Lower respiratory tract infections caused by Pseudomonas aeruginosa are a global concern. Patients with chronic lung diseases such as cystic fibrosis and non-cystic fibrosis bronchiectasis often do not receive adequate antibiotic delivery through conventional routes. P. aeruginosa employs several mechanisms, including biofilm formation and efflux pumps to limit the accumulation of bactericidal drug concentrations. Direct drug delivery to the lung epithelial lining fluid can increase antibiotic concentration and reduce treatment failure rates. This review discusses current research and developments in inhaled antibiotic formulations for treating P. aeruginosa infections. Recent studies on particle engineering for the dry powder inhalers of antibiotics emphasized three fundamental principles of development: micro, nano, and nano-in-microparticles. Carrier-free microparticles showed potential for high-dose delivery but suffered from poor aerosolization, which could be improved through a drug–drug combination. Amino acids in a co-spray-dried system improved powders’ aerodynamics and reduced moisture sensitivity while incorporating the chitosan/poly(lactic-co-glycolic acid) (PLGA)-modified release of the drug. Nano-in-microsystems, embedding lipid carriers, showed improved antibiofilm activity and controlled release. We also highlight emerging biologics, including antibacterial proteins/peptides, vaccines, bacteriophages, and probiotics. Research on antibiotics and biologics for inhalation suggests excellent safety profiles and encouraging efficacy for some formulations, including antimicrobial peptides and bacteriophage formulations. Further research on novel molecules and synergistic biologic combinations, supported by comprehensive animal lung safety investigations, will be required in future developments.

BACKGROUND:Pacific region-specific data on the clinical course of COVID-19 are limited. We aimed to describe clinical features and outcomes from Aotearoa New Zealand patients, focusing on Māori and Pacific peoples. METHODS:We conducted a retrospective cohort study among adults (≥16 years) hospitalised due to COVID-19 at 11 hospitals from January to May 2022. We included all Māori and Pacific patients and every second non-Māori, non-Pacific (NMNP) patient using data from chart review and national datasets. RESULTS:Of 2319 patients, 582 (25%) were Māori, 914 (39%) Pacific peoples and 862 NMNP (median age 52, 57 and 63 years respectively). Vaccination coverage (≥2 doses) was 73.4% (n = 437) for Māori, 76.7% (n = 701) for Pacific peoples (n = 701) and 84.8% (n = 731) for NMNP. Among 832 (35.9%) with complications, Māori had a greater risk than NMNP of acute kidney injury (risk ratio (RR) 1.87, P < 0.001), cardiac arrhythmia (RR = 1.60, P = 0.023), shock (RR = 2.64, P = 0.005), myocardial infarction (RR 2.21, P = 0.042), cardiac arrest (RR 2.68, P = 0.046) and acute respiratory distress syndrome (RR = 2.81, P = 0.008). Pacific patients experienced a greater risk than NMNP of acute kidney injury (RR = 2.18, P < 0.001) and pneumonia (RR = 1.32, P = 0.047) and a lower risk of thromboembolism (RR = 0.35, P = 0.004) and myocarditis/pericarditis (RR = 0.23, P = 0.003). During admission, 23 (3.3%) Māori, 36 (3.9%) Pacific and 28 (3.2%) NMNP patients died, with no difference in age-standardised mortality. CONCLUSIONS:The clinical course of patients hospitalised by COVID-19 varied between ethnic groups, likely reflecting differential access to social determinants of health. Healthcare services that respond to this variability are needed to achieve the highest attainable health for all.

INTRODUCTION:Tuberculosis (TB) is a global health problem that poses a challenge to global treatment programs. Rifampicin is a potent and highly effective drug for TB treatment; however, higher oral doses than the standard dose (10 mg/kg/day) rifampicin may offer better efficacy in TB treatment. AREAS COVERED:High oral dose rifampicin is not implemented in anti-TB regimens yet and requires about a 3-fold increase in dose for increased efficacy. We discuss inhaled delivery of rifampicin as an alternative or adjunct to oral high-dose rifampicin. Clinical results of safety, tolerability, and patient compliance with antibiotic dry powder inhalers are reviewed. EXPERT OPINION:Clinical trials suggest that an approximately 3-fold increase in the standard oral dose of rifampicin may be required for better clinical outcomes. On the other hand, animal studies suggest that inhaled rifampicin can deliver a high concentration of the drug to the lungs and achieve approximately double the plasma concentration than that from oral rifampicin. Clinical trials on inhaled antibiotics suggest that dry powder inhalation is a patient-friendly and well-tolerated approach in treating respiratory infections compared to conventional treatments. Rifampicin, a well-known anti-TB drug given orally, is a good candidate for clinical development as a dry powder inhaler.

Objectives: COVID-19 severity prediction scores need further validation due to evolving COVID-19 illness. We evaluated existing COVID-19 risk prediction scores in Aotearoa New Zealand, including for M & amacr;ori and Pacific peoples who have been inequitably affected by COVID-19. Methods: We conducted a multicenter retrospective cohort study in adults hospitalized with COVID-19 from January to May 2022, including all M & amacr;ori and Pacific patients, and every second non-M & amacr;ori, non-Pacific (NMNP) patient to achieve equal analytic power by ethnic grouping. We assessed the accuracy of existing severity scores (4C Mortality, CURB-65, PRIEST, and VACO) to predict death in the hospital or within 28 days. Results: Of 2319 patients, 582 (25.1%) identified as M & amacr;ori, 914 (39.4%) as Pacific, and 862 (37.2%) as NMNP. There were 146 (6.3%, 95% confidence interval 5.4-7.4%) deaths, with a predicted probability of death higher than observed mortality for VACO (10.4%), modified PRIEST (15.1%) and 4C mortality (15.5%) scores, but lower for CURB-65 (4.5%). C-statistics (95% CI) of severity scores were: 4C mortality: M & amacr;ori 0.82 (0.75, 0.88), Pacific 0.87 (0.83, 0.90), NMNP 0.90 (0.86, 0.93); CURB-65: M & amacr;ori 0.83 (0.69, 0.92), Pacific 0.87 (0.82, 0.91), NMNP 0.86 (0.80, 0.91); modified PRIEST: M & amacr;ori 0.85 (0.79, 0.90), Pacific 0.81 (0.76, 0.86), NMNP 0.83 (0.78, 0.87); and VACO: M & amacr;ori 0.79 (0.75, 0.83), Pacific 0.71 (0.58, 0.82), NMNP 0.78 (0.73, 0.83). Conclusions: Following re-calibration, existing risk prediction scores accurately predicted mortality.

Objectives: This multicenter cohort study describes Aotearoa New Zealand children hospitalized during the country's first wave of sustained SARS-CoV-2 transmission, Omicron variant. Methods: Children younger than 16 years, hospitalized for > 6 hours with COVID-19 across New Zealand from January to May 2022 were included. Admissions for all M & amacr;ori and Pacific and every second non-Maori non-Pacific children were selected to support equal explanatory power for ethnic grouping. Attribution of hospital admission, demography, clinical presentation, comorbidity, treatment, and outcome data were collected. Results: Of 444 hospitalizations of children positive for COVID-19, 292 (65.5%) from 290 children were considered admissions attributable to COVID-19. Of these admissions, 126 (43.4%) were aged under 1; 118 (40.7%), 99 (34.1%), and 87 (30.0%) were children of M & amacr;ori, Pacific, and non-Maori non-Pacific ethnicity, respectively. Underlying respiratory disease was the most common comorbidity, present in 22 children (7.6%); 16 children (5.5%) were immunosuppressed. Median length of stay was 1 day (interquartile range 0.0-2.0). Four children received antiviral, 69 (24%) antibacterial, and 24 (8%) supplemental oxygen. Although eight children required intensive care, there were no deaths. Conclusions: Children hospitalized during the first significant wave of SARS-CoV-2 infection in New Zealand presented with a multi-system viral illness and rarely with severe disease.

BackgroundNafamostat mesylate is a potent in vitro antiviral agent that inhibits the host transmembrane protease serine 2 enzyme used by severe acute respiratory syndrome coronavirus 2 for cell entry.MethodsThis open-label, pragmatic, randomized clinical trial in Australia, New Zealand, and Nepal included noncritically ill hospitalized patients with coronavirus disease 2019 (Covid-19). Participants were randomly assigned to usual care or usual care plus nafamostat. The primary end point was death (any cause) or receipt of new invasive or noninvasive ventilation or vasopressor support within 28 days after randomization. Analysis was with a Bayesian logistic model in which an adjusted odds ratio <1.0 indicates improved outcomes with nafamostat. Enrollment was closed due to falling numbers of eligible patients.ResultsWe screened 647 patients in 21 hospitals (15 in Australia, 4 in New Zealand, and 2 in Nepal) and enrolled 160 participants from May 2021 to August 2022. In the intention-to-treat population, the primary end point occurred in 8 (11%) of 73 patients with usual care and 4 (5%) of 82 with nafamostat. The median adjusted odds ratio for the primary end point for nafamostat was 0.40 (95% credible interval, 0.12 to 1.34) with a posterior probability of effectiveness (adjusted odds ratio <1.0) of 93%. For usual care compared with nafamostat, hyperkalemia occurred in 1 (1%) of 67 and 7 (9%) of 78 participants, respectively, and clinically relevant bleeding occurred in 1 (1%) of 73 and 7 (8%) of 82 participants.ConclusionsAmong hospitalized patients with Covid-19, there was a 93% posterior probability that nafamostat reduced the odds of death or organ support. Prespecified stopping criteria were not met, precluding definitive conclusions. Hyperkalemia and bleeding were more common with nafamostat. (Funded by ASCOT and others; ClinicalTrials.gov number, NCT04483960.)

We reviewed clinical records to determine whether the use of bronchial brushings improved diagnostic yield in a setting where bronchoscopy for suspected primary lung cancer is routinely guided by prior chest computed tomography but endobronchial ultrasound-guided sampling is unavailable. For 29% of cases who had brushings and at least one other test taken (bronchial biopsies or washings), the histological diagnosis was made solely on the basis of samples obtained by brushings.

Background: Impaired lung function is associated with cardiovascular mortality, but the origins of this association are poorly understood. We investigated associations between lung function and cardiovascular risk scores in a general population cohort of men and women aged 45 years. Methods: Participants are members of an unselected birth cohort followed to adulthood. Lung function determined at ages 32 and 45 by spirometry, body plethysmography, gas diffusion, and airway conductance were the main predictors. Future cardiovascular risk was estimated at age 45 using a multivariable cardiovascular risk algorithm - PREDICT. Risk scores were log-transformed and used as the dependent variable in linear regression analyses. We investigated cross-sectional associations with lung function at age 45 and longitudinal associations using changes in lung function between ages 32-45 as the predictors. Results: 863 of 1037 original cohort participants had data for analysis. Low lung volumes (FEV1, FVC, VA, TLC, and FRC) were associated with greater cardiovascular risk scores in the cross-sectional analyses at age 45 and the longitudinal analyses. These associations were stronger in women than in men, were independent of smoking history, and present in never smokers, even after adjusting for body mass index. Associations were not found for measures of airway function (FEV1/FVC ratio and sGaw) or gas transfer (TLco/VA). Conclusions: Low lung volumes at age 45 and accelerated pulmonary function decline are associated with a higher estimated cardiovascular risk scores in mid-adulthood. This association is stronger in women and is not explained by smoking or obesity.

BackgroundOptimal thromboprophylaxis for hospitalized patients with coronavirus disease 2019 (Covid-19) is uncertain.MethodsIn an open-label, adaptive platform trial, we randomly assigned hospitalized adults with Covid-19 to low-dose low-molecular-weight heparin thromboprophylaxis or intermediate-dose or low-dose plus aspirin. In response to external evidence, the aspirin intervention was discontinued and a therapeutic-dose arm added. The primary end point was death or the requirement for new organ support by day 28, analyzed with a Bayesian logistic model. Enrolment was closed as a result of operational constraints.ResultsBetween February 2021 and March 2022, 1574 patients were randomly assigned. Among 1526 participants included in the analysis (India, n=1273; Australia and New Zealand, n=138; and Nepal, n=115), the primary outcome occurred in 35 (5.9%) of 596 in low-dose, 25 (4.2%) of 601 in intermediate-dose, 20 (7.2%) of 279 in low-dose plus aspirin, and 7 (14%) of 50 in therapeutic-dose anticoagulation. Compared with low-dose thromboprophylaxis, the median adjusted odds ratio for the primary outcome for intermediate-dose was 0.74 (95% credible interval [CrI], 0.43 to 1.27; posterior probability of effectiveness [adjusted odds ratio<1; Pr], 86%), for low-dose plus aspirin 0.88 (95% CrI, 0.47 to 1.64; Pr, 65%), and for therapeutic-dose anticoagulation 2.22 (95% CrI, 0.77 to 6.20; Pr, 7%). Overall thrombotic and bleeding rates were 0.8% and 0.4%, respectively. There were 10 serious adverse reactions related to anticoagulation strategy, of which nine were grade 1 or 2 across study interventions and one grade 4 episode of retroperitoneal hematoma in a patient receiving intermediate-dose anticoagulation.ConclusionsIn hospitalized non–critically ill adults with Covid-19, compared with low-dose, there was an 86% posterior probability that intermediate-dose, 65% posterior probability that low-dose plus aspirin, and a 7% posterior probability that therapeutic-dose anticoagulation reduced the odds of death or requirement for organ support. No treatment strategy met prespecified stopping criteria before trial closure, precluding definitive conclusions. (Funded by Australian National Health and Medical Research Council or Medical Research Future Fund Investigator and Practitioner Grants and others; ClinicalTrials.gov number, NCT04483960.)

People living rurally frequently experience health disparities especially if living with a long-term condition (LTC) or multi-morbidity. Self-management support is a key component of LTC management and commonly included in rehabilitation programmes to enhance ability to self-manage health and encourage physical activity. Such programmes are however often condition focussed and despite evidence for their effectiveness, are not always feasible to deliver in rural settings. Generic programmes are arguably more optimal in the rural context and delivery can be face to face or remotely (via telehealth). The aim of this explorative integrative review was to collate and present international evidence for development, delivery, integration, and support of community-based, generic LTC group rehabilitation programmes delivered rurally in person, or remotely using telehealth. Electronic databases were systematically searched using MeSH terms and keywords. For inclusion, articles were screened for relevance to the aim, and practical information pertaining to the aim were extracted, charted, and organized deductively into themes of Development, Delivery, Integration, and Support. Within each theme, data were synthesized inductively into categories (Theory, Context, Interpersonal aspects, and Technology and Programme aspects). Fifty-five studies were included. Five studies contributed information about community based programmes delivered via the internet. Development was the only theme populated by information from all categories. The theme of Support was only populated with information from one category. Our review has drawn together a large body of diverse work. It has focused on finding practical information pertaining to the best ways to develop, deliver, integrate, and support a community-based generic rehabilitation programme for people living with long-term health conditions, delivered rurally and/or potentially via the internet. Practical suggestions were thematically organized into categories of theory, context, interpersonal aspects, and technology and programme aspects. While the findings of this review might appear simple and self-evident, they are perhaps difficult to enact in practice.

Inhaled drug delivery is a promising approach to achieving high lung drug concentrations to facilitate efficient treatment of tuberculosis (TB) and to reduce the overall duration of treatment. Rifampicin is a good candidate for delivery via the pulmonary route. There have been no clinical studies yet at relevant inhaled doses despite the numerous studies investigating its formulation and preclinical properties for pulmonary delivery. This review discusses the clinical implications of pulmonary drug delivery in TB treatment, the drug delivery systems reported for pulmonary delivery of rifampicin, animal models, and the animal studies on inhaled rifampicin formulations, and the research gaps hindering the transition from preclinical development to clinical investigation. A review of reports in the literature suggested there have been minimal attempts to test inhaled formulations of rifampicin in laboratory animals at relevant high doses and there is a lack of appropriate studies in animal models. Published studies have reported testing only low doses (≤ 20 mg/kg) of rifampicin, and none of the studies has investigated the safety of inhaled rifampicin after repeated administration. Preclinical evaluations of inhaled anti-TB drugs, such as rifampicin, should include high-dose formulations in preclinical models, determined based on allometric conversions, for relevant high-dose anti-TB therapy in humans. Graphical abstract

INTRODUCTION:High dose powder inhalation is evolving as an important approach to to treat lung infections. It is important to its identify applications, consider the factors affecting high dose powder delivery, and assess the effect of high dose drugs in patients. AREA COVERED:Both current and pipeline high dose inhalers and their applications have been summarized. Challenges and opportunities to high dose delivery have been highlighted after reviewing formulation techniques in the context of factors affecting aerosolization, devices, and patient factors. EXPERT OPINION:High dose inhaled delivery of antimicrobials is an innovative way to increase treatment efficacy of respiratory infections, tackle drug resistance, and the scarcity of new antimicrobials. The high dose inhaled technology also has potential for systemic action; however, innovations in formulation strategies and devices are required to realize its full potential. Advances in formulation strategies include the use of excipients or the engineering of particles to decrease the cohesive property of microparticles and their packing density. Similarly, selection of a synergistic drug instead of an excipient can be considered to increase aerosolization and stability. Device development focused on improving dispersion and loading capacity is also important, and modification of existing devices for high dose delivery can also be considered.

School of Pharmacy, University of Otago, Adams Building, 18 Frederick Street, P.O. Box 56, Dunedin 9054, New Zealand Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, 270 Great King Street, P.O. Box 913, Dunedin 9054, New Zealand Department of Medicine, Dunedin School of Medicine, University of Otago, P.O. Box 56, Dunedin 9054, New Zealand Centre for International Health, Department of Preventive and Social Medicine, Dunedin School of Medicine, University of Otago, PO Box 56, Dunedin 9054, New Zealand

AIM As New Zealand transitions towards endemic SARS-CoV-2, understanding patient factors predicting severity, as well as hospital resourcing requirements will be essential for future planning. METHODS We retrospectively enrolled patients hospitalised with COVID-19 from 26 February to 5 October 2020 as part of the COVID-19 HospitalisEd Patient SeverIty Observational Study NZ (COHESION). Data on demographics, clinical course and outcomes were collected and analysed as a descriptive case series. RESULTS Eighty-four patients were identified across eight district health boards. Forty-one (49%) were male. The median age was 58 years [IQR: 41.7-70.3 years]. By ethnicity, hospitalisations included 38 NZ European (45%), 19 Pasifika (23%), 13 Māori (15%), 12 Asian (14%) and 2 Other (2%). Pre-existing co-morbidities included hypertension (26/82, 32%), obesity (16/66, 24%) and diabetes (18/81, 22%). The median length of stay was four days [IQR: 2-15 days]. Twelve patients (12/83, 14%) were admitted to an intensive care unit or high dependency unit (ICU/HDU). Ten (10/83, 12%) patients died in hospital of whom seven (70%) were not admitted to ICU/HDU; the median age at death was 83 years. CONCLUSION Despite initially low case numbers in New Zealand during 2020, hospitalisation with COVID-19 was associated with a high mortality and hospital resource requirements.

Background and objective The long-term effects of cannabis on small airway function remain unclear. We investigated associations between cannabis use and small airway function in a general population sample. Methods Cannabis use was ascertained at multiple ages from age 18 to 45 years and quantified as joint-years among 895 participants in the Dunedin Multidisciplinary Health and Development Study. Small airway function at ages 38 and 45 years was measured using impulse oscillometry (IOS) before and after inhalation of salbutamol. Analyses used multiple linear regression adjusting for tobacco use, body mass index and height. Longitudinal analyses of cannabis use between 38 and 45 years also adjusted for IOS at age 38 years. Results Associations between lifetime cannabis joint-years and IOS differed between men and women: in women, cannabis use was associated with pre-bronchodilator resistance at 5 Hz (R-5) and 20 Hz (R-20), reactance at 5 Hz, area of reactance and resonant frequency, and marginally associated with the difference between R-5 and R-20. Cannabis use was only statistically significantly associated with pre-bronchodilator resonant frequency in men. Cannabis use between the ages of 38 and 45 years was associated with a similar pattern of changes in IOS measures. After salbutamol, cannabis use was only statistically significantly associated with R-5 and R-20 among women and none of the IOS measures among men. Conclusions Cannabis use is associated with small airway dysfunction at age 45 years, indicating an increase in peripheral airway resistance and reactance. These associations were greater and mostly only statistically significant among women. Associations were weaker and mostly nonsignificant after bronchodilator use, suggesting that cannabis-induced changes in small airways may be at least partially reversible.

Inhaled delivery of rifampicin has the potential to achieve high drug concentrations in the lung and the blood for efficient treatment of tuberculosis (TB). Due to its existence as polymorphs, in vivo evaluation of the respiratory tract safety of inhalable amorphous and crystalline rifampicin particles, at clinically relevant high-dose, is necessary. This study investigates the lung and liver safety and the tissue distribution of rifampicin after intra-tracheal administration of high (≥25 mg/kg) doses of amorphous and crystalline powder formulations to Sprague Dawley rats. Powder formulations were administered by intra-tracheal insufflation to rats. Lung and liver safety were evaluated by histopathology. Serum alanine transaminase (ALT) and aspartate aminotransferase (AST) assays were performed to study the hepatic effects. Rifampicin was quantified in the tissues using LC-MS/MS. Intra-tracheal administration of rifampicin decreased the drug burden on the liver compared to oral administration based on its lower serum ALT activity. Repeated-dose intra-tracheal rifampicin was well tolerated by rats, confirmed by the absence of drug or delivery induced complexities. The histopathological evaluation of rat lungs, after both single and repeated drug administration for seven days, suggested the absence of drug-induced toxicity. Following single intra-tracheal delivery of 50 mg/kg doses, comparable rifampicin concentrations to that from same oral dose were observed in lung, liver, heart and brain. Inhaled delivery of high-dose rifampicin was safe to rat lungs and liver suggesting its potential for localized as well as systemic drug delivery without toxicity concerns.

Abstract Background There is concern that long-acting bronchodilators (long-acting muscarinic antagonists [LAMAs]) and long-acting beta2-agonists [LABAs]) may further increase the already elevated risk of cardiovascular events in patients with chronic obstructive pulmonary disease (COPD). Guidelines recommend stepwise escalation from one to two long-acting bronchodilators in patients with uncontrolled symptoms, but information about the impact of this treatment intensification on acute coronary syndrome (ACS) risk is limited. Methods We undertook a nested case-control study using national administrative data to estimate the risk of ACS in users of dual LAMA and LABA therapy, and users of LABA monotherapy, relative to users of LAMA monotherapy. The underlying study cohort comprised patients aged >45 years who initiated long-acting bronchodilator therapy for COPD between 2006 and 2013 (n = 83,417). Cases were patients diagnosed with fatal or non-fatal ACS after cohort entry (n = 5,399). Up to 10 controls per case, matched by age, sex, date of cohort entry, and COPD severity, were randomly selected from the study cohort using risk set sampling. Odd ratios and 95% confidence intervals were estimated using conditional logistic regression. Results Relative to current use of LAMA monotherapy, the adjusted odds ratios for current use of dual LAMA and LABA therapy, and of LABA monotherapy, were 1.28 (95% CI 1.13–1.44) and 1.0 (95% CI 0.91–1.10), respectively. Conclusions Use of two long-acting bronchodilators rather than LAMA monotherapy, is associated with a higher risk of ACS, while the risks associated with LAMA and LABA monotherapy are comparable. Key messages The clinical benefit of adding a second long-acting bronchodilator to LAMA or LABA monotherapy is modest and, at the same time, is associated with an increased risk of ACS in a patient group already at high risk.