Incidence of amoxycillin-clavulanic acid associated hepatotoxicity in an Australian children's hospital.

OBJECTIVES: Amoxycillin/clavulanic acid is the most common antimicrobial cause of drug-induced liver injury in adults. It is a less common cause of severe drug-related hepatotoxicity in children despite its frequent use. We studied the incidence, characteristics and predictive factors for amoxycillin/clavulanic acid hepatoxicity in children. DESIGN: Retrospective cohort study of children who received oral or intravenous amoxycillin/clavulanic acid at a quaternary children's hospital over a 5-year period. Children were included if they had liver function tests (LFTs) determined at baseline, during and within 3 months after the treatment course. Causality was assessed using the Naranjo criteria for adverse drug reactions and Roussel Uclaf Causality Assessment Method. RESULTS: Of 3271 children prescribed amoxycillin/clavulanic acid, 374 were included. Forty-nine (13%) had LFT abnormalities related to amoxycillin/clavulanic acid. Fourteen (3.6%) fulfilled Common Terminology Criteria for Adverse Events (CTCAE) grade 2 criteria with clinically significant hepatotoxicity. Age <2 years, sepsis, post-gastrointestinal surgical indications, prolonged treatment course of >7 days and higher cumulative amoxycillin (>10 g) and clavulanic acid dose (>1 g) were predictive of hepatotoxicity. The median time to resolution of LFT abnormalities was 4 weeks (range 3-7). CONCLUSIONS: The incidence of amoxycillin/clavulanic acid related LFT abnormalities (CTCAE Grade 2 or above) in children was 3.6%. A prolonged treatment course >7 days, high cumulative amoxycillin (10 g) and clavulanic acid (>1 g) doses, those aged <2 years, and patients with sepsis or post-gastrointestinal surgery were predictive of a higher likelihood of abnormal LFTs. LFT monitoring should be considered in children receiving ≥7 days of treatment, particularly in those with other predisposing factors.

Efficacy of amoxicillin/clavulanic acid after surgical drainage of perianal abscess in the prevention of the development of anal fistula (PERIQxA study): study protocol for a multicenter randomized, double-blind clinical trial.

BACKGROUND: Anorectal fistula, which is a relatively common pathology, is the chronic manifestation of the acute perirectal process that forms an anal abscess. The development of a fistula after incision and drainage of an anal abscess is seen in approximately 26-37%. Its treatment is a relevant topic, and the role of the use of antibiotic therapy in its prevention remains controversial, after the publication of several studies with contradictory results and several methodological limitations. Our hypothesis is that the combination of amoxicillin and clavulanic acid will reduce the incidence of anal fistula. METHOD: The aim of this study is to evaluate the efficacy of antibiotherapy after surgical drainage of perianal abscess in the development of perianal fistula. The PERIQxA study is a multicenter, randomized, double-blind controlled trial. The study has been designed to include 286 adult patients who will be randomly (1:1) assigned to either the experimental (amoxicillin/clavulanic acid 875/125 mg TDS for 7 days) or the control arm (placebo). The primary outcome measure is the percentage of patients that develop perianal fistula after surgery and during follow-up (6 months). DISCUSSION: This clinical trial is designed to evaluate the efficacy and safety of amoxicillin/clavulanic in the prevention of perianal fistula. The results of this study are expected to contribute to stablish the potential role of antibiotherapy in the therapeutics for anal abscess. TRIAL REGISTRATION: EudraCT Number: 2021-003376-14. Registered on November 26, 2021.

Exploratory Pilot Studies to Demonstrate Mechanisms of Preventing Antibiotic-Associated Diarrhea and the Role for Probiotics.

Context: Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. One of the most common indications for probiotic treatment is the prevention of antibiotic-associated diarrhea (AAD). Unfortunately, many probiotic products used for AAD are not supported by rigorous independent research, and often results in non-evidence-based usage. Additionally, it is not clear when is the most appropriate time to take a probiotic when on an antibiotic course. Objectives: The primary aim is to determine the ability of BB-12 to impact antibiotic-induced reduction in short chain fatty acid concentration (SCFA), as reflected by the levels of acetate on day 14. Secondarily to determine the ability of BB-12 to impact antibiotic-induced disruption of the gut microbiota with 16S rDNA profiling, with the addition of the time variable of probiotic consumption. Study Design and Interventions: A five group randomized controlled trial, finished in December 2022, we are currently analyzing all the data, but will be finished much prior to NAPCRG. All participants were given a 7-day prescription for amoxicillin-clavulanic acid 875mg taken twice daily. One group received no other interventions. While the other participants were broken into 4 groups. Two groups consumed the yogurt intervention (either yogurt+probiotic or control yogurt) four hours after the antibiotic and two groups consumed the yogurt intervention (either yogurt+probiotic or control yogurt) concomitantly with antibiotics. This timing question is important, as it is unknown if the optimal time for patients to administer probiotics is concurrently with, or after four hours following antibiotic consumption. Setting: Capital Areal Primary Care Practice Based Research Network. Population Studied: 118 participants, ages 18-65 years, generally healthy. Outcome Measures: Change in SCFA among the five groups, microbiome reduced disruption and clinically diagnosed diarrhea. Results: Study is complete and analysis is underway. Should have full results by end of July 2023, much before NAPCRG. .

Pivmecillinam with Amoxicillin/Clavulanic acid as step down oral therapy in febrile Urinary Tract Infections caused by ESBL-producing Enterobacterales (PACUTI).

BACKGROUND: Oral treatment alternatives for febrile urinary tract infections are limited in the era of increasing antimicrobial resistance. We aim to evaluate if the combination of pivmecillinam and amoxicillin/clavulanic acid is non-inferior to current alternatives for step-down therapy in adult patients with febrile urinary tract infection. METHODS: We plan to perform an investigator-initiated non-inferiority trial. Adult hospitalised patients treated with 1-5 days of intravenous antibiotics for acute febrile urinary tract infection caused by extended spectrum beta-lactamase (ESBL) producing Enterobacterales will be randomised 1:1 to either control (7-10 days of either oral ciprofloxacin 500 mg twice daily or oral trimethoprim-sulfamethoxazole 800 mg/160 mg twice daily or intravenous ertapenem 1 g once daily, depending on sex, drug allergy, glomerular filtration rate and susceptibility testing) or intervention (10 days of pivmecillinam 400 mg three times daily and amoxicillin/clavulanic acid 500/125 mg three times daily). The primary outcome will be clinical cure 10 days (+/- 2 days) after antibiotic treatment completion. Clinical cure is defined as being alive with absence of fever and return to non-infected baseline of urinary tract symptoms without additional antibiotic treatment or re-hospitalisation (for urinary tract infection) based on a centralised allocation-blinded structured telephone interview. We plan to recruit 330 patients to achieve 90% power based on a sample size simulation analysis using a two-group comparison, one-sided alpha of 2.5%, an absolute non-inferiority margin of 10% and expecting 93% clinical cure rate and 10% loss to follow-up. The primary endpoint will be analysed using generalised estimated equations and reported as risk difference for both intention-to-treat and per protocol populations. Patients are planned to be recruited from at least 10 centres in Sweden from 2023 to 2026. DISCUSSION: If the combination of pivmecillinam and amoxicillin/clavulanic acid is found to be non-inferior to the control drugs there are potential benefits in terms of tolerability, frequency of interactions, outpatient treatment, side effects, nosocomial infections and drive for further antimicrobial resistance compared to existing drugs. TRIAL REGISTRATION: NCT05224401. Registered on February 4, 2022.

Treatment Failure and Adverse Events After Amoxicillin-Clavulanate vs Amoxicillin for Pediatric Acute Sinusitis.

Importance: Acute sinusitis is one of the most common indications for antibiotic prescribing in children, with an estimated 4.9 million such prescriptions in the US annually. Consensus does not exist regarding the optimal empirical antibiotic. Objective: To compare amoxicillin-clavulanate vs amoxicillin for the treatment of acute sinusitis in outpatient children. Design, Setting, and Participants: Cohort study of children and adolescents aged 17 years or younger with a new outpatient diagnosis of acute sinusitis and a same-day new prescription dispensation of amoxicillin-clavulanate or amoxicillin in a nationwide health care utilization database. Propensity score matching was used to mitigate confounding. Exposure: A new prescription dispensation of amoxicillin-clavulanate or amoxicillin. Main Outcomes and Measures: Treatment failure, defined as an aggregate of a new antibiotic dispensation, emergency department or inpatient encounter for acute sinusitis, or inpatient encounter for a sinusitis complication, was assessed 1 to 14 days after cohort enrollment. Adverse events were evaluated, including gastrointestinal symptoms, hypersensitivity and skin reactions, acute kidney injury, and secondary infections. Results: The cohort included 320 141 patients. After propensity score matching, there were 198 942 patients (99 471 patients per group), including 100 340 (50.4%) who were female, 101 726 (51.1%) adolescents aged 12 to 17 years, 52 149 (26.2%) children aged 6 to 11 years, and 45 067 (22.7%) children aged 0 to 5 years. Treatment failure occurred in 1.7% overall; 0.01% had serious failure (an emergency department or inpatient encounter). There was no difference in the risk of treatment failure between the amoxicillin-clavulanate and amoxicillin groups (relative risk [RR], 0.98 [95% CI, 0.92-1.05]). The risk of gastrointestinal symptoms (RR, 1.15 [95% CI, 1.05-1.25]) and yeast infections (RR, 1.33 [95% CI, 1.16-1.54]) was higher with amoxicillin-clavulanate. After patients were stratified by age, the risk of treatment failure after amoxicillin-clavulanate was an RR of 0.98 (95% CI, 0.86-1.12) for ages 0 to 5 years; RR was 1.06 (95% CI, 0.92-1.21) for 6 to 11 years; and RR was 0.87 (95% CI, 0.79-0.95) for 12 to 17 years. The age-stratified risk of adverse events after amoxicillin-clavulanate was an RR of 1.23 (95% CI, 1.10-1.37) for ages 0 to 5 years; RR was 1.19 (95% CI, 1.04-1.35) for 6 to 11 years; and RR was 1.04 (95% CI, 0.95-1.14) for 12 to 17 years. Conclusions and Relevance: In children with acute sinusitis who were treated as outpatients, there was no difference in the risk of treatment failure between those who received amoxicillin-clavulanate compared with amoxicillin, but amoxicillin-clavulanate was associated with a higher risk of gastrointestinal symptoms and yeast infections. These findings may help inform decisions for empirical antibiotic selection in acute sinusitis.

Drug-Induced Liver Injury with Commonly Used Antibiotics in the All of Us Research Program.

Antibiotics are a known cause of idiosyncratic drug-induced liver injury (DILI). According to the Centers for Disease Control and Prevention, the five most commonly prescribed antibiotics in the United States are azithromycin, ciprofloxacin, cephalexin, amoxicillin, and amoxicillin-clavulanate. We quantified the frequency of acute DILI for these common antibiotics in the All of Us Research Program, one of the largest electronic health record (EHR)-linked research cohorts in the United States. Retrospective analyses were conducted applying a standardized phenotyping algorithm to de-identified clinical data available in the All of Us database for 318,598 study participants. Between February 1984 and December 2022, more than 30% of All of Us participants (n = 119,812 individuals) had been exposed to at least 1 of our 5 study drugs. Initial screening identified 591 potential case patients that met our preselected laboratory-based phenotyping criteria. Because DILI is a diagnosis of exclusion, we then used phenome scanning to narrow the case counts by (i) scanning all EHRs to identify all alternative diagnostic explanations for the laboratory abnormalities, and (ii) leveraging International Classification of Disease 9th revision (ICD)-9 and ICD 10th revision (ICD)-10 codes as exclusion criteria to eliminate misclassification. Our final case counts were 30 DILI cases with amoxicillin-clavulanate, 24 cases with azithromycin, 24 cases with ciprofloxacin, 22 cases with amoxicillin alone, and < 20 cases with cephalexin. These findings demonstrate that data from EHR-linked research cohorts can be efficiently mined to identify DILI cases related to the use of common antibiotics.

Effect of Prophylactic Antibiotics on Mortality in Severe Alcohol-Related Hepatitis: A Randomized Clinical Trial.

Importance: The benefits of prophylactic antibiotics for hospitalized patients with severe alcohol-related hepatitis are unclear. Objective: To determine the efficacy of amoxicillin-clavulanate, compared with placebo, on mortality in patients hospitalized with severe alcohol-related hepatitis and treated with prednisolone. Design, Setting, and Participants: Multicenter, randomized, double-blind clinical trial among patients with biopsy-proven severe alcohol-related hepatitis (Maddrey function score ≥32 and Model for End-stage Liver Disease [MELD] score ≥21) from June 13, 2015, to May 24, 2019, in 25 centers in France and Belgium. All patients were followed up for 180 days. Final follow-up occurred on November 19, 2019. Intervention: Patients were randomly assigned (1:1 allocation) to receive prednisolone combined with amoxicillin-clavulanate (n = 145) or prednisolone combined with placebo (n = 147). Main Outcome and Measures: The primary outcome was all-cause mortality at 60 days. Secondary outcomes were all-cause mortality at 90 and 180 days; incidence of infection, incidence of hepatorenal syndrome, and proportion of participants with a MELD score less than 17 at 60 days; and proportion of patients with a Lille score less than 0.45 at 7 days. Results: Among 292 randomized patients (mean age, 52.8 [SD, 9.2] years; 80 [27.4%] women) 284 (97%) were analyzed. There was no significant difference in 60-day mortality between participants randomized to amoxicillin-clavulanate and those randomized to placebo (17.3% in the amoxicillin-clavulanate group and 21.3% in the placebo group [P = .33]; between-group difference, -4.7% [95% CI, -14.0% to 4.7%]; hazard ratio, 0.77 [95% CI, 0.45-1.31]). Infection rates at 60 days were significantly lower in the amoxicillin-clavulanate group (29.7% vs 41.5%; mean difference, -11.8% [95% CI, -23.0% to -0.7%]; subhazard ratio, 0.62; [95% CI, 0.41-0.91]; P = .02). There were no significant differences in any of the remaining 3 secondary outcomes. The most common serious adverse events were related to liver failure (25 in the amoxicillin-clavulanate group and 20 in the placebo group), infections (23 in the amoxicillin-clavulanate group and 46 in the placebo group), and gastrointestinal disorders (15 in the amoxicillin-clavulanate group and 21 in the placebo group). Conclusion and Relevance: In patients hospitalized with severe alcohol-related hepatitis, amoxicillin-clavulanate combined with prednisolone did not improve 2-month survival compared with prednisolone alone. These results do not support prophylactic antibiotics to improve survival in patients hospitalized with severe alcohol-related hepatitis. Trial Registration: ClinicalTrials.gov Identifier: NCT02281929.

Acute coronary syndrome after initiation of amoxicillin/clavulanate.

We report the case of a 54 year old man referred to the Emergency Department for rapid onset of an itchy rash and oppressive epigastric pain after assumption of amoxicillin/clavulanate. Electrocardiogram aand laboratory findings were consistent with acute coronaty syndrome. After coronary angiography, diagnosis of type II Kounis syndrome was made.

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.

Penicillin allergy that persisted after 66 years: case report.

The most common documented allergy is due to penicillin use, and penicillin allergy is often diagnosed early in childhood. However, fewer than 1% of the approximately 10% of the population with reported penicillin allergy have a true allergy. Antimicrobial stewardship programmes have employed pharmacist-led protocols to rechallenge patients with a documented history of penicillin allergy. There are published data to suggest that patients with a history of penicillin allergy can be successfully rechallenged and desensitised. We report a case of a 74-year-old woman with a documented childhood history of penicillin allergy who was rechallenged with amoxicillin/clavulanate (Augmentin) in the hospital during admission. She was given one trial dose of amoxicillin/clavulanate for the treatment of urinary tract infection to cover organisms detected in the urine culture. Amoxicillin/clavulanate was determined to be the most suitable antibiotic for empirical treatment. Given a documented history of penicillin allergy from over 60 years ago, the likelihood of reactivity was suspected to be low to none. The patient, however, developed an allergic reaction after the one-time oral amoxicillin/clavulanate 875/125 mg dose trial.

Assessment of the Frequency, Phenotypes, and Outcomes of Acute Liver Injury Associated with Amoxicillin/Clavulanate in 1.4 Million Patients in the Veterans Health Administration.

INTRODUCTION: Drug-induced liver injury is a significant health issue, yet the exposure-based incidence remains to be characterized. OBJECTIVE: We aimed to assess the frequency, phenotypes, and outcomes of acute liver injury associated with amoxicillin/clavulanate using a large electronic health record system. METHODS: Using the Veterans Health Administration electronic health record system, we developed the framework to identify unexplained acute liver injury, defined by alanine aminotransferase and/or alkaline phosphatase elevation temporally linked to prescription records of amoxicillin/clavulanate, a major culprit of clinically significant drug-induced liver injury, excluding other competing causes. The population was subcategorized by pre-existing liver conditions and inpatient status at the time of exposure for the analysis. RESULTS: Among 1,445,171 amoxicillin/clavulanate first exposures in unique individuals [92% men; mean age (standard deviation): 59 (15) years], 6476 (incidence: 0.448%) acute liver injuries were identified. Of these, 4427 (65%) had alternative causes, yielding 2249 (incidence: 0.156%) with unexplained acute liver injuries. The incidence of unexplained acute liver injury was lowest in outpatients without underlying liver disease (0.067%) and highest in inpatients with pre-existing liver conditions (0.719%). Older age, male sex, and American Indian or Alaska Native (vs White) were associated with a higher incidence of unexplained acute liver injury. Cholestatic injury affected 74%, exhibiting a higher frequency with advanced age, inpatient exposure, and pre-existing liver conditions. Hepatocellular injury with bilirubin elevation affected 0.003%, with a higher risk at age >45 years. During a 12-month follow-up, patients with unexplained acute liver injury had a higher adjusted overall mortality risk than those without evident acute liver injury. CONCLUSIONS: This framework identifies unexplained acute liver injury following drug exposure in large electronic health record datasets. After validating in other systems, this framework can aid in deducing drug-induced liver injury in the general patient population and regulatory decision making to promote drug safety and public health.

A novel quantitative computer-assisted drug-induced liver injury causality assessment tool (DILI-CAT).

BACKGROUND AND AIMS: We hypothesized that a drug's clinical signature (or phenotype) of liver injury can be assessed and used to quantitatively develop a computer-assisted DILI causality assessment-tool (DILI-CAT). Therefore, we evaluated drug-specific DILI-phenotypes for amoxicillin-clavulanate (AMX/CLA), cefazolin, cyproterone, and Polygonum multiflorum using data from published case series, to develop DILI-CAT scores for each drug. METHODS: Drug specific phenotypes were made up of the following three clinical features: (1) latency, (2) R-value, and (3) AST/ALT ratio. A point allocation system was developed with points allocated depending on the variance from the norm (or "core") for the 3 variables in published datasets. RESULTS: The four drugs had significantly different phenotypes based on latency, R-value, and AST/ALT ratio. The median cyproterone latency was 150 days versus < 43 days for the other three drugs (median: 26 for AMX/CLA, 20 for cefazolin, and 20 for Polygonum multiflorum; p<0.001). The R-value for the four drugs was also significantly different among drugs (cyproterone [median 12.4] and Polygonum multiflorum [median 10.9]) from AMX/CLA [median 1.44] and cefazolin [median 1.57; p<0.001]). DILI-CAT scores effectively separated cyproterone and Polygonum multiflorum from AMX/CLA and cefazolin, respectively (p<0.001). As expected, because of phenotypic overlap, AMX/CLA and cefazolin could not be well differentiated. CONCLUSIONS: DILI-CAT is a data-driven, diagnostic tool built to define drug-specific phenotypes for DILI adjudication. The data provide proof of principle that a drug-specific, data-driven causality assessment tool can be developed for different drugs and raise the possibility that such a process could enhance causality assessment methods.

Efficacy and safety of switching from intravenous to oral antibiotics (amoxicillin-clavulanic acid) versus a full course of intravenous antibiotics in neonates with probable bacterial infection (RAIN): a multicentre, randomised, open-label, non-inferiority trial.

BACKGROUND: Switching from intravenous antibiotic therapy to oral antibiotic therapy among neonates is not yet practised in high-income settings due to uncertainties about exposure and safety. We aimed to assess the efficacy and safety of early intravenous-to-oral antibiotic switch therapy compared with a full course of intravenous antibiotics among neonates with probable bacterial infection. METHODS: In this multicentre, randomised, open-label, non-inferiority trial, patients were recruited at 17 hospitals in the Netherlands. Neonates (postmenstrual age ≥35 weeks, postnatal age 0-28 days, bodyweight ≥2 kg) in whom prolonged antibiotic treatment was indicated because of a probable bacterial infection, were randomly assigned (1:1) to switch to an oral suspension of amoxicillin 75 mg/kg plus clavulanic acid 18·75 mg/kg (in a 4:1 dosing ratio, given daily in three doses) or continue on intravenous antibiotics (according to the local protocol). Both groups were treated for 7 days. The primary outcome was cumulative bacterial reinfection rate 28 days after treatment completion. A margin of 3% was deemed to indicate non-inferiority, thus if the reinfection rate in the oral amoxicillin-clavulanic acid group was less than 3% higher than that in the intravenous antibiotic group the null hypothesis would be rejected. The primary outcome was assessed in the intention-to-treat population (ie, all patients who were randomly assigned and completed the final follow-up visit on day 35) and the per protocol population. Safety was analysed in all patients who received at least one administration of the allocated treatment and who completed at least one follow-up visit. Secondary outcomes included clinical deterioration and duration of hospitalisation. This trial was registered with ClinicalTrials.gov, NCT03247920, and EudraCT, 2016-004447-36. FINDINGS: Between Feb 8, 2018 and May 12, 2021, 510 neonates were randomly assigned (n=255 oral amoxicillin-clavulanic group; n=255 intravenous antibiotic group). After excluding those who withdrew consent (n=4), did not fulfil inclusion criteria (n=1), and lost to follow-up (n=1), 252 neonates in each group were included in the intention-to-treat population. The cumulative reinfection rate at day 28 was similar between groups (one [<1%] of 252 neonates in the amoxicillin-clavulanic acid group vs one [<1%] of 252 neonates in the intravenous antibiotics group; between-group difference 0 [95% CI -1·9 to 1·9]; pnon-inferiority<0·0001). No statistically significant differences were observed in reported adverse events (127 [50%] vs 113 [45%]; p=0·247). In the intention-to-treat population, median duration of hospitalisation was significantly shorter in the amoxicillin-clavulanic acid group than the intravenous antibiotics group (3·4 days [95% CI 3·0-4·1] vs 6·8 days [6·5-7·0]; p<0·0001). INTERPRETATION: An early intravenous-to-oral antibiotic switch with amoxicillin-clavulanic acid is non-inferior to a full course of intravenous antibiotics in neonates with probable bacterial infection and is not associated with an increased incidence of adverse events. FUNDING: The Netherlands Organization for Health Research and Development, Innovatiefonds Zorgverzekeraars, and the Sophia Foundation for Scientific Research.

Positive drug provocation with beta-lactam antibiotics in children: A single test may not be enough.

BACKGROUND: Drug provocation tests (DPTs) are considered the gold standard for diagnosing beta-lactam allergy. However, positive results tend to be mild and difficult to interpret. This study aimed to describe pediatric patients with a presumedly positive or inconclusive DPT, assess the decision to repeat the DPT, and describe its outcome. METHODS: Retrospective review of all presumedly positive or inconclusive DPTs performed in six pediatric allergy clinics from 2017 to 2019. We describe the interpretation of results, focusing on the decision to repeat the DPT and its outcome. RESULTS: Of 439 children challenged with a beta-lactam, 26 (5.9%) with a presumedly positive or inconclusive result were included in this study. Most were girls (n = 16, 61.5%), and the median age was 5 years (range 1-13). The initial DPT used amoxicillin (n = 13, 50.0%), amoxicillin-clavulanic acid (n = 12, 46.2%), or cefadroxil (n = 1, 3.8%). Reactions were early (n = 11, 42.3 %), delayed (n = 14, 53.8 %), or not registered (n = 1, 3.8 %), but mild in all cases. A second confirmatory DPT was proposed in 19 patients (73.1%) and performed in 17 patients (65.4%). Nine DPTs were performed from 1 day to 4 months after the first DPT, and the remaining eight took place 6 months to 2 years later. Fifteen children tolerated the drug in the second DPT: 88.2% of those reevaluated and 57.5% of the whole study group. CONCLUSION: The positive predictive value of DPT may be lower than expected. Given the mildness of observed reactions, a second confirmatory DPT is warranted within a few weeks or months.

Positive drug provocation with beta-lactam antibiotics in children: A single test may not be enough

Background: Drug provocation tests (DPTs) are considered the gold standard for diagnosing beta-lactam allergy. However, positive results tend to be mild and difficult to interpret. This study aimed to describe pediatric patients with a presumedly positive or inconclusive DPT, assess the decision to repeat the DPT, and describe its outcome.Methods: Retrospective review of all presumedly positive or inconclusive DPTs performed in six pediatric allergy clinics from 2017 to 2019. We describe the interpretation of results, focusing on the decision to repeat the DPT and its outcome.Results: Of 439 children challenged with a beta-lactam, 26 (5.9%) with a presumedly positive or inconclusive result were included in this study. Most were girls (n = 16, 61.5%), and the median age was 5 years (range 1–13). The initial DPT used amoxicillin (n = 13, 50.0%), amoxicillin-clavulanic acid (n = 12, 46.2%), or cefadroxil (n = 1, 3.8%). Reactions were early (n = 11, 42.3 %), delayed (n = 14, 53.8 %), or not registered (n = 1, 3.8 %), but mild in all cases. A second confirmatory DPT was proposed in 19 patients (73.1%) and performed in 17 patients (65.4%). Nine DPTs were performed from 1 day to 4 months after the first DPT, and the remaining eight took place 6 months to 2 years later. Fifteen children tolerated the drug in the second DPT: 88.2% of those reevaluated and 57.5% of the whole study group.Conclusion: The positive predictive value of DPT may be lower than expected. Given the mildness of observed reactions, a second confirmatory DPT is warranted within a few weeks or months (AU)

Amoxicillin hypersensitivity: Patient outcomes in a seven-year retrospective study.

BACKGROUND: The beta-lactam antibiotic amoxicillin and the beta-lactamase inhibitor clavulanic acid in combination with amoxicillin are known to cause both immediate- and nonimmediate-type hypersensitivity. OBJECTIVE: To characterize a large cohort of patients with a history of amoxicillin or amoxicillin-clavulanic acid hypersensitivity. METHODS: A retrospective analysis was conducted of the demographics, presentation, investigation, and management of 331 patients presenting to 1 allergy center with a history of hypersensitivity to amoxicillin or amoxicillin-clavulanic acid. RESULTS: Hypersensitivity was confirmed in 37 of 221 patients (17%) who took amoxicillin and 47 of 110 patients (43%) who took amoxicillin-clavulanic acid as the index drug. In immediate hypersensitivity, skin test results confirmed the diagnosis in 66 of 139 patients (47%). Penicillin cross-reactivity was observed in 16 of 36 patients (44%). Of the 16 patients who were cross-reactive, 13 (81%) reacted to amoxicillin-clavulanic acid as the index drug. All patients who had negative skin test results (73/139) underwent drug provocation. The negative predictive value of skin tests was 89%. In nonimmediate hypersensitivity, delayed intradermal tests confirmed diagnosis in 12 of 170 patients (7%). Of the 12 patients whose skin test results were positive, 8 (67%) presented with drug reaction with eosinophilia and systemic symptoms. All patients with a negative skin test result (158/170) underwent drug provocation. The negative predictive value of skin tests was 95%. Penicillin cross-reactivity was observed in 3 of 12 patients (25%). Ten patients were diagnosed with hypersensitivity to clavulanic acid. CONCLUSION: The negative predictive value of skin tests in both immediate and nonimmediate hypersensitivity reactions is excellent and excludes severe allergy. Nonimmediate hypersensitivity is rare. Confirmed hypersensitivity is more likely if amoxicillin-clavulanic acid is the index drug. Cross-reactivity was more common in patients presenting with immediate hypersensitivity, typically involving benzylpenicillin. A minority of patients were allergic to clavulanic acid.