Rising to the Challenge: An ID Provider-Led Initiative to Address Penicillin Allergy Labels at a Large Veterans Affairs Medical Center.

Background: Given the negative consequences associated with a penicillin allergy label, broader penicillin allergy delabeling initiatives are highly desirable but hindered by the shortage of allergists in the United States. To address this problem at our facility, the infectious diseases section introduced a quality improvement initiative to evaluate and remove allergy labels among inpatient veterans. Methods: Between 15 November 2022 and 15 December 2023, we identified inpatients with a penicillin allergy label. We subsequently interviewed eligible candidates to stratify penicillin allergy risk and attempt to remove the allergy label directly via chart review, following inpatient oral amoxicillin challenge or outpatient community care allergy referral. Delabeling outcomes, subsequent penicillin-class prescriptions, and relabeling were tracked after successful allergy label removal. Results: We screened 272 veterans, of whom 154 were interviewed for this intervention. A total of 53 patients were delabeled: 26 directly, 23 following oral amoxicillin challenge, and 4 following outpatient allergy referrals. Of the patients who were delabeled, 25 received subsequent penicillin-class prescriptions. No adverse reactions occurred following inpatient oral amoxicillin challenges. Patients with a low-risk penicillin allergy history were more likely to undergo a challenge if admitted with an infectious diseases-related condition. Only 1 inappropriate relabeling event occurred during the study period, which was subsequently corrected. Conclusions: An infectious diseases provider-led initiative resulted in penicillin allergy label removal in more than one third of inpatients evaluated using direct removal or oral amoxicillin challenge. Efforts focused on patients who had been admitted for infections were particularly successful.

Comparing skin and serum testing to direct challenge outcomes in children with beta-lactam allergies.

BACKGROUND: There is a scarcity of prospective studies investigating the relative roles of skin prick and intradermal testing, serum-specific Immunoglobulin E, and extended oral challenges in diagnosing children with reported beta-lactam allergies. OBJECTIVE: To determine the sensitivity and specificity of skin testing and serum-specific Immunoglobulin E in children with beta-lactam allergies, with immediate and non-immediate historic reactions. METHODS: Four hundred children with parent-reported beta-lactam allergies were recruited into an open-label prospective study. Detailed allergy histories were collected. Those with medically observed and documented histories of anaphylaxis, requiring epinephrine, or SCARs were excluded. In total, 380 children underwent all testing modalities and a direct provocation test. Each child was followed up for a minimum of three years. RESULTS: True allergy in children was uncommon, 8·3% reacted to the direct provocation challenge or the 5-day extended oral provocation challenge. Children reporting cephalosporin allergy or a reaction within one year were more likely to react to direct provocation testing. The sensitivity, specificity, and positive predictive value of skin testing was 12·5%, 98·8% and 20·0% for direct challenge outcomes, 4·76%, 99·0% and 25·0% for extended challenge outcomes, and 6·9%, 99·0% and 40·0% for both challenges combined. Follow-up investigations revealed that 5·7% of children had a mild repeat reaction and 2·7% continued to avoid the culprit despite successful delabeling. The relabeling rate for children readmitted to hospital was 15% with the relabeing being unfounded. CONCLUSION: Genuine beta-lactam allergies were rare, with over 90% of children effectively delabeled. Skin and serum-specific Immunoglobulin E testing did not aid the diagnosis of beta-lactam antibiotic allergy in children, regardless of medical history. Extended oral challenges proved valuable in confirming allergies and boosted parental confidence.

The Effect of a Single-Dose Aminoglycoside With a Beta-Lactam for the Treatment of Gram-Negative Bacteremia.

Introduction: Aminoglycosides possess activity against aerobic gram-negative organisms and are often used in combination with beta-lactam antibiotics. Previous studies evaluating combination therapy in gram-negative bacteremia have not shown clear benefits, however antimicrobial resistance was not prevalent in these studies. Our objective is to elucidate potential benefits of adding a single dose of an aminoglycoside to a beta-lactam in patients with gram-negative bacteremia. Methods: This study was a single-center, retrospective, cohort study including patients 18 years old or older and treated for at least 24 hours for a confirmed gram-negative bacteremia. Patients were divided into two groups: receipt of beta-lactam monotherapy (n = 164) and receipt of a beta-lactam in addition to a single dose of an aminoglycoside (n = 79) within 24 hours of bacteremia onset. The primary endpoint was infection-related 30-day mortality per provider documentation. Key secondary outcomes include incidence of acute kidney injury (AKI) and time to improvement of AKI. Data were analyzed using Chi-square or Fisher's exact tests, student's T test, and descriptive statistics as appropriate. Results: The primary outcome occurred in 13/164 vs 2/79 patients in the monotherapy and combination groups (P = 0.10). Incidence of AKI (14% vs. 12%) and time to recovery from AKI (90 hours; IQR [50 - 133] vs 78 hours; IQR [42 - 128]) were comparable between groups (P = 1.00 and P = 0.73, respectively). Conclusions: The addition of a single-dose aminoglycoside was not significantly associated with reduced mortality or increased time to recovery from AKI in our patient population. Larger studies, particularly in more severely ill patient populations, are needed.

A call to address penicillin allergy labels in patients with hematopoietic stem cell transplants: How to avoid rash decisions.

Among patients with hematopoietic stem cell transplants, infections, particularly multidrug-resistant infections, pose a grave threat. In this setting, penicillin allergy labels are both common and harmful. Though the majority of patients who report penicillin allergy can actually tolerate penicillin, penicillin allergy labels are associated with use of alternative antibiotics, which are often more broad spectrum, less effective, and more toxic. In turn, they are associated with more severe infections, multidrug-resistant infections, Clostridium difficile, and increased mortality. Evaluating penicillin allergy labels can immediately expand access to preferred therapeutic options, which are critical to care in patients with recent hematopoietic stem cell transplants. Point-of-care assessment and clinical decision tools now exist to aid the nonallergist in assessment of penicillin allergy. This can aid in expanding use of other beta-lactam antibiotics and assist in risk-stratifying patients to determine a testing strategy. In patients with low-risk reaction histories, direct oral challenges can be employed to efficiently delabel patients across clinical care settings. We advocate for multidisciplinary efforts to evaluate patients with penicillin allergy labels prior to transplantation.

Unraveling the impact of therapeutic drug monitoring via machine learning for patients with sepsis.

Clinical studies investigating the benefits of beta-lactam therapeutic drug monitoring (TDM) among critically ill patients are hindered by small patient groups, variability between studies, patient heterogeneity, and inadequate use of TDM. Accordingly, definitive conclusions regarding the efficacy of TDM remain elusive. To address these challenges, we propose an innovative approach that leverages data-driven methods to unveil the concealed connections between therapy effectiveness and patient data, collected through a randomized controlled trial (DRKS00011159; 10th October 2016). Our findings reveal that machine learning algorithms can successfully identify informative features that distinguish between healthy and sick states. These hold promise as potential markers for disease classification and severity stratification, as well as offering a continuous and data-driven "multidimensional" Sequential Organ Failure Assessment (SOFA) score. The positive impact of TDM on patient recovery rates is demonstrated by unraveling the intricate connections between therapy effectiveness and clinically relevant data via machine learning.

Adverse Events Comparison of Double Beta-Lactam Combinations for Bloodstream Infections: Ampicillin plus Ceftriaxone and Ampicillin/Cloxacillin.

In Japan, only ampicillin/cloxacillin (ABPC/MCIPC) is available as an anti-staphylococcal penicillin-based treatment for Staphylococcus aureus bacteremia. However, the incidence of adverse events associated with double beta-lactam administration remains unknown. Therefore, we investigated the adverse events of double beta-lactam administration in patients with bacteremia. Adult patients (≥18 years) with bacteremia treated with ABPC, ABPC + ceftriaxone (CTRX), or ABPC/MCIPC were retrospectively analyzed. The primary outcome of this study was the incidence of adverse events such as acute kidney injury, liver dysfunction, and myelosuppression. Chi-square tests and t-tests were used for bivariate analysis. Propensity score (PS) matching was conducted to adjust for confounding factors. We included 277 ABPC-, 57 ABPC + CTRX-, and 43 ABPC/MCIPC-treated patients. Significant differences were noted in age, number of male patients, proportion of patients with qSOFA score ≥2, incidence of chronic kidney disease, treatment duration, mechanical ventilation use, vasopressor use, and proportion of patients with acute kidney injury (AKI) KDIGO grade ≥2. Further, a significant difference was observed between ABPC and ABPC/MCIPC, with a hazard ratio of 1.83 in AKI. In the PS-matched cohort, AKI incidence associated with ABPC/MCIPC was significantly higher than that associated with ABPC. ABPC + CTRX may be safe, whereas ABPC/MCIPC presents a higher risk of AKI and may not be suitable.

Parenteral Beta-Lactam/Beta-Lactamase Inhibitor Ordering in Hospitals That Provide Care for Pediatric Patients.

OBJECTIVES: The purpose of this study was to define current practices related to beta-lactam/beta-lactamase inhibitor (BL/BLI) dose descriptions in hospitals that provide care for pediatric patients and to identify perceived implications of standardizing BL/BLI dose communication and ordering to a total drug-based strategy. METHODS: A 27-item electronic survey was distributed via 4 pediatric pharmacy and infectious diseases listservs. Survey questions pertained to hospital demographics, dosing communication practices, BL/BLI ordering and labeling practices, obstacles to safe BL/BLI use, and the effects of potential standardization to a total drug communication strategy. SPSS was used for quantitative analysis and MAXQDA was used for qualitative analysis. RESULTS: A total of 140 unique survey responses were analyzed after exclusion of incomplete responses and reconciliation of multiple responses from the same institution. Overall, 56.2% of institutions order BL/BLIs by BL component for pediatric patients, and 22% of institutions order by BL component for adult patients. Approximately half (51.8%) of respondents felt that standardizing to total drug would have a negative effect at their institution; perception of potential effect varied based on the institution's ordering strategy. CONCLUSION: Communication and ordering of BL/BLIs is inconsistent across institutions and between pediatric and adult patients. In the short term, the perception is that standardization would compound institutional challenges.

Dose optimization of ß-lactam antibiotics in children: from population pharmacokinetics to individualized therapy.

INTRODUCTION: ß-Lactams are the most widely used antibiotics in children. Their optimal dosing is essential to maximize their efficacy, while minimizing the risk for toxicity and the further emergence of antimicrobial resistance. However, most ß-lactams were developed and licensed long before regulatory changes mandated pharmacokinetic studies in children. As a result, pediatric dosing practices are poorly harmonized and off-label use remains common today. AREAS COVERED: ß-Lactam pharmacokinetics and dose optimization strategies in pediatrics, including fixed dose regimens, therapeutic drug monitoring, and model-informed precision dosing are reviewed. EXPERT OPINION/COMMENTARY: Standard pediatric doses can result in subtherapeutic exposure and non-target attainment for specific patient subpopulations (neonates, critically ill children, e.g.). Such patients could benefit greatly from more individualized approaches to dose optimization, beyond a relatively simple dose adaptation based on weight, age, or renal function. In this context, Therapeutic Drug Monitoring (TDM) and Model-Informed Precision Dosing (MIPD) emerge as particularly promising avenues. Obstacles to their implementation include the lack of strong evidence of clinical benefit due to the paucity of randomized clinical trials, of standardized assays for monitoring concentrations, or of adequate markers for renal function. The development of precision medicine tools is urgently needed to individualize therapy in vulnerable pediatric subpopulations.

A Systematic Review of the Pharmacokinetics and Pharmacodynamics of Novel Beta-Lactams and Beta-Lactam with Beta-Lactamase Inhibitor Combinations for the Treatment of Pneumonia Caused by Carbapenem-Resistant Gram-Negative Bacteria.

BACKGROUND: Novel beta-lactams show activity against many multidrug-resistant Gram-negative bacteria that cause severe lung infections. Understanding pharmacokinetic/pharmacodynamic characteristics of these agents may help optimise outcomes in the treatment of pneumonia. OBJECTIVES: To describe and appraise studies that report pulmonary pharmacokinetic and pharmacodynamic data of cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam and meropenem/vaborbactam. METHODS: MEDLINE (PubMed), Embase, Web of Science and Scopus libraries were used for the literature search. Pulmonary population pharmacokinetic and pharmacokinetic/pharmacodynamic studies on adult patients receiving cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, and meropenem/vaborbactam published in peer-reviewed journals were included. Two independent authors screened, reviewed and extracted data from included articles. A reporting guideline for clinical pharmacokinetic studies (ClinPK statement) was used for bias assessment. Relevant outcomes were included, such as population pharmacokinetic parameters and probability of target attainment of dosing regimens. RESULTS: Twenty-four articles were included. There was heterogeneity in study methods and reporting of results, with diversity across studies in adhering to the ClinPK statement checklist. Ceftolozane/tazobactam was the most studied agent. Only two studies collected epithelial lining fluid samples from patients with pneumonia. All the other phase I studies enrolled healthy subjects. Significant population heterogeneity was evident among available population pharmacokinetic models. Probabilities of target attainment rates above 90% using current licensed dosing regiments were reported in most studies. CONCLUSIONS: Although lung pharmacokinetics was rarely described, this review observed high target attainment using plasma pharmacokinetic data for all novel beta-lactams. Future studies should describe lung pharmacokinetics in patient populations at risk of carbapenem-resistant pathogen infections.

Retrospective analysis of a flucloxacillin oral absorption test in patients requiring flucloxacillin therapy: results and determination of factors associated with adequate absorption.

OBJECTIVES: Flucloxacillin has the most narrow spectrum to treat staphylococcal infections, but has a large variability in bioavailability which hampers its intravenous (iv) to oral switch. To identify patients with adequate absorption, the use of an oral absorption test (OAT) measuring total plasma concentrations of flucloxacillin before and after an oral dose of 1 gram flucloxacillin, was previously published. The current pilot study aims to evaluate the fraction of patients with adequate absorption using a similar OAT; to assess the therapeutic consequences and to identify potential factors associated with adequate absorption. METHODS: Demographic data of adult patients treated with iv flucloxacillin and requiring prolonged therapy were collected retrospectively between May 2020 and November 2021 at Ghent University Hospital. A previously published OAT protocol was used, with addition of a protocol for intermittent dosing of iv flucloxacillin. Adequate absorption was defined as an increase in plasma concentration of at least 10 mg/L. RESULTS: The flucloxacillin OAT was performed in 99 patients, of which 62% were men, with a median age of 58 years and 95% received intermittent dosing of iv flucloxacillin. Of the 99 patients, 55% had a result indicating an adequate absorption and 49% of all patients were switched to oral flucloxacillin afterwards. Inadequate absorption was found to be associated with higher Body Mass Index and higher flucloxacillin baseline concentration, while co-administration of acetylsalicylic acid was associated with an adequate absorption. CONCLUSIONS: Based on the OAT, 49% of all patients were switched to oral flucloxacillin instead of broader-spectrum anti-staphylococcal antibiotics. This implicates that an OAT could be a valuable antimicrobial stewardship measure by restricting the use of broad-spectrum antibiotics. For each of the associations found, a hypothesis was formulated about the underlying reason or mechanism; these should be confirmed in future studies with prospective and multicentric design.

Monitoring of Haemophilus influenzae isolated from carriage, lower respiratory tract infections and blood over a six-month period in Belgium.

INTRODUCTION: H. influenzae carriage may evolve into respiratory or systemic infections. However, no surveillancesystem is in place in Belgium to monitor carriage strains. MATERIAL AND METHODS: This study provides a detailed description of H. influenzae strains isolated from both carriage and lower respiratory infections, collected during a six-month national surveillance. Subsequently, a comparison is conducted with invasive isolates collected during the same period at the National Reference Centre (NRC). RESULTS AND DISCUSSION: From November 2021 to April 2022, 39 clinical laboratories collected 142 and 210 strains of H. influenzae from carriage and infection, respectively, and 56 strains of blood were submitted to the NRC. In each group, the biotype II comprised more than 40%, followed by biotypes III and I. The majority of strains were non-typeable H. influenzae, with a notable increase in the number of encapsulated strains in the invasive group (14.3% vs. 1-2%). A beta-lactamase was identified in 18.5% and 12.5% of surveillance and invasive strains, respectively. Resistance to the amoxicillin-clavulanic acid combination accounted for 7% in the surveillance strains and 10.7% in invasive strains. The overall resistance to third-generation cephalosporins at 1.2% is consistent with rates observed in other European countries. Of particular significance is the identification of mutations in the ftsI gene in both carriage and infected strains, which are associated with high-level beta-lactam resistance. CONCLUSION: NRC must engage in regular and systematic monitoring of beta-lactam susceptibility of H. influenzae to guarantee safe empiric therapy in severe cases and identify potential transitions from low-level to high-level resistance in the future.

Rapid and Simple Morphological Assay for Determination of Susceptibility/Resistance to Combined Ciprofloxacin and Ampicillin, Independently, in Escherichia coli.

Current antibiograms cannot discern the particular effect of a specific antibiotic when the bacteria are incubated with a mixture of antibiotics. To prove that this task is achievable, Escherichia coli strains were treated with ciprofloxacin for 45 min, immobilized on a slide and stained with SYBR Gold. In susceptible strains, the nucleoid relative surface started to decrease near the MIC, being progressively condensed as the dose increased. The shrinkage level correlated with the DNA fragmentation degree. Ciprofloxacin-resistant bacilli showed no change. Additionally, E. coli strains were incubated with ampicillin for 45 min and processed similarly. The ampicillin-susceptible strain revealed intercellular DNA fragments that increased with dose, unlike the resistant strain. Co-incubation with both antibiotics revealed that ampicillin did not modify the nucleoid condensation effect of ciprofloxacin, whereas the quinolone partially decreased the background of DNA fragments induced by ampicillin. Sixty clinical isolates, with different combinations of susceptibility-resistance to each antibiotic, were co-incubated with the EUCAST breakpoints of susceptibility of ciprofloxacin and ampicillin. The morphological assay correctly categorized all the strains for each antibiotic in 60 min, demonstrating the feasible independent evaluation of a mixture of quinolone and beta-lactam. The rapid phenotypic assay may shorten the incubation times and necessary microbial mass currently required for evaluation.

Towards pharmacokinetic boosting of phenoxymethylpenicillin (penicillin-V) using probenecid for the treatment of bacterial infections.

In the face of increasing antimicrobial tolerance and resistance there is a global obligation to optimise oral antimicrobial dosing strategies including narrow spectrum penicillins, such as penicillin-V. We conducted a randomised, crossover study in healthy volunteers to characterise the influence of probenecid on penicillin-V pharmacokinetics and estimate the pharmacodynamics against Streptococcus pneumoniae. Twenty participants took six doses of penicillin-V (250 mg, 500 mg or 750 mg four times daily) with and without probenecid. Total and free concentrations of penicillin-V and probenecid were measured at two timepoints. A pharmacokinetic model was developed, and the probability of target attainment (PTA) calculated. The mean difference (95% CI) between penicillin-V alone and in combination with probenecid for serum total and free penicillin-V concentrations was significantly different at both timepoints (total: 45 min 4.32 (3.20-5.32) mg/L p < 0.001, 180 min 2.2 (1.58-3.25) mg/L p < 0.001; free: 45 min 1.15 (0.88-1.42) mg/L p < 0.001, 180 min 0.5 (0.35-0.76) mg/L p < 0.001). There was no difference between the timepoints in probenecid concentrations. PTA analysis shows probenecid allows a fourfold increase in MIC cover. Addition of probenecid was safe and well tolerated. The data support further research into improved dosing structures for complex outpatient therapy and might also be used to address penicillin supply shortages.

A comparison of antibiotic resistance genes and mobile genetic elements in wild and captive Himalayan vultures.

As the most widely distributed scavenger birds on the Qinghai-Tibetan Plateau, Himalayan vultures (Gyps himalayensis) feed on the carcasses of various wild and domestic animals, facing the dual selection pressure of pathogens and antibiotics and are suitable biological sentinel species for monitoring antibiotic resistance genes (ARGs). This study used metagenomic sequencing to comparatively investigate the ARGs and mobile genetic elements (MGEs) of wild and captive Himalayan vultures. Overall, the resistome of Himalayan vultures contained 414 ARG subtypes resistant to 20 ARG types, with abundances ranging from 0.01 to 1,493.60 ppm. The most abundant resistance type was beta-lactam (175 subtypes), followed by multidrug resistance genes with 68 subtypes. Decreases in the abundance of macrolide-lincosamide-streptogramin (MLS) resistance genes were observed in the wild group compared with the zoo group. A total of 75 genera (five phyla) of bacteria were predicted to be the hosts of ARGs in Himalayan vultures, and the clinical (102 ARGs) and high-risk ARGs (35 Rank I and 56 Rank II ARGs) were also analyzed. Among these ARGs, twenty-two clinical ARGs, nine Rank I ARG subtypes, sixteen Rank II ARG subtypes were found to differ significantly between the two groups. Five types of MGEs (128 subtypes) were found in Himalayan vultures. Plasmids (62 subtypes) and transposases (44 subtypes) were found to be the main MGE types. Efflux pump and antibiotic deactivation were the main resistance mechanisms of ARGs in Himalayan vultures. Decreases in the abundance of cellular protection were identified in wild Himalayan vultures compared with the captive Himalayan vultures. Procrustes analysis and the co-occurrence networks analysis revealed different patterns of correlations among gut microbes, ARGs, and MGEs in wild and captive Himalayan vultures. This study is the first step in describing the characterization of the ARGs in the gut of Himalayan vultures and highlights the need to pay more attention to scavenging birds.

An enantioselective formal synthesis of thienamycin.

Thienamycin is a carbapenem antibiotic with potent activity against gram-negative and gram-positive bacteria. Due to its promising activity but lack of chemical stability, thienamycin serves as inspiration for new synthetic antibiotic scaffolds. In this study, we report a nine-step enantioselective formal synthesis of thienamycin. Our route utilizes an asymmetric reduction, enabled by NaBH4 and D-tartaric acid, followed by a series of diastereoselective reactions to access the key azetidinone precursor to thienamycin. This azetidinone precursor could be used as an intermediate to further develop and expand the scope of next-generation beta-lactam antibiotic scaffolds.

Delabelling beta-lactam allergy.

Background: Hypersensitivity to beta-lactam (BL) antibiotics is one of the most frequent reported drug allergies. In our population, it is common to find labels of BL allergy in electronic medical records (EMRs) that have not been assessed. The objective of our study was to detect patients with beta-lactam allergy labels in their EMRs and to assess how many of them are false after a correct diagnostic evaluation. Methods: A multicentre prospective study was performed with patients labelled as allergic to BLs in their EMRs in the previous 5 years. Demographical and clinical data, as well as variables regarding the BL allergy label and the characteristics of the index reaction from clinical history and EMRs, were recorded. Then, diagnostic assessments including clinical history, skin tests (STs), and drug provocation tests (DPTs) were conducted in order to confirm or exclude the diagnosis of BL allergy. Results: A total of 249 patients completed the study, of which 160 (64.3%) were women with a median age of 57 years (interquartile range [IQR], 45-68). The most frequent BL allergy labels detected were for penicillin (124), amoxicillin/clavulanic acid (61), and amoxicillin (54). Of the 204 patients who underwent STs, 20.1% were positive. DPTs were performed in 224 patients, showing good tolerance in 87.1% of cases. After the allergy diagnosis work-up, 186 patients (74.7%) were diagnosed as non-allergic to BL antibiotics. Conclusion: In our study population, the number of patients labelled as allergic to BLs in their EMRs was similar to that in previously published studies, with proportions near to 75%-80% being falsely labelled as allergic to BLs.

Ampicillin-Sulbactam for Carbapenem-Susceptible Acinetobacter baumannii Pneumonia: A Case for High-Dose, Continuous Infusion Dosing Strategy in the Trauma ICU.

Background: The optimal ampicillin-sulbactam dosing regimen for carbapenem-susceptible Acinetobacter baumannii isolates in critically ill trauma patients has not been clearly defined. One strategy to provide the adequate sulbactam dose includes high-dose continuous infusion. Case(s) Description: We present three cases of critically ill trauma patients with augmented renal clearance treated with high-dose ampicillin-sulbactam through an intravenous continuous infusion for ventilator-associated pneumonia. All A. baumannii isolates were susceptible to sulbactam with low minimum inhibitory concentrations. All achieved clinical cure at the end of therapy and no recurrent pneumonia was noted. No clinically substantial adverse effect attributable to ampicillin-sulbactam therapy occurred. Discussion: There is limited evidence to endorse high-dose, continuous infusion ampicillin-sulbactam for treatment of infections caused by carbapenem-susceptible A. baumannii. This report presents three critically ill trauma patients with augmented renal clearance that achieved positive clinical outcomes with higher doses of ampicillin-sulbactam administered through a continuous infusion.

Piperacillin-Tazobactam versus Cefotaxime as Empiric Treatment for Febrile Urinary Tract Infection in Hospitalized Children.

BACKGROUND: According to international pediatric urinary tract infection (UTI) guidelines, selecting ampicillin/sulbactam or amoxicillin/clavulanate is recommended as the first-line treatment for pediatric UTI. In Korea, elevated resistance to ampicillin and ampicillin/sulbactam has resulted in the widespread use of third-generation cephalosporins for treating pediatric UTIs. This study aims to compare the efficacy of piperacillin-tazobactam (TZP) and cefotaxime (CTX) as first-line treatments in hospitalized children with UTIs. MATERIALS AND METHODS: The study, conducted at Jeju National University Hospital, retrospectively analyzed medical records of children hospitalized for febrile UTIs between 2014 and 2017. UTI diagnosis included unexplained fever, abnormal urinalysis, and the presence of significant uropathogens. Treatment responses, recurrence, and antimicrobial susceptibility were assessed. RESULTS: Out of 323 patients, 220 met the inclusion criteria. Demographics and clinical characteristics were similar between TZP and CTX groups. For children aged ≥3 months, no significant differences were found in treatment responses and recurrence. Extended-spectrum beta-lactamase (ESBL)-positive strains were associated with recurrence in those <3 months. CONCLUSION: In Korea, escalating resistance to empirical antibiotics has led to the adoption of broad-spectrum empirical treatment. TZP emerged as a viable alternative to CTX for hospitalized children aged ≥3 months with UTIs. Consideration of ESBL-positive strains and individualized approaches for those <3 months are crucial.

Influence of ß-lactam pharmacodynamics on the systems microbiology of gram-positive and gram-negative polymicrobial communities.

Objectives: We sought to evaluate the pharmacodynamics of ß-lactam antibacterials against polymicrobial communities of clinically relevant gram-positive and gram-negative pathogens. Methods: Two Enterococcus faecalis isolates, two Staphylococcus aureus isolates, and three Escherichia coli isolates with varying ß-lactamase production were evaluated in static time-killing experiments. Each gram-positive isolate was exposed to a concentration array of ampicillin (E. faecalis) or cefazolin (S. aureus) alone and during co-culture with an E. coli isolate that was ß-lactamase-deficient, produced TEM-1, or produced KPC-3/TEM-1B. The results of the time-killing experiments were summarized using an integrated pharmacokinetic/pharmacodynamics analysis as well as mathematical modelling to fully characterize the antibacterial pharmacodynamics. Results: In the integrated analysis, the maximum killing of ampicillin (Emax) against both E. faecalis isolates was ≥ 4.11 during monoculture experiments or co-culture with ß-lactamase-deficient E. coli, whereas the Emax was reduced to ≤ 1.54 during co-culture with ß-lactamase-producing E. coli. In comparison to monoculture experiments, culturing S. aureus with KPC-producing E. coli resulted in reductions of the cefazolin Emax from 3.25 and 3.71 down to 2.02 and 2.98, respectively. Two mathematical models were created to describe the interactions between E. coli and either E. faecalis or S. aureus. When in co-culture with E. coli, S. aureus experienced a reduction in its cefazolin Kmax by 24.8% (23.1%RSE). Similarly, ß-lactamase-producing E. coli preferentially protected the ampicillin-resistant E. faecalis subpopulation, reducing Kmax,r by 90.1% (14%RSE). Discussion: ß-lactamase-producing E. coli were capable of protecting S. aureus and E. faecalis from exposure to ß-lactam antibacterials.

Challenging dogmas: Intravenous versus oral beta-lactam antibiotic provocation tests.

Background: Drug provocation tests (DPT) are considered the gold standard procedure to ascertain the diagnosis of beta-lactam (BL) allergy. Regarding route of administration, current recommendations prioritize oral challenges, considering them safer, and reserving the intravenous route for drugs for which this is the only formulation. Objective: To compare in terms of tolerance and safety two protocols of BL DPT, using an oral protocol (OR-DPT) and an intravenous protocol (IV-DPT). Methods: A descriptive, retrospective study was performed, including adult patients who underwent IV-DPT or OR-DPT for suspected immediate or delayed hypersensitivity to BL antibiotics, over a period of 4 years (between January 2018 and December 2021). Demographical data, index hypersensivity reactions' characteristics and tolerance to DPT were reviewed. Results: A total of 1036 patients underwent DPT, mean age of 56.8 (standard deviation, SD, 17.8) years, 655 were women (63.2%). Immediate drug hypersensitivity reactions (DHR) had occurred in 564 of patients (54.4%). OR-DPT were performed in 439 (42.4%) and IV-DPT in 597 (57.6%). The frequency of reactions during DPT, regardless of the route used, was low (3.6%): only 16 (3.6%) in OR-DPT and 21 (3.5%) in IV-DPT. From IV-DPT, 16 out 21 DHR during DPT were immediate compared with 4 out of 16 in OR-DPT. Adjusted relative risk of developing a hypersensitivity reaction during IV-DPT versus OR-DPT was 1.13 (95% confidence interval (CI)0.57-2.22). Conclusion: The results suggest that OR-DPT and IV-DPT are both safe procedures when adequately performed. However, IV-DPT protocols showed a higher rate of immediate DHR during DPT probably due to the selection of basal high-risk patients to undergo IV-DPT. In conclusion, IV-DPT may be considered as an option for challenges in drug-allergy studies, entailing a precise administration.