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Background Use of serum procalcitonin (PCT), an inflammatory biomarker for bacterial infections, has shown promising results for early stopping antibiotic treatment among patients with respiratory infections and sepsis. There is need for additional data regarding effectiveness and safety of this concept among patients with cancer. Methods Individual data of patients with a documented diagnosis of cancer and proven or suspected respiratory infection and/or sepsis were extracted from previous trials where adult patients were randomized to receive antibiotic treatment based on a PCT protocol or usual care (control group). The primary efficacy and safety endpoints were antibiotic exposure and 28-day all-cause mortality. Results This individual-patient data meta-analysis included 777 patients with a diagnosis of cancer from 15 randomized-controlled trials. Regarding efficacy, there was a 18% reduction in antibiotic exposure in patients randomized to PCT-guided care compared to usual care ([days] 8.2 ± 6.6 vs. 9.8 ± 7.3; adjusted difference, − 1.77 [95% CI, − 2.74 to − 0.80]; p  < 0.001). Regarding safety, there were 72 deaths in 379 patients in the PCT-guided group (19.0%) compared to 91 deaths in 398 participants in the usual care group (22.9%) resulting in an adjusted OR of 0.78 (95% CI, 0.60 to 1.02). A subgroup analysis showed a significant reduction in mortality in patients younger than 70 years (adjusted OR, 0.58 [95% CI, 0.40 to 0.86]). Conclusion Result of this individual patient meta-analysis from 15 previous trials suggests that among patients with cancer and suspected or proven respiratory infection or sepsis, use of PCT to guide antibiotic treatment decisions results in reduced antibiotic exposure with a possible reduction in mortality, particularly among younger patients.

2017 ESCMID practice guidelines reported safety concerns and weak evidence of benefit supporting use of aerosolized antibiotics in mechanically ventilated patients. Our primary goal was to assess current patterns of aerosolized antibiotic prescription in mechanically ventilated patients. A sequential global survey was performed prior to the release of the ESCMID guidelines, from the 1st of February to the 30th of April 2017, using an electronic platform. Responses were analyzed comparing geographical regions. A total of 410 units responded, with 261 (177 from Europe) being eligible for the full survey. 26.8% of units reported not using aerosolized antibiotics. The two major indications amongst prescribing units were ventilator-associated pneumonia and ventilator-associated tracheobronchitis (74.3% and 49.4%, respectively). 63.6% of units indicated prescription solely in response to multi-drug resistant organisms. In comparison with a survey undertaken in 2014, there was a significant reduction in use of aerosolized antibiotics for prophylaxis (50.6% vs 7.7%, p < 0.05) and colonization (52.9% vs 25.3%, p < 0.05). The large majority of units (91.7%) reported only prescribing in patients with positive pulmonary cultures. Asia appeared to be an outlier, with 53.3% of units reporting empirical use. The most commonly used device was the jet nebulizer. The most commonly prescribed drugs were colistin methanesulfonate (57.6%), colistin base (41.9%) and amikacin (31.4%), although there was considerable heterogeneity across geographical areas. A significant gap exists between ESCMID clinical practice recommendations and the use of aerosolized antibiotics in clinical practice. Our findings indicate an urgent need for high-quality education to bring practice into line with evidence-based guidelines.

Differentiating acute bacterial infection from other causes of lower respiratory tract illness is challenging. In this trial, procalcitonin was investigated as a point-of-care test to aid in determining whether antibiotics were needed in the treatment of these illnesses.

Despite preventive strategies and increased awareness, a high incidence of respiratory viral infections still occur in patients with hematologic malignancies (HMs) and in recipients of hematopoietic cell transplant (HCT). Progression of these viral infections to lower respiratory tract may prove fatal, especially in HCT recipients. Increasing evidence on the successful use of ribavirin (alone or in combination with immunomodulators) for the treatment of respiratory syncytial virus infections in HM patients and HCT recipients is available from retrospective studies; however, prospective clinical trials are necessary to establish its efficacy with confidence. The impact on progression to pneumonitis and/or mortality of treating parainfluenza virus infections with available (ribavirin) or investigational (DAS181) antiviral agents still needs to be determined. Influenza infections have been successfully treated with neuraminidase inhibitors (oseltamivir or zanamivir); however, the efficacy of these agents for influenza pneumonia has not been established, and immunocompromised patients are highly susceptible to emergence of antiviral drug resistance, most probably due to prolonged viral shedding. Infection control measures and an appreciation of the complications following respiratory viral infections in immunocompromised patients remain crucial for reducing transmission. Future studies should focus on strategies to identify patients at high risk for increased morbidity and mortality from these infections and to determine the efficacy of novel or available antiviral drugs.

In February, 2017, the US Food and Drug Administration approved the blood infection marker procalcitonin for guiding antibiotic therapy in patients with acute respiratory infections. This meta-analysis of patient data from 26 randomised controlled trials was designed to assess safety of procalcitonin-guided treatment in patients with acute respiratory infections from different clinical settings. Based on a prespecified Cochrane protocol, we did a systematic literature search on the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, and pooled individual patient data from trials in which patients with respiratory infections were randomly assigned to receive antibiotics based on procalcitonin concentrations (procalcitonin-guided group) or control. The coprimary endpoints were 30-day mortality and setting-specific treatment failure. Secondary endpoints were antibiotic use, length of stay, and antibiotic side-effects. We identified 990 records from the literature search, of which 71 articles were assessed for eligibility after exclusion of 919 records. We collected data on 6708 patients from 26 eligible trials in 12 countries. Mortality at 30 days was significantly lower in procalcitonin-guided patients than in control patients (286 [9%] deaths in 3336 procalcitonin-guided patients vs 336 [10%] in 3372 controls; adjusted odds ratio [OR] 0·83 [95% CI 0·70 to 0·99], p=0·037). This mortality benefit was similar across subgroups by setting and type of infection (pinteractions>0·05), although mortality was very low in primary care and in patients with acute bronchitis. Procalcitonin guidance was also associated with a 2·4-day reduction in antibiotic exposure (5·7 vs 8·1 days [95% CI −2·71 to −2·15], p<0·0001) and a reduction in antibiotic-related side-effects (16% vs 22%, adjusted OR 0·68 [95% CI 0·57 to 0·82], p<0·0001). Use of procalcitonin to guide antibiotic treatment in patients with acute respiratory infections reduces antibiotic exposure and side-effects, and improves survival. Widespread implementation of procalcitonin protocols in patients with acute respiratory infections thus has the potential to improve antibiotic management with positive effects on clinical outcomes and on the current threat of increasing antibiotic multiresistance. National Institute for Health Research.

Viral infections are a leading cause of morbidity and mortality worldwide, and the importance of public health practices including handwashing and vaccinations in reducing their spread is well established. Furthermore, it is well known that proper nutrition can help support optimal immune function, reducing the impact of infections. Several vitamins and trace elements play an important role in supporting the cells of the immune system, thus increasing the resistance to infections. Other nutrients, such as omega-3 fatty acids, help sustain optimal function of the immune system. The main aim of this manuscript is to discuss of the potential role of micronutrients supplementation in supporting immunity, particularly against respiratory virus infections. Literature analysis showed that in vitro and observational studies, and clinical trials, highlight the important role of vitamins A, C, and D, omega-3 fatty acids, and zinc in modulating the immune response. Supplementation with vitamins, omega 3 fatty acids and zinc appears to be a safe and low-cost way to support optimal function of the immune system, with the potential to reduce the risk and consequences of infection, including viral respiratory infections. Supplementation should be in addition to a healthy diet and fall within recommended upper safety limits set by scientific expert bodies. Therefore, implementing an optimal nutrition, with micronutrients and omega-3 fatty acids supplementation, might be a cost-effective, underestimated strategy to help reduce the burden of infectious diseases worldwide, including coronavirus disease 2019 (COVID-19).

AbstractObjectiveTo determine the effect of population level implementation of a test-and-treat approach to correction of suboptimal vitamin D status (25-hydroxyvitamin D (25(OH)D) <75 nmol/L) on risk of all cause acute respiratory tract infection and covid 19.DesignPhase 3 open label randomised controlled trial.SettingUnited Kingdom.Participants6200 people aged ≥16 years who were not taking vitamin D supplements at baseline.InterventionsOffer of a postal finger prick test of blood 25(OH)D concentration with provision of a six month supply of lower dose vitamin D (800 IU/day, n=1550) or higher dose vitamin D (3200 IU/day, n=1550) to those with blood 25(OH)D concentration <75 nmol/L, compared with no offer of testing or supplementation (n=3100). Follow-up was for six months.Main outcome measuresThe primary outcome was the proportion of participants with at least one swab test or doctor confirmed acute respiratory tract infection of any cause. A secondary outcome was the proportion of participants with swab test confirmed covid-19. Logistic regression was used to calculate odds ratios and associated 95% confidence intervals. The primary analysis was conducted by intention to treat.ResultsOf 3100 participants offered a vitamin D test, 2958 (95.4%) accepted and 2674 (86.3%) had 25(OH)D concentrations <75 nmol/L and received vitamin D supplements (n=1328 lower dose, n=1346 higher dose). Compared with 136/2949 (4.6%) participants in the no offer group, at least one acute respiratory tract infection of any cause occurred in 87/1515 (5.7%) in the lower dose group (odds ratio 1.26, 95% confidence interval 0.96 to 1.66) and 76/1515 (5.0%) in the higher dose group (1.09, 0.82 to 1.46). Compared with 78/2949 (2.6%) participants in the no offer group, 55/1515 (3.6%) developed covid-19 in the lower dose group (1.39, 0.98 to 1.97) and 45/1515 (3.0%) in the higher dose group (1.13, 0.78 to 1.63).ConclusionsAmong people aged 16 years and older with a high baseline prevalence of suboptimal vitamin D status, implementation of a population level test-and-treat approach to vitamin D supplementation was not associated with a reduction in risk of all cause acute respiratory tract infection or covid-19.Trial registrationClinicalTrials.gov NCT04579640.

Colistin is an antibiotic of last resort, but has poor efficacy and resistance is a growing problem. Whilst it is well established that colistin disrupts the bacterial outer membrane (OM) by selectively targeting lipopolysaccharide (LPS), it was unclear how this led to bacterial killing. We discovered that MCR-1 mediated colistin resistance in Escherichia coli is due to modified LPS at the cytoplasmic rather than OM. In doing so, we also demonstrated that colistin exerts bactericidal activity by targeting LPS in the cytoplasmic membrane (CM). We then exploited this information to devise a new therapeutic approach. Using the LPS transport inhibitor murepavadin, we were able to cause LPS accumulation in the CM of Pseudomonas aeruginosa , which resulted in increased susceptibility to colistin in vitro and improved treatment efficacy in vivo. These findings reveal new insight into the mechanism by which colistin kills bacteria, providing the foundations for novel approaches to enhance therapeutic outcomes. Antibiotics are life-saving medicines, but many bacteria now have the ability to resist their effects. For some infections, all frontline antibiotics are now ineffective. To treat infections caused by these highly resistant bacteria, clinicians must use so-called ‘antibiotics of last resort’. These antibiotics include a drug called colistin, which is moderately effective, but often fails to eradicate the infection. One of the challenges to making colistin more effective is that its mechanism is poorly understood. Bacteria have two layers of protection against the outside world: an outer cell membrane and an inner cell membrane. To kill them, colistin must punch holes in both. First, it disrupts the outer membrane by interacting with molecules called lipopolysaccharides. But how it disrupts the inner membrane was unclear. Bacteria have evolved several different mechanisms that make them resistant to the effects of colistin. Sabnis et al. reasoned that understanding how these mechanisms protected bacteria could reveal how the antibiotic works to damage the inner cell membrane. Sabnis et al. examined the effects of colistin on Escherichia coli bacteria with and without resistance to the antibiotic. Exposing these bacteria to colistin revealed that the antibiotic damages both layers of the cell surface in the same way, targeting lipopolysaccharide in the inner membrane as well as the outer membrane. Next, Sabnis et al. used this new information to make colistin work better. They found that the effects of colistin were magnified when it was combined with the experimental antibiotic murepavadin, which caused lipopolysaccharide to build up at the inner membrane. This allowed colistin to punch more holes through the inner membrane, making colistin more effective at killing bacteria. To find out whether this combination of colistin and murepavadin could work as a clinical treatment, Sabnis et al. tested it on mice with Pseudomonas aeruginosa infections in their lungs. Colistin was much better at killing Pseudomonas aeruginosa and treating infections when combined with murepavadin than it was on its own. Pseudomonas aeruginosa bacteria can cause infections in the lungs of people with cystic fibrosis. At the moment, patients receive colistin in an inhaled form to treat these infections, but it is not always successful. The second drug used in this study, murepavadin, is about to enter clinical trials as an inhaled treatment for lung infections too. If the trial is successful, it may be possible to use both drugs in combination to treat lung infections in people with cystic fibrosis.

Key Points Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) are examples of emerging zoonotic coronavirus infections capable of person-to-person transmission that result in large-scale epidemics with substantial effects on patient health and socioeconomic factors. Unlike patients with mild illnesses that are caused by other human-pathogenic coronaviruses, patients with SARS or MERS coronavirus infections may develop severe acute respiratory disease with multi-organ failure. The case–fatality rates of SARS and MERS are approximately 10% and 35%, respectively. Both SARS and MERS pose major clinical management challenges because there is no specific antiviral treatment that has been proven to be effective in randomized clinical trials for either infection. Substantial efforts are underway to discover new therapeutic agents for coronavirus infections. Virus-based therapies include monoclonal antibodies and antiviral peptides that target the viral spike glycoprotein, viral enzyme inhibitors, viral nucleic acid synthesis inhibitors and inhibitors of other viral structural and accessory proteins. Host-based therapies include agents that potentiate the interferon response or affect either host signalling pathways involved in viral replication or host factors utilized by coronaviruses for viral replication. The major challenges in the clinical development of novel anti-coronavirus drugs include the limited number of suitable animal models for the evaluation of potential treatments for SARS and MERS, the current absence of new SARS cases, the limited number of MERS cases — which are also predominantly geographically confined to the Middle East — as well as the lack of industrial incentives to develop antivirals for mild infections caused by other, less pathogenic coronaviruses. The continuing threat of MERS-CoV to global health 3 years after its discovery presents a golden opportunity to tackle current obstacles in the development of new anti-coronavirus drugs. A well-organized, multidisciplinary, international collaborative network consisting of clinicians, virologists and drug developers, coupled to political commitment, should be formed to carry out clinical trials using anti-coronavirus drugs that have already been shown to be safe and effective in vitro and/or in animal models, particularly lopinavir–ritonavir, interferon beta-1b and monoclonal antibodies and antiviral peptides targeting the viral spike glycoprotein. Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which are caused by coronaviruses, have attracted substantial attention owing to their high mortality rates and potential to cause epidemics. Yuen and colleagues discuss progress with treatment options for these syndromes, including virus- and host-targeted drugs, and the challenges that need to be overcome in their further development. In humans, infections with the human coronavirus (HCoV) strains HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 usually result in mild, self-limiting upper respiratory tract infections, such as the common cold. By contrast, the CoVs responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which were discovered in Hong Kong, China, in 2003, and in Saudi Arabia in 2012, respectively, have received global attention over the past 12 years owing to their ability to cause community and health-care-associated outbreaks of severe infections in human populations. These two viruses pose major challenges to clinical management because there are no specific antiviral drugs available. In this Review, we summarize the epidemiology, virology, clinical features and current treatment strategies of SARS and MERS, and discuss the discovery and development of new virus-based and host-based therapeutic options for CoV infections.

A first step in primary disease prevention is identifying common, modifiable risk factors that contribute to a significant proportion of disease development. Infant respiratory viral infection and childhood asthma are the most common acute and chronic diseases of childhood, respectively. Common clinical features and links between these diseases have long been recognized, with early-life respiratory syncytial virus (RSV) and rhinovirus (RV) lower respiratory tract infections (LRTIs) being strongly associated with increased asthma risk. However, there has long been debate over the role of these respiratory viruses in asthma inception. In this article, we systematically review the evidence linking early-life RSV and RV LRTIs with asthma inception and whether they could therefore be targets for primary prevention efforts.