penicillins is unknown, ranging from 0% to 27.9% in published studies. OBJECTIVES: To analyze the rate of resensitization in patients with suggestive AR-PEN by repeating STs (retest) after an initial evaluation (IE). MATERIAL AND METHODS: Patients with suspected AR-PEN were prospectively evaluated between 2017 and 2020. They underwent STs, and a randomized group also underwent a drug provocation test (DPT) with the culprit. Only patients with negative STs and/or DPT were included. All included cases were retested by STs at 2-8 weeks. RESULTS: A total of 545 patients were included: 296 reporting immediate reactions (IRs) and 249 non-immediate reactions (NIRs). Eighty (14.7%) cases had positive results in retest (RT+): 63 (21.3%) IRs and 17 (6.8%) NIRs (p < 0.0001). The rate of RT+ was higher in anaphylaxis compared with all other reactions (45.8% vs 9.1%, p < 0.0001). The risk of RT+ was higher from the fifth week after IE (OR: 4.64, CI: 2.1-11.6; p < 0.001) and increased with the patient's age (OR: 1.02; CI: 1.01-1.04; p = 0.009). CONCLUSIONS: Due to the high rate of resensitization, retest should be included in the diagnostic algorithm of IRs to penicillins after an initial negative study, especially in anaphylaxis, to avoid potentially severe reactions after subsequent prescriptions of these drugs.

Drug Allergy Alert System in a Spanish University Hospital: Description and Dynamics of Use.

INTRODUCTION: The drug allergy alert system reduces the frequency of adverse drug events, although it is subjected to collateral effects, since 80-90% of alerts are not real, and a large percentage of alerts are overridden (46.2-96.2%). We reviewed how the alert system is used at University Hospital Fundación Alcorcon (HUFA). METHODS: Data were obtained from the drug allergy alert and the alert overriding notification forms (both in the period 2011-20). We also recorded drug allergy diagnoses at HUFA, drug consumption in primary care in 2016. We calculated the incidence of drug allergy alert activation, temporal trends in use, and correlations between the number of drugs in several datasets. RESULTS: We collected 15,535 alerts. NSAIDs and penicillins were the drugs with the highest number of drug allergy alerts (36.55% and 26.91%, respectively). A correlation was found between the number of drug alerts and the type of drug allergy in HUFA in 2016. Only 6.83% of the alerts were removed, and, of these, 21.77% were reactivated. Approximately 100 overrides were recorded per year from 2016 (6.8% of 8,434 activated alerts during 2014-2020). CONCLUSIONS: The number of drug allergy alerts recorded via the drug allergy alert system of HUFA correlates with the distribution of drug allergy diagnoses in the hospital, although many of the alerts could be false positives (as per current published evidence). We detected a very low frequency of removed alerts (6.83%), a relevant frequency of reactivations (one quarter), and a very low frequency of overrides (6.8%).

Self-reported allergy to penicillin and clindamycin administration may be risk factors for dental implant failure: A systematic review, meta-analysis and delabeling protocol.

OBJECTIVE: Growing evidence is highlighting the inefficacy of clindamycin as an effective substitute to amoxicillin in patients self-reporting a penicillin allergy. The hypothesis is that implant failure is higher in these patients, when compared to patients receiving penicillin. To test this hypothesis, a systematic review and meta-analysis was undertaken and a protocol for delabeling penicillin allergic patients was presented. MATERIALS AND METHODS: A systematic review was undertaken by searching across three different databases, namely PubMed, Scopus and Web of Science. RESULTS: Out of 572 results, four studies were eligible to be included. Fixed-effects meta-analysis showed a higher number of failed implants in patients who were administered clindamycin, because of a self-reported allergy to penicillin. Results showed that these patients are over three times more likely (OR = 3.30, 95% C.I. 2.58-4.22, p-value < .00001) to undergo implant failure with an average cumulative proportion of 11.0% (95% C.I. 3.5-22.0%) versus 3.8% (95% C.I. 1.2-7.7%) of patients not requiring clindamycin and administered amoxicillin. A protocol for penicillin allergy delabeling is proposed. CONCLUSIONS: Current evidence is still limited and based on retrospective observational studies, it is difficult to state if penicillin allergy, clindamycin administration or a combination of both is responsible for the current trends and reported findings.

A critical appraisal of acute sore throat guidelines using the AGREE II instrument: a scoping review.

BACKGROUND: Conflicting international guidelines exist on the management of sore throat by antibiotics. OBJECTIVES: To assess with the Appraisal of Guidelines for Research and Evaluation II (AGREE) instrument the quality of guidelines for uncomplicated acute group A beta-haemolytic streptococcal (GABHS) sore-throat. To make a sensitivity analysis restricted to guidelines with a rigour of development score higher than 60% and to describe their recommendations on scores, tests, and antibiotic therapy, including their justification. METHODS: A guideline literature review of acute GABHS sore throat, published between January 2000 and December 2019 in primary care and secondary care. The PubMed database, the Canadian Medical Association Infobase on Clinical Practice Guidelines and the International Network Guidelines were used. The quality of guidelines was assessed using the AGREE II instrument. The guidelines were classified into 2 categories: high-quality guidelines had to rate >60% for the rigour of development score, the others were classified as low-quality guidelines. RESULTS: Significant heterogeneity between the 15 guidelines concerned the scores of the 6 assessment domains. Among them, 6 guidelines presented a score above 60% with regards to the rigor of development domain and used a systematic literature search method, citing meta-analyses of recent randomised clinical trials. Most of the 6 high-quality guidelines no longer recommended the systematic use of diagnostic scores and tests, nor antibiotic therapy to prevent acute rheumatic fever or loco-regional complications, except for high-risk patients. CONCLUSION: Major discrepancies emphasise the need for only high-quality guidelines, based on adequately assessed evidence. Restricted antibiotic prescriptions to severe cases or high-risk patients would avoid antibiotic resistance.

Antibiotic associated diarrhea in outpatient pediatric antibiotic therapy.

BACKGROUND: Antibiotic-associated diarrhea is one of the most frequent side effects of antimicrobial therapy. We assessed the epidemiological data of antibiotic-associated diarrhea in pediatric patients in our region. METHODS: The prospective multi-center study included pediatric patients who were initiated an oral antibiotic course in outpatient clinics and followed in a well-established surveillance system. This follow-up system constituded inclusion of patient by the primary physician, supply of family follow-up charts to the family, passing the demographics and clinical information of patient to the Primary Investigator Centre, and a close telephone follow-up of patients for a period of eight weeks by the Primary Investigator Centre. RESULTS: A result of 758 cases were recruited in the analysis which had a frequency of 10.4% antibiotic-associated diarrhea. Among the cases treated with amoxicillin-clavulanate 10.4%, and cephalosporins 14.4% presented with antibiotic-associated diarrhea. In the analysis of antibiotic-associated diarrhea occurrence according to different geographical regions of Turkey, antibiotic-associated diarrhea episodes differed significantly (p = 0.014), particularly higher in The Eastern Anatolia and Southeastern Anatolia. Though most commonly encountered with cephalosporin use, antibiotic-associated diarrhea is not a frequent side effect. CONCLUSION: This study on pediatric antibiotic-associated diarrhea displayed epidemiological data and the differences geographically in our region.

Optimizing Cefazolin Prophylaxis in Obstetrical Patients with Reported Beta-Lactam Allergy Undergoing Cesarean Delivery.

OBJECTIVES: Evaluate the impact of an allergy history-guided algorithm for optimizing perioperative cefazolin use in patients with reported beta-lactam allergy undergoing cesarean delivery. METHODS: The Allergy Clarification for Cefazolin Evidence-based Prescribing Tool (ACCEPT) was developed through consensus by allergists, anesthesiologists, and infectious diseases specialists, and implemented over a 2-month period (December 1, 2018, to January 31, 2019). A segmented regression on monthly cefazolin use was conducted during the baseline (January 1 to November 30, 2018) and intervention (February 1 to December 31, 2019) periods to evaluate the impact of ACCEPT on the monthly use of perioperative cefazolin in patients with reported beta-lactam allergy undergoing cesarean delivery. The frequency of perioperative allergic reactions and surgical site infections was collected during both periods. RESULTS: Of the 3128 eligible women who underwent a cesarean delivery, 282 (9%) reported a beta-lactam allergy. The most common beta-lactam allergens were penicillin (64.3%), amoxicillin (16.0%), and cefaclor (6.0%). The most frequently reported allergic reactions were rash (38.1%), hives (21.4%), and unknown (11.6%). Use of cefazolin increased from 52% (baseline) to 87% during the intervention period. Segmented regression analysis confirmed a statistically significant increase following implementation (incidence rate ratio 1.62, 95% CI 1.19-2.21, P = 0.002). There was 1 perioperative allergic reaction in the baseline period and 2 during the intervention period. Cefazolin use remained high (92%) 2 years after algorithm implementation. CONCLUSIONS: Implementation of a simple allergy history-guided algorithm in obstetrical patients with reported beta-lactam allergy resulted in a sustained increase in perioperative cefazolin prophylaxis.

A case of persistent IgE sensitisation almost two decades following ampicillin anaphylaxis.

BACKGROUND: Although most immunoglobulin E (IgE)-mediated penicillin allergy wanes with time, sensitisation may occasionally persist for many years. Previous reports on the loss of penicillin-specific IgE sensitisation were based on non-anaphylaxis cases and, although uncommon, persistent sensitisation may still be possible in the minority of cases. OBJECTIVE: This case highlights that irrespective of the elapsed duration since the index reaction, it is important to remain vigilant when approaching patients with a history of severe reactions. MATERIAL AND METHODS: We described a case of persistent IgE sensitisation almost two decades following ampicillin anaphylaxis. RESULTS: A 78-year-old male with a history of perioperative penicillin anaphylaxis in 2003 was referred for allergy workup in 2022 before his knee joint replacement surgery. The patient had strictly avoided all beta-lactams since the index reaction. However, his penicillin-specific sensitisation persisted, evidenced by positive skin tests (with generalised urticaria after intradermal testing) and basophil activation tests. CONCLUSION: To our knowledge, this was the first case of positive BAT tested around two decades following the index reaction. This case illustrates that a cautious approach may still be warranted in patients with a history of severe reaction to penicillin regardless of the duration since the reported index reaction.

New Semisynthetic Penicillins Obtained by Coupling of the 6-Aminopenicillanic Acid with 5-Mercapto-1,2,4-triazoles-3,4-disubstituted.

In a basic medium, 5-Mercapto-1,2,4-triazoles pass into the thiol form, allowing their transformation into sodium salts, which, in reaction with sodium monochloroacetate, lead to sodium 5-thioacetates of 1,2,4-triazoles-3,4-disubstituted. Sulfur derivatives converted to pivalic mixed anhydrides were used as active forms in the acylation of 6-amino penicillanic acid (6-AP) to obtain new semisynthetic penicillins. They contain in the molecule, together with the ß-lactam ring, the nucleus 3-[(5-nitroindazol-1'-yl-methyl)]-4-aryl-5-mercapto-1,2,4-triazole, both contributing to an important antibacterial effect. The structure of the new antibiotics was confirmed by the results of elemental and spectral analysis (FT-IR, 1H- and 13C-NMR). The synthetic penicillins were tested for toxicological action and antibacterial activity and the obtained results were close to those for amoxicillin, the reference drug.

Factors associated with testing positive for syphilis among MSM who present as sexual contacts of syphilis from a clinic-based population.

OBJECTIVES: There has been a significant increase in syphilis in men who have sex with men (MSM) in the UK over the past 20 years. Partner notification strategies have increased the number of MSM attending STI clinics as sexual contacts of syphilis. Current guidelines suggest testing and consideration of presumptive antimicrobial treatment. Syphilis treatment with benzathine penicillin requires clinic resources, is painful and is associated with complications. It is important we consider strategies to rationalise presumptive antimicrobial use and promote antimicrobial stewardship. METHODS: We aimed to determine if there are any factors associated with having syphilis among MSM attending as sexual contacts of syphilis in a cross-sectional study. We examined the clinical records of MSM attending as sexual contacts of syphilis from January to December 2019. RESULTS: Of the 6613 MSM who attended for STI testing, 142 of 6613 (2.1%) presented as sexual contacts of syphilis. The median age was 40 years (IQR=31-51), 43 of 142 (30%) were HIV positive, 38 of 142 (27%) had been diagnosed and treated for syphilis in the past, and 11 of 142 (8%) presented with symptoms (possible lesions of primary or secondary syphilis). Thirteen (9%, 95% CI=4.4 to 13.9) tested positive for syphilis on the day of presentation. MSM who were symptomatic (genital ulcer or body rash), HIV positive or had a history of syphilis were significantly more likely to test positive for syphilis (OR=51.88, 95% CI: 3.01 to 893.14, p=0.007). CONCLUSIONS: We have shown that in our clinic-based population of MSM who presented as sexual contacts of syphilis, the factors associated with testing positive for syphilis were: having HIV, having a history of syphilis or presenting with symptoms (possible lesions of primary or secondary syphilis). These factors could be used to rationalise antibiotic treatment among MSM presenting as sexual contacts of syphilis. Further research is needed to validate this finding in other populations of MSM and people affected by syphilis.

Next-generation sequencing and genotype association studies reveal the association of HLA-DRB3*02:02 with delayed hypersensitivity to penicillins.

BACKGROUND: Nonimmediate (delayed)-allergic reactions to penicillins are common and some of them can be life-threatening. The genetic factors influencing these reactions are unknown/poorly known/poorly understood. We assessed the genetic predictors of a delayed penicillin allergy that cover the HLA loci. METHODS: Using next-generation sequencing (NGS), we genotyped the MHC region in 24 patients with delayed hypersensitivity compared with 20 patients with documented immediate hypersensitivity to penicillins recruited in Italy. Subsequently, we analyzed in silico Illumina Immunochip genotyping data that covered the HLA loci in 98 Spanish patients with delayed hypersensitivity and 315 with immediate hypersensitivity compared to 1,308 controls. RESULTS: The two alleles DRB3*02:02:01:02 and DRB3*02:02:01:01 were reported in twenty cases with delayed reactions (83%) and ten cases with immediate reactions (50%), but not in the Allele Frequency Net Database. Bearing at least one of the two alleles increased the risk of delayed reactions compared to immediate reactions, with an OR of 8.88 (95% CI, 3.37-23.32; p < .0001). The haplotype (ACAA) from rs9268835, rs6923504, rs6903608, and rs9268838 genetic variants of the HLA-DRB3 genomic region was significantly associated with an increased risk of delayed hypersensitivity to penicillins (OR, 1.7; 95% CI: 1.06-1.92; p = .001), but not immediate hypersensitivity. CONCLUSION: We showed that the HLA-DRB3 locus is strongly associated with an increased risk of delayed penicillin hypersensitivity, at least in Southwestern Europe. The determination of HLA-DRB3*02:02 alleles in the risk management of severe delayed hypersensitivity to penicillins should be evaluated further in larger population samples of different origins.

Effects of piperacillin/tazobactam or cefepime on folinate dose in patients receiving high-dose methotrexate: A retrospective cohort study using Japanese administrative claims data.

INTRODUCTION: Delayed methotrexate (MTX) clearance with the co-administration of piperacillin/tazobactam (PIPC/TAZ) has been reported. Penicillins have been associated with reduced MTX clearance but the evidence is limited. There are no cases described with cefepime but penicillins are listed as interacting with MTX. We aimed to reveal whether the co-administration of PIPC/TAZ or CFPM affects MTX clearance using data from an administrative database. METHODS: We used data from the JMDC database, a large insurance claims database constructed in Japan. We included patients who were prescribed PIPC/TAZ or CFPM between days 1 and 3 in high-dose MTX (HD-MTX). We compared one co-administration episode (with PIPC/TAZ or CFPM) to one control episode (without), as a match-control study of two different episodes in the same patient. The primary outcomes were the duration and cumulative dose of leucovorin (LV) as a surrogate indicator of delayed MTX clearance. RESULTS: Three patients who were co-administered PIPC/TAZ and 16 patients who were co-administered CFPM with HD-MTX were included. In the PIPC/TAZ group, the duration and the cumulative doses of LV were similar in co-administration and control episode (median 3.0 vs. 3.0 days and 288.0 vs. 219.0 mg). In the CFPM group, the duration and the cumulative doses of LV were not significantly different in co-administration and control episode (3.0 vs. 4.0 days and 169.5 vs. 258.0 mg). CONCLUSIONS: Our findings revealed that PIPC/TAZ did not necessarily cause a delay in MTX clearance during HD-MTX therapy. Moreover, the co-administration of CFPM with HD-MTX did not affect MTX clearance.

Penicillin allergy SHACK: Survey of hospital and community knowledge.

AIM: Penicillin allergy accounts for the majority of all reported adverse drug reactions in adults and children. Foregoing first-line antibiotic therapy due to penicillin allergy label is associated with an increased prevalence of infections by resistant organisms and longer hospitalisation. Clinician awareness of allergy assessment, referral indications, management of allergy and anaphylaxis is therefore vital but globally lacking. We aim to assess the knowledge of penicillin allergy, assessment and management in Western Australian health professionals. METHODS: An anonymous survey was distributed to pharmacists, nurses and physicians within Western Australian paediatric and adult Hospitals, Community and General Practice. RESULTS: In total, 487/611 were completed and included in the statistical analysis. Only 62% (301/487) of respondents routinely assessed for patient medication allergies. Of those who assessed allergy, 9% (28/301) of respondents met the Australian standards for allergy assessment. Only 22% (106/487) of participants correctly cited all indications for management with adrenaline in anaphylaxis to antibiotics and 67% (197/292) of physicians rarely or never referred to an allergy service. Paediatric clinicians had an increased understanding of allergy assessment and anaphylaxis management. Recent penicillin allergy education within a 5-year period led to significant improvements in allergy knowledge. CONCLUSION: Overall, knowledge, assessment and management of penicillin allergies among practitioners in Western Australia are currently inadequate in adults and paediatric clinicians to provide safe and effective clinical care. The implementation of a targeted education program for WA health professionals is urgently required and is expected to improve clinician knowledge and aid standardised penicillin assessment (de-labelling) practices.

Beta-lactam-induced immediate hypersensitivity reactions: A genome-wide association study of a deeply phenotyped cohort.

BACKGROUND: ß-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (type I) reactions mediated by antigen-specific IgE. OBJECTIVE: We sought to identify genetic predisposing factors for immediate reactions to ß-lactam antibiotics. METHODS: Patients with a clinical history of immediate hypersensitivity reactions to either penicillins or cephalosporins, which were immunologically confirmed, were recruited from allergy clinics. A genome-wide association study was conducted on 662 patients (the discovery cohort) with a diagnosis of immediate hypersensitivity and the main finding was replicated in a cohort of 98 Spanish cases, recruited using the same diagnostic criteria as the discovery cohort. RESULTS: Genome-wide association study identified rs71542416 within the Class II HLA region as the top hit (P = 2 × 10-14); this was in linkage disequilibrium with HLA-DRB1∗10:01 (odds ratio, 2.93; P = 5.4 × 10-7) and HLA-DQA1∗01:05 (odds ratio, 2.93, P = 5.4 × 10-7). Haplotype analysis identified that HLA-DRB1∗10:01 was a risk factor even without the HLA-DQA1∗01:05 allele. The association with HLA-DRB1∗10:01 was replicated in another cohort, with the meta-analysis of the discovery and replication cohorts showing that HLA-DRB1∗10:01 increased the risk of immediate hypersensitivity at a genome-wide level (odds ratio, 2.96; P = 4.1 × 10-9). No association with HLA-DRB1∗10:01 was identified in 268 patients with delayed hypersensitivity reactions to ß-lactams. CONCLUSIONS: HLA-DRB1∗10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required.

A Continuing Education Activity Durably Addressed Knowledge Gaps Related to Penicillin Allergies Among Pharmacists and Pharmacy Technicians.

Background: Penicillin allergy is one of the most frequent self-reported allergies; however, only about 10% of reported allergies are accurate. Objectives: Through the creation of a continuing pharmacy education (CPE) activity, we sought to assess knowledge gaps and comfort levels in the management of penicillin allergies. Methods: A 1-hour enduring-content CPE activity was offered as an interactive course from September 20, 2019, to September 20, 2020. Participants completed 3 surveys (pre-survey, post-survey, and follow-up survey). Participants were pharmacists and pharmacy technicians who completed, at a minimum, the activity and both pre- and post-surveys. The primary outcome was the percentage of participants scoring >80% on knowledge-based questions on the post-survey compared with the pre-survey. Secondary outcomes included pre-post comparisons on knowledge-based questions, participants' self-report of an allergy, and comfort levels dispensing cephalosporins in a patient with a self-reported penicillin allergy. Results: A total of 389 participants completed the CPE activity, with 176 included for analysis. Significantly more participants scored >80% on knowledge-based questions on the post-survey compared with the pre-survey (71.6% vs 22.7%, P < .001). There was no significant difference between the percentage of participants scoring >80% on the post-survey and the follow-up survey (71.6% vs 65%, P = .119). The majority of participants (74%) felt comfortable dispensing a cephalosporin in a patient with a penicillin allergy on the pre-survey, with similar percentages on the post- and follow-up surveys (77% and 90%, respectively). Conclusion: A targeted continuing education program improved overall knowledge, which was sustained for up to 2 months.

Antistaphylococcal penicillins vs. cefazolin in the treatment of methicillin-susceptible Staphylococcus aureus infective endocarditis: a quasi-experimental monocentre study.

Whether cefazolin is as effective and safer than antistaphylococcal penicillins (ASPs) for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) infective endocarditis (IE) is still debated in the absence of a randomized controlled trial. In this quasi-experimental study, we aimed to assess the effectiveness and safety of these two treatments in MSSA-IE, using the ASPs nationwide shortage in April 2016 as a unique opportunity to overcome the indication bias associated with observational studies. In this single-centre study, we compared patients with Duke-Li definite MSSA-IE treated with ASPs from January 2015 to March 2016 versus those treated with cefazolin from April 2016 to December 2018, when ASPs were not available. Effectiveness outcome was 90-day all-cause mortality. Safety outcomes included significant decrease in GFR and significant increase in serum liver enzymes. Logrank test was used to compare survival rates. Of 73 patients with MSSA-IE, 35 and 38 were treated with ASPs and cefazolin, respectively. Baseline patients' characteristics (demography, native or prosthetic valve IE, clinical characteristics, cardiac and septic complications) were similar between groups. Ninety-day all-cause mortality was 28.6% and 21.1%, in patients treated with ASPs and cefazolin, respectively (logrank p = 0.5727). There was no difference between groups for incident renal or liver toxicity events: acute kidney injury 45.7% vs. 44.7% (p = 0.933), increased ALT 5.7% vs. 13.2% (p = 0.432), bilirubin increase 5.7% vs. 10.5% (p = 0.676), in ASPs vs. cefazolin groups, respectively. In this quasi-experimental, effectiveness and safety did not statistically differ between ASPs and cefazolin for MSSA-IE treatment.

Outcomes in reported penicillin allergic mothers and neonates requiring Group B streptococcal prophylaxis: a retrospective observational cohort study.

BACKGROUND: Infectious morbidity and mortality in the first week of life is commonly caused by early-onset neonatal Group B streptococcus (GBS) disease. This infection is spread from GBS positive mothers to neonates by vertical transmission during delivery and results in serious illness for newborns. Intrapartum prophylactic antibiotics have decreased the incidence of early-onset neonatal GBS disease by 80%. Patients labeled with a penicillin allergy (PcnA) alternatively receive either vancomycin or clindamycin but effectiveness is controversial. We evaluated the influence of a reported PcnA label versus no PcnA label on inpatient maternal and neonatal outcomes. METHODS: Our goal was to examine the relationship between a PcnA label, maternal and neonatal outcomes, and hospital costs. We collected retrospective data with institutional IRB approval from 2016 - 2018 for hospitalized patients who were GBS positive, pregnant at time of admission, ≥ 18 years of age, received antibiotic prophylaxis for GBS, were labeled as PcnA or non-PcnA, and completed a vaginal delivery. Patient characteristics and maternal/neonatal outcomes were examined. Statistical tests included calculations of means, medians, proportions, Mann-Whitney, two-sample t-tests, Chi-squared or Fisher's Exact tests, and generalized linear and logistic regression models. Significance was set at p < 0.05. RESULTS: Most PcnA patients were white, older, had a higher median body mass index and mean heart rate, and a greater proportion used tobacco than non-PcnA patients. In regression analyses, PcnA hospitalized patients received a shorter duration of antibiotic treatment than non-PcnA patients [incidence rate ratio (IRR): 0.45, 95% CI: 0.38-0.53]. PcnA patients were also more likely to have their baby's hospital LOS be > 48 h [adjusted odds ratio (AOR): 1.35, 95% CI: 1.07-1.69] even though the PcnA mothers' LOS was not different from non-PcnA mothers. Cost of care, mortality, intensive care, median parity, mean gravidity, and miscarriage were similar between the groups. CONCLUSIONS: In hospitalized obstetric patients, a PcnA label was associated with a shorter maternal course of antibiotic treatment and a longer neonatal LOS. Further prospective studies are needed to clarify the underlying reasons for these outcomes.

Drugs That Changed Society: History and Current Status of the Early Antibiotics: Salvarsan, Sulfonamides, and ß-Lactams.

The appearance of antibiotic drugs revolutionized the possibilities for treatment of diseases with high mortality such as pneumonia, sepsis, plaque, diphtheria, tetanus, typhoid fever, and tuberculosis. Today fewer than 1% of mortalities in high income countries are caused by diseases caused by bacteria. However, it should be recalled that the antibiotics were introduced in parallel with sanitation including sewerage, piped drinking water, high standard of living and improved understanding of the connection between food and health. Development of salvarsan, sulfonamides, and ß-lactams into efficient drugs is described. The effects on life expectancy and life quality of these new drugs are indicated.