Polyethylene glycol hypersensitivity, patient outcomes in a 7-year retrospective study.

BACKGROUND: Immediate IgE-mediated hypersensitivity reactions to polyethylene glycol (PEG) are rare. Our understanding of PEG hypersensitivity is limited. OBJECTIVE: To evaluate the clinical characteristics and investigation outcomes of the largest cohort of patients with PEG allergy reported. METHODS: A total of 44 patients investigated for suspected PEG allergy across 4 United Kingdom tertiary allergy centers between October 2013 and December 2020 were studied. Clinical characteristics, index reaction, and approaches to and outcomes of allergy investigations were analyzed. RESULTS: PEG hypersensitivity was confirmed in 42 of 44 cases. Macrogol laxatives were the most common index drugs reported (23%), followed by depo-medroxyprogesterone (19%), oral penicillin V (10%), and depo-methylprednisolone (10%). In general, 61% experienced grade III anaphylaxis. Intradermal testing (IDT) increased the diagnostic sensitivity from 51% to 85%. Five patients experienced systemic reactions during IDT. Of the 5 patients, 2 were skin prick test positive to a high molecular weight PEG. Three patients with negative skin test results had positive drug provocation test results. Seven patients with PEG allergy reported tolerance to H1-antihistamines containing PEG. Administration of messenger RNA COVID-19 or Oxford/AstraZeneca COVID-19 vaccines was tolerated in all 16 patients to whom they were administered. CONCLUSION: PEG hypersensitivity is an uncommon cause of drug-induced anaphylaxis. Four index drugs accounted for two-thirds of the cases, and reactions to these drugs should prompt PEG hypersensitivity investigations. PEG IDT increases diagnostic yield. The role of skin prick test with higher molecular weight PEGs requires further attention. Further studies are required to understand PEG thresholds and PEG equivalent doses of various administration routes. COVID-19 vaccines were tolerated by all exposed.

Vitamin B12 Hypersensitivity: A Retrospective Multicenter Study.

BACKGROUND: Vitamin B12 (Vit B12) deficiency affects approximately 20% of those above the age of 60 years in the United Kingdom and United States. If untreated, it leads to detrimental health outcomes. OBJECTIVE: To investigate a cohort of patients with Vit B12 hypersensitivity (VB12H) referred to 3 UK allergy centers and design a pathway for the investigation of VB12H. METHODS: A total of 29 patients seen between 2014 and 2022 underwent skin prick testing (1 mg/mL) with cyanocobalamin (CC) and hydroxycobalamin (HC) and intradermal testing (0.1 and 0.01 mg/mL). Patients with negative skin tests underwent a Vit B12 drug provocation test (DPT) with either the index or the alternative drug. RESULTS: Of 29 patients, 18 (62%) presented with immediate VB12H. Eight experienced anaphylaxis (4 to HC and 4 to CC) and had positive skin tests to the index drug. One patient reacted to oral and 7 patients to injectable Vit B12. Seven patients sensitized to one form of Vit B12-tolerated DPT with an alternative Vit B12. One patient with immediate VB12H reacted to polyethylene glycol (PEG) in oral cobalamin. Of 29 patients, 8 presented with delayed hypersensitivity reaction; 4 patients tolerated the intramuscular index formulation, whereas 2 patients tolerated the per oral formulation. One patient presented with symptoms consistent with symmetrical drug-related intertriginous and flexural exanthema. Three patients were referred because of cobalt allergy. CONCLUSION: Confirmed VB12H is rare. We propose a comprehensive evaluation protocol that includes Vit B12 skin tests and considers PEG allergy in patients presenting with VB12H.

Dysregulated anti-oxidant signalling and compromised mitochondrial integrity negatively influence regulatory T cell function and viability in liver disease.

BACKGROUND: Dysregulated inflammatory responses and oxidative stress are key pathogenic drivers of chronic inflammatory diseases such as liver cirrhosis (LC). Regulatory T cells (Tregs) are essential to prevent excessive immune activation and maintain tissue homeostasis. While inflammatory cues are well known to modulate the function and stability of Tregs, the extent to which Tregs are influenced by oxidative stress has not been fully explored. METHODS: The phenotypic and functional properties of CD4+CD25+CD127lo/- Tregs isolated from patients with LC were compared to healthy controls (HC). Treg redox state was investigated by characterizing intracellular reactive oxygen species (ROS), NADPH oxidase-2 (Nox2) activity, mitochondrial function, morphology, and nuclear factor-erythroid 2-related factor (Nrf2) antioxidant signalling. The relevance of Nrf2 and its downstream target, Heme-oxygenase-1 (HO-1), in Treg function, stability, and survival, was further assessed using mouse models and CRISPR/Cas9-mediated HO-1 knock-out. FINDINGS: Circulating Tregs from LC patients displayed a reduced suppressive function, correlating with liver disease severity, associated with phenotypic abnormalities and increased apoptosis. Mechanistically, this was linked to a dysregulated Nrf2 signalling with resultant lower levels of HO-1, enhanced Nox2 activation, and impaired mitochondrial respiration and integrity. The functional deficit in LC Tregs could be partially recapitulated by culturing control Tregs in patient sera. INTERPRETATION: Our findings reveal that Tregs rely on functional redox homeostasis for their function, stability, and survival. Targeting Treg specific anti-oxidant pathways may have therapeutic potential to reverse the Treg impairment in conditions of oxidative damage such as advanced liver disease. FUNDING: This study was funded by the Wellcome Trust (211113/A/18/Z).

Sphingosine-1-phosphate induces airway smooth muscle hyperresponsiveness and proliferation.

BACKGROUND: The emerging role of sphingosine-1-phosphate (S1P) in regulating smooth muscle functions has led to the exploration of the possibility that this sphingolipid could represent a potential therapeutic target in asthma and other lung diseases. Several studies in animal surrogates have suggested a role for S1P-mediated signaling in the regulation of airway smooth muscle (ASM) contraction, airway hyperresponsiveness, and airway remodeling, but evidence from human studies is lacking. OBJECTIVE: We sought to compare the responsiveness of the airways to S1P in healthy and asthmatic individuals in vivo, in isolated human airways ex vivo, and in murine airways dissected from healthy and house dust mite (HDM)-sensitized animals. METHODS: Airway responsiveness was measured by spirometry during inhalation challenges and by wire myography in airways isolated from human and mouse lungs. Thymidine incorporation and calcium mobilization assays were used to study human ASM cell responses. RESULTS: S1P did not induce contraction of airways isolated from healthy and HDM-exposed mice, nor in human airways. Similarly, there was no airway constriction observed in healthy and asthmatic subjects in response to increasing concentrations of inhaled S1P. However, a 30-minute exposure to S1P induced a significant concentration-dependent enhancement of airway reactivity to methacholine and to histamine in murine and human airways, respectively. HDM-sensitized mice demonstrated a significant increase in methacholine responsiveness, which was not further enhanced by S1P treatment. S1P also concentration-dependently enhanced proliferation of human ASM cells, an effect mediated through S1P receptor type 2, as shown by selective antagonism and S1P receptor type 2 small-interfering RNA knockdown. CONCLUSIONS: Our data suggest that S1P released locally into the airways may be involved in the regulation of ASM hyperresponsiveness and hyperplasia, defining a novel target for future therapies.

Determining the minimal important differences in the RQLQ score with grass and tree allergy immunotherapy versus placebo in adults with moderate-to-severe allergy.

BACKGROUND: Pollen from grasses and trees can trigger allergic rhinitis (AR), where the symptoms and associated consequences can negatively affect quality of life (QoL). The Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) is frequently used in clinical trials of AR to assess QoL. To help interpret RQLQ data, the minimal important difference (MID) can be used to assess whether a mean difference in QoL between treatment groups is clinically meaningful. In seasonal allergy, an MID differs according to the allergen, pollen exposure, symptom severity, patient age and treatment; the same MID cannot be applied to all scenarios. METHODS: Using data from four Phase III clinical trials of SQ sublingual immunotherapy-tablets in adults with moderate-to-severe allergy, between-group MIDs were derived for the RQLQ in grass pollen allergy (during the peak [n = 501] and entire [n = 514] pollen seasons), and in tree pollen allergy (during the birch [n = 516] and tree [n = 518] pollen seasons), using anchor-based methodology, supported by distribution-based methods. RESULTS: For grass pollen allergy, anchor-based derived between-group MIDs were 0.22 for the entire pollen season (n = 343) and 0.10 for the peak pollen season (n = 335). For tree pollen allergy, anchor-based derived between-group MIDs were 0.26 for the tree pollen season (n = 306) and 0.16 for the birch pollen season (n = 305) (representative of peak season). Distribution-based derived MIDs were supportive of the anchor-based values. CONCLUSIONS: This analysis has derived between-group MIDs specific to the trial populations evaluated and to the conditions under which the data were obtained, and highlights the need for a range of MIDs to reflect the unique nature of seasonal allergic disease.

Piperacillin-Tazobactam Hypersensitivity: A Large, Multicenter Analysis.

BACKGROUND: Piperacillin/tazobactam is a broad-spectrum penicillin. Hypersensitivity reactions are less commonly reported than with other penicillins except in patients with cystic fibrosis. OBJECTIVE: Detailed clinical characterization of a patient cohort referred with suspected piperacillin-tazobactam hypersensitivity. METHODS: Retrospective analysis of the demographic characteristics, clinical presentation, investigation, and management of 87 patients presenting to 5 European allergy centers. Patients underwent skin prick and intradermal testing with piperacillin/tazobactam, major (penicilloyl-polylysine) and minor (sodium penilloate) determinants, amoxicillin, benzylpenicillin, flucloxacillin, co-amoxiclav, clavulanic acid, and meropenem with immediate and, where appropriate, delayed reading of tests. Skin test-negative patients underwent drug provocation to piperacillin/tazobactam and/or other penicillins. A multistep protocol was used, depending on risk assessment. RESULTS: Forty-eight of 87 (55%) patients were diagnosed with hypersensitivity to piperacillin/tazobactam with either positive skin or drug provocation test results, of whom 10 (21%) had a diagnosis of cystic fibrosis. Twenty-six (54%) patients presented with immediate and 22 (45%) with nonimmediate hypersensitivity. Patients with cystic fibrosis predominantly presented with nonimmediate hypersensitivity (70%). Reactions were severe in 52% of immediate reactors (Brown's anaphylaxis grade 3) and moderately severe (systemic involvement) in 75% of nonimmediate reactors. The number of patients with negative skin test results tolerating reintroduction was comparable in immediate (80%) and nonimmediate (88%) hypersensitivity. One-third of patients were cross-sensitized to other penicillins. The cross-sensitization pattern raised the possibility of tazobactam allergy in 3 patients. In 21 patients selectively sensitized to piperacillin/tazobactam (12 immediate, 9 nonimmediate), tolerance to other beta-lactams was demonstrated by drug provocation testing. CONCLUSIONS: Piperacillin-tazobactam caused immediate and nonimmediate hypersensitivity with similar frequency. Most patients were selectively sensitized and tolerated other penicillins. Some patients may be allergic to the beta-lactamase inhibitor only.

Synchronous Telemedicine in Allergy: Lessons Learned and Transformation of Care During the COVID-19 Pandemic.

BACKGROUND: The outbreak of the COVID-19 pandemic facilitated a rapid transition to non-face-to-face models of care across the allergy services. OBJECTIVE: To describe the outcomes of the use of synchronous telemedicine for outpatient consultations in a tertiary adult allergy center. METHODS: We retrospectively reviewed all non-face-to-face appointments during the second month of the pandemic in the United Kingdom. RESULTS: A total of 637 non-face-to-face appointments for unique patients were booked between April 1 and 30, 2020; 91% were new consultations. Most referrals (81.5%) were related to nondrug reactions. The overall "Did Not Attend" rate was 15.7%. A total of 439 patients were assessed for nondrug reactions; 87% were new appointments. Food-related reactions (50.4%), urticaria/angioedema (23.2%), and rhinitis (18.1%) were the most common reasons for new referrals. Two hundred twenty-one (57.7%) of these patients required further allergy testing, primarily for suspected food allergy. More than 42% of the new patients, mainly referred for urticaria/angioedema, were discharged after their remote assessment. Less than 10% of the follow-up patients required additional testing. Ninety-seven new patients were assessed for a suspected drug reaction, predominantly to beta-lactam antibiotics (57.7%). Sixty-nine patients (71%) required further investigations, but a notable 29% did not require further allergy input. The overall experience was very good/good for most patients (85%). CONCLUSION: Telemedicine can transform the current models of allergy care. Screening criteria for selecting suitable new patients are required. A telemedicine-based drug allergy service model can be more time- and cost-effective, and improve patient access to specialist care.

Lemon seed allergy: a case presentation.

BACKGROUND: We report a case of IgE-mediated hypersensitivity to lemon seed. We demonstrate for the first time a pattern of cross-sensitisation between seeds of citrus hybrid species from similar ancestral species origins. CASE REPORT: Described is a case of a 26-year-old female with recurrent anaphylaxis on exposure to lemon seed with sensitisation shown on prick to prick testing. Prick to prick testing was also performed to a variety of citrus fruit seeds and edible foods from additional notable families of the Sapindale order. CONCLUSION: In cases of unexplained or recurrent anaphylaxis in adult patients, citrus seed allergy should be considered.

Mouse γ-Synuclein Promoter-Mediated Gene Expression and Editing in Mammalian Retinal Ganglion Cells.

Optic neuropathies are a group of optic nerve (ON) diseases caused by various insults including glaucoma, inflammation, ischemia, trauma, and genetic deficits, which are characterized by retinal ganglion cell (RGC) death and ON degeneration. An increasing number of genes involved in RGC intrinsic signaling have been found to be promising neural repair targets that can potentially be modulated directly by gene therapy, if we can achieve RGC specific gene targeting. To address this challenge, we first used adeno-associated virus (AAV)-mediated gene transfer to perform a low-throughput in vivo screening in both male and female mouse eyes and identified the mouse γ-synuclein (mSncg) promoter, which specifically and potently sustained transgene expression in mouse RGCs and also works in human RGCs. We further demonstrated that gene therapy that combines AAV-mSncg promoter with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing can knock down pro-degenerative genes in RGCs and provide effective neuroprotection in optic neuropathies.SIGNIFICANCE STATEMENT Here, we present an RGC-specific promoter, mouse γ-synuclein (mSncg) promoter, and perform extensive characterization and proof-of-concept studies of mSncg promoter-mediated gene expression and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing in RGCs in vivo To our knowledge, this is the first report demonstrating in vivo neuroprotection of injured RGCs and optic nerve (ON) by AAV-mediated CRISPR/Cas9 inhibition of genes that are critical for neurodegeneration. It represents a powerful tool to achieve RGC-specific gene modulation, and also opens up a promising gene therapy strategy for optic neuropathies, the most common form of eye diseases that cause irreversible blindness.

Beta-lactam allergy in Chinese patients and factors predicting genuine allergy.

INTRODUCTION: Beta-lactams (BL) are the most frequently reported drug allergy, but the vast majority of patients are found not to be genuinely allergic after evaluation. Few studies have investigated the clinical predictors of genuine BL allergy, and the prevalence in hospitalized Chinese patients is unknown. METHODS: Patients admitted to a tertiary hospital in Hong Kong (HK) were analyzed to identify the prevalence and factors associated with the presence of BL allergy labels among hospitalized Chinese patients. A combined cohort of patients having completed allergy investigation for suspected BL allergies in the United Kingdom (UK) and HK were analyzed to identify predictors of genuine allergy. RESULTS: The prevalence of BL allergy labels in hospitalized HK Chinese was 5%, which was associated with female gender and concomitant non-BL antibiotic allergy labels. The rate of genuine BL allergy patients referred for suspected allergies in the UK and HK cohort was only 14%. History of anaphylaxis and interval of less than a year since the index reaction were independent clinical predictors of genuine BL allergy. The negative predictive value of penicillin skin testing was 90%, confirming the need for drug provocation testing after negative skin testing. There was a high rate of confirmed piperacillin-tazobactam allergy. DISCUSSION: The estimated true prevalence of genuine BL allergy in hospitalized HK Chinese is around 0.5%. This high rate of BL mislabeling highlights the need for comprehensive allergy evaluation and screening. History of anaphylaxis and duration since the index reaction are important predictors of genuine allergy. Piperacillin-tazobactam allergy may pose a unique challenge in this population with a high prevalence of suspected allergies, surging antibiotic resistance, and lack of testing available.

Flucloxacillin Hypersensitivity: Patient Outcomes in a Multicenter Retrospective Study.

BACKGROUND: Flucloxacillin is a narrow-spectrum, beta-lactamase-resistant penicillin. Type I (IgE-mediated) and type IV (T-cell-mediated) reactions are less frequently reported than with other penicillins. OBJECTIVE: To undertake a detailed clinical characterization of a cohort of patients referred with suspected flucloxacillin hypersensitivity. METHODS: We retrospectively analyzed demographic characteristics, presentation, investigation, and management of 108 patients presenting to 4 UK centers. Patients underwent skin prick and intradermal testing with flucloxacillin, major (benzylpenicilloyl poly-l-lysine) and minor determinants, amoxicillin, and benzylpenicillin with immediate and, where appropriate, delayed reading of the test. In the immediate group, a further 14 patients were tested to ampicillin and 16 to Augmentin (co-amoxiclav-combination of clavulanic acid and amoxicillin). Skin test-negative patients underwent oral drug provocation. A multistep protocol was used, depending on risk assessment. RESULTS: Forty of 108 (37%) patients were diagnosed with hypersensitivity to flucloxacillin, of whom 33 (82.5%) showed immediate and 7 (17.5%) nonimmediate hypersensitivity, respectively. In the immediate group, most reactions were severe: 19 of 33 (58%). Intradermal testing had a higher negative predictive value (86%) in the immediate group than in the nonimmediate group (67%). Only a minority of patients (6 of 17 [35%]) with IgE-mediated allergy were cross-sensitized on intradermal testing with other penicillins, compared with 3 of 4 (75%) in the delayed group. CONCLUSIONS: Immediate hypersensitivity reactions to flucloxacillin are more common than delayed. Cross-sensitization to other penicillins appears higher in delayed reactions than in immediate. The negative predictive value of intradermal testing is higher in the immediate group than in the nonimmediate group. Drug provocation testing remains the diagnostic criterion standard.

Identifying Low-Risk Beta-Lactam Allergy Patients in a UK Tertiary Centre.

BACKGROUND: There are marked geographical as well as temporal differences in patient sensitization profiles to ß-lactams (BL). OBJECTIVE: To determine the utility of skin test reagents and identify a cohort of patients where skin testing can be safely omitted in a cohort of patients referred to a UK tertiary referral center. METHODS: A retrospective study of the clinical characteristics of 1092 patients referred for BL allergy testing was analyzed using multivariate regression analysis. The effectiveness of skin test reagents was also evaluated. RESULTS: Multivariate logistic regression identified that a history of anaphylaxis (odds ratio [OR] 10.98, P = .001) and the patients' recall of the index drug (apart from ampicillin and meropenem, OR 3.51-12.43, P < .05) were independent predictors of type I BL allergic status and a time of less than 1 year elapsed since index reaction significantly increasing the odds of a patient with a history of anaphylaxis, having a type I BL allergy (OR 38.66, P = .003). An absence of anaphylactic severity, unknown name of the index drug and a reaction occurring more than 1 year before testing, has a negative predictive value (NPV) of 98.4%, which was similar to the NPV of skin testing of 98.9% for type I BL allergy. The NPV of skin testing with benzylpenicillin + amoxicillin ± index BL was similar with (98.9%) or without (98.1%) the use of benzylpenicillin polylysine and minor determinant for type I BL allergy. CONCLUSION: We identified a "low risk" cohort of patients where the history is of similar reliability to skin testing in predicting nonallergic status for BL allergy.

Memantine can relieve the neuronal impairment caused by neurotropic virus infection.

Neurotropic viruses, such as the rabies virus (RABV) and Japanese encephalitis virus (JEV), induce neuronal dysfunction and complication, causing neuronal damage. Currently, there are still no effective clinical treatments for neuronal injury caused by neurotropic viruses. Memantine, a drug capable of passing through the blood-brain barrier, noncompetitively and reversibly binds to n-methyl- d-aspartic acid (NMDA) receptors. Memantine is used to treat Alzheimer's disease by blocking the activation of extra axonal ion channels, thus preventing neuronal degeneration by inhibiting the abnormal cytosolic Ca 2+ increase. To explore whether memantine can alleviate neurological disturbances caused by RABV and JEV, the following experiments were carried out: (1) for primary neurons cultured in vitro infected with RABV, the addition of memantine showed neuroprotection. (2) In the RABV challenge experiments, memantine had limited therapeutic effect, mildly extending the survival time of mice. In contrast, memantine significantly prolonged the survival time of mice infected with JEV, by reducing the intravascular cuff and inflammatory cell infiltration in mice. Furthermore, memantine decreases the amount of JEV virus in mice brain.

The development of AZD7624 for prevention of exacerbations in COPD: a randomized controlled trial.

Background: p38 mitogen-activated protein kinase (MAPK) plays a central role in the regulation and activation of pro-inflammatory mediators. COPD patients have increased levels of activated p38 MAPK, which correlate with increased lung function impairment, alveolar wall inflammation, and COPD exacerbations. Objectives: These studies aimed to assess the effect of p38 inhibition with AZD7624 in healthy volunteers and patients with COPD. The principal hypothesis was that decreasing lung inflammation via inhibition of p38α would reduce exacerbations and improve quality of life for COPD patients at high risk for acute exacerbations. Methods: The p38 isoform most relevant to lung inflammation was assessed using an in situ proximity ligation assay in severe COPD patients and donor controls. Volunteers aged 18-55 years were randomized into the lipopolysaccharide (LPS) challenge study, which investigated the effect of a single dose of AZD7624 vs placebo on inflammatory biomarkers. The Proof of Principle study randomized patients aged 40-85 years with a diagnosis of COPD for >1 year to AZD7624 or placebo to assess the effect of p38 inhibition in decreasing the rate of exacerbations. Results: The p38 isoform most relevant to lung inflammation was p38α, and AZD7624 specifically inhibited p38α and p38ß isoforms in human alveolar macrophages. Thirty volunteers were randomized in the LPS challenge study. AZD7624 reduced the increase from baseline in sputum neutrophils and TNF-α by 56.6% and 85.4%, respectively (p<0.001). In the 213 patients randomized into the Proof of Principle study, there was no statistically significant difference between AZD7624 and placebo when comparing the number of days to the first moderate or severe exacerbation or early dropout. Conclusion: Although p38α is upregulated in the lungs of COPD patients, AZD7624, an isoform-specific inhaled p38 MAPK inhibitor, failed to show any benefit in patients with COPD.

Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects.

BACKGROUND: Inhaled LPS causes neutrophilic airway inflammation in healthy subjects. We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response. METHODS: Three randomised, double-blind, placebo-controlled, single dose crossover studies were performed. Active treatments were the oral p38 MAPK inhibitor PH-797804 30 mg (study 1), PH-797804 30 mg and the inhaled p38 MAPK inhibitor PF-03715455 20 mg (study 2) and inhaled fluticasone propionate 500 µg (study 3). The primary endpoint was sputum neutrophil percentage. RESULTS: Sputum neutrophil percentage post-LPS challenge was significantly inhibited (15.1 and 15.3% reduction) by PH-797804 compared to placebo in studies 1 and 2 (p = 0.0096 and 0.0001, respectively), and by PF-03715455 (8.0% reduction, p = 0.031); fluticasone propionate had no effect. PH-797804 significantly inhibited the increase in inflammatory mediators (IL-6, MCP-1, MIP1ß and CC16) in sputum supernatant, while PF-03715455 had no effect. PH-797804 and PF-03715455 both inhibited IL-6, MCP-1, MIP1ß, CC16 and CRP levels in plasma, with PH-797804 having greater effects. Fluticasone propionate had no effect on sputum supernatant or plasma biomarkers. CONCLUSIONS: PH-797804 had the greatest impact on neutrophilic airway inflammation. Oral administration of p38 MAPK inhibitors may optimise pulmonary anti-inflammatory effects.

Phase 1 study assessing the steady-state concentration of ceftazidime and avibactam in plasma and epithelial lining fluid following two dosing regimens.

OBJECTIVES: The aim of this Phase 1, open-label study (NCT01395420) was to measure and compare concentrations of ceftazidime and avibactam in bronchial epithelial lining fluid (ELF) and plasma, following administration of two different dosing regimens in healthy subjects. PATIENTS AND METHODS: Healthy volunteers received 2000 mg of ceftazidime + 500 mg of avibactam (n = 22) or 3000 mg of ceftazidime + 1000 mg of avibactam (n = 21), administered intravenously every 8 h for 3 days (total of nine doses). Bronchoscopy with bronchoalveolar lavage was performed once per subject, 2, 4, 6 or 8 h after the last infusion. Pharmacokinetic parameters were estimated from individual plasma concentrations and the composite ELF concentration-time profile. Safety was assessed. RESULTS: Forty-three subjects received treatment (2000 mg of ceftazidime + 500 mg of avibactam, n = 22; 3000 mg of ceftazidime + 1000 mg of avibactam, n = 21). Plasma and ELF concentrations increased dose-proportionally for both drugs, with 1.5- and 2-fold increases in AUCτ, for respective components. Ceftazidime Cmax and AUCτ in ELF were ∼ 23%-26% and 31%-32% of plasma exposure. Avibactam Cmax and AUCτ in ELF were ∼ 28%-35% and 32%-35% of plasma exposure. ELF and plasma elimination were similar for both drugs. No serious adverse events were observed. CONCLUSIONS: Both ceftazidime and avibactam penetrated dose-proportionally into ELF, with ELF exposure to both drugs ∼ 30% of plasma exposure.