The post-antibiotic era is here Kwon, Jennie H.; Powderly, William G.
Science (American Association for the Advancement of Science),
07/2021, Letnik:
373, Številka:
6554
Journal Article
Recenzirano
Imagine a world where routine surgery or chemotherapy is considered too dangerous because there are no drugs to prevent or treat bacterial infections. Unless researchers develop new antibiotics and ...therapeutics, the decimation of modern medicine will soon become a reality. Scientists have long recognized that much stronger incentives for research and development are needed to avoid this scenario. Yet, the rise of “superbugs” has continued, making a pandemic of antibiotic resistance a major threat to global health.
Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has created a global pandemic infecting over 230 million people and costing millions of ...lives. Therapies to attenuate severe disease are desperately needed. Cenicriviroc (CVC), a C-C chemokine receptor type 5 (CCR5) and C-C chemokine receptor type 2 (CCR2) antagonist, an agent previously studied in advanced clinical trials for patients with HIV or nonalcoholic steatohepatitis (NASH), may have the potential to reduce respiratory and cardiovascular organ failures related to COVID-19. Inhibiting the CCR2 and CCR5 pathways could attenuate or prevent inflammation or fibrosis in both early and late stages of the disease and improve outcomes of COVID-19. Clinical trials using CVC either in addition to standard of care (SoC; e.g., dexamethasone) or in combination with other investigational agents in patients with COVID-19 are currently ongoing. These trials intend to leverage the anti-inflammatory actions of CVC for ameliorating the clinical course of COVID-19 and prevent complications. This article reviews the literature surrounding the CCR2 and CCR5 pathways, their proposed role in COVID-19, and the potential role of CVC to improve outcomes.
Abstract
The Infectious Diseases Society of America (IDSA) has grown and evolved considerably since its foundation in 1963 as an academic professional society. It currently has >11 000 members, both ...domestic and international, drawn from the breadth of infectious diseases practice, from basic research to public health. Governance of the Society has not evolved as rapidly, and, in the last few years, it was increasingly evident to many members that the IDSA leadership was less representative of the membership than it ought to be. As a result of a rigorous review of its governance structure, the Society has committed to a policy of inclusion, diversity, access, and equity. It has also reformed the methods by which future IDSA leaders are identified and given roles. These changes should increase the opportunities for all members of the Society to participate in its volunteer leadership.
Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality. These guidelines for its management have been built on the previous Infectious Diseases Society of ...America guidelines from 2000 and include new sections. There is a discussion of the management of cryptococcal meningoencephalitis in 3 risk groups: (1) human immunodeficiency virus (HIV)–infected individuals, (2) organ transplant recipients, and (3) non–HIV-infected and nontransplant hosts. There are specific recommendations for other unique risk populations, such as children, pregnant women, persons in resource-limited environments, and those with Cryptococcus gattii infection. Recommendations for management also include other sites of infection, including strategies for pulmonary cryptococcosis. Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and cryptococcomas. Three key management principles have been articulated: (1) induction therapy for meningoencephalitis using fungicidal regimens, such as a polyene and flucytosine, followed by suppressive regimens using fluconazole; (2) importance of early recognition and treatment of increased intracranial pressure and/or IRIS; and (3) the use of lipid formulations of amphotericin B regimens in patients with renal impairment. Cryptococcosis remains a challenging management issue, with little new drug development or recent definitive studies. However, if the diagnosis is made early, if clinicians adhere to the basic principles of these guidelines, and if the underlying disease is controlled, then cryptococcosis can be managed successfully in the vast majority of patients.
Background. An infectious disease (ID) consultation (consult) is often obtained to treat patients with cryptococcosis due to the complex nature of the disease, but has never been demonstrated to ...impact outcomes. Methods. We assembled a retrospective cohort of 147 consecutive cases of cryptococcosis in patients without human immunodeficiency virus. Patients who were diagnosed <24 hours prior to death were excluded. Survival analysis was performed with Cox regression with survival censored past 90 days. Results. The patients with an ID consult had a higher fungal burden but a lower 90-day mortality compared with patients without ID involvement (27% vs 45%; P < .001), with an adjusted hazard ratio of not receiving an ID consult of 4.2 (95% confidence interval, 2.2-7.6). The ID consult group was more likely to receive an indicated lumber puncture (86% vs 32%; P < .001), and more likely to be treated with amphotericin B (AmB) (87% vs 24%; P < .001) and flucytosine (5-FC) (57% vs 16%; P < .001) when indicated. The duration of therapy with AmB (14 vs 11 days; P = .05) and 5-FC (7.5 days vs 1 day; P < .001) was longer in the ID consult group. Conclusions. Patients who received an ID consult were significantly less likely to die in the 90 days following diagnosis. Patients seen by ID physicians were more likely to be managed according to evidence-based practice established by randomized controlled trials and published in Infectious Diseases Society of America guidelines. These data suggest that an ID consult should be an integral part of clinical care of patients with cryptococcosis.
Cryptococcal epidemiology is changing in the modern antiretroviral era, and immune status informs outcomes. We describe the differences in clinical presentation and mortality of cryptococcosis by ...immune status in the antiretroviral therapy era.
We conducted a single-center retrospective cohort study of patients diagnosed with cryptococcosis from 2002 through 2017. Data included demographics, clinical features, diagnostics, and mortality.
We identified 304 patients with Cryptococcus neoformans infections: 105 (35%) were people living with human immunodeficiency virus (HIV), 41 (13%) had a history of transplantation, and 158 (52%) were non-HIV nontransplant (NHNT). Age analysis showed that people living with HIV were younger (40 years) than transplant (53 years) and NHNT (61 years) (P < .001). Fevers and headache were more common in people living with HIV (70% and 57%) than in transplant (49% and 29%) and NHNT (49% and 38%) (P = .003 and P = .001), respectively. Meningitis was more common in people living with HIV (68%) than in transplant recipients (32%) or NHNT (39%, P < .001). Disseminated cryptococcosis was more common in people living with HIV (97%) as compared with transplant (66%) or NHNT (73%) (P < .001). Time to diagnosis from hospitalization was longer for transplant (median 2 days, interquartile range IQR ± 9 days) and NHNT patients (median 2 days, IQR ± 7 days) as compared with people living with HIV (median 1 day, IQR ± 2 days) (P = .003). NHNT patients had a higher risk of 90-day mortality (hazard ratio 3.3; 95% confidence interval, 1.9-5.8) as compared with people living with HIV.
The majority of cryptococcosis occurs in NHNT patients. NHNT patients had more localized pulmonary cryptococcosis and significantly higher 90-day mortality. Cryptococcosis in NHNT patients appears to be a distinct entity that needs further study and requires a higher level of clinical suspicion than it currently receives.
Candida bloodstream infection is associated with high mortality. Infectious disease consultation improves outcomes in several infections, including Staphylococcus aureus and cryptococcosis, as well ...as multidrug-resistant organisms. We aimed to examine the association between infectious disease consultation and differences in management with mortality in candida bloodstream infections.
In this retrospective, single-centre cohort study, we reviewed the medical charts of all patients admitted to Barnes-Jewish Hospital (St Louis, MO, USA), a tertiary referral centre, aged 18 years or older with candida bloodstream infection from 2002 to 2015. We collected data for demographics, comorbidities, predisposing factors, all-cause mortality, antifungal use, central-line removal, and ophthalmological and echocardiographic evaluation to assess 90-day all-cause mortality between individuals with and without an infectious disease consultation. For the survival analysis we used Cox proportional hazards model with inverse weighting by propensity score to assess the effects of infectious disease consultation on mortality and differences in management.
Between Jan 1, 2002, and Dec 31, 2015, of 1794 patients assessed for eligibility, we analysed 1691 patients with candida bloodstream infection; 776 (45·9%) who had an infectious disease consultation and 915 (54·1%) who did not have an infectious disease consultation. All 1691 patients were included in the analysis. None were missing data. Most underlying comorbidities were evenly distributed between groups. 90-day mortality was lower in the infectious disease consultation group than in patients who did not receive an infectious disease consultation (29% 222/776 vs 51% 468/915; p<0·0001). In the model with inverse weighting by the propensity score, infectious disease consultation was associated with a hazard ratio of 0·81 (95% CI 0·73–0·91; p<0·0001) for mortality. In the consultation group, median duration of antifungal therapy was longer (18 IQR 14–35 vs 14 6–20 days; p<0·0001) and central-line removal (587 76% of 776 vs 538 59% of 915; p<0·0001), echocardiography use (442 57% of 776 vs 305 33% of 915; p<0·0001), and ophthalmological examination (412 53% of 776 vs 160 17% of 915; p<0·0001) were more frequently done. Fewer patients in the infectious disease consultation group were not treated (13 2% of 776 vs 128 14% of 915; p<0·0001).
Patients with candida bloodstream infection receiving an infectious disease consultation have lower mortality. This finding might be attributable to these individuals receiving a higher number of non-pharmacological, evidence-based interventions and lower amounts of non-treatment. These data suggest that an infectious disease consultation should be an integral part of clinical care of patients with candida bloodstream infection.
Astellas Global Development Pharma, Washington University Institute of Clinical and Translational Sciences, and the Agency for Healthcare Research and Quality.
Integrase strand transfer inhibitors (INSTIs) are associated with weight gain in people with HIV (PWH). Less is known about the risk of other metabolic outcomes such as diabetes mellitus and ...hyperglycemia.
IBM® MarketScan® databases for commercially and Medicaid-insured adults were used to identify PWH newly initiating antiretroviral therapy (ART). The primary outcome was a composite of new-onset diabetes mellitus/hyperglycemia in the 6 months following ART initiation and was identified using International Classification of Disease, Ninth revision, Clinical Modification (ICD-9-CM) and ICD-10-CM diagnosis and procedure codes and Current Procedural Terminology, 4th Edition (CPT-4) codes. To examine the relationship between INSTI use and the composite outcome, we estimated the risk using Cox proportional hazards models with calendar time-specific standardized mortality ratio weights.
Of 42 382 PWH who initiated ART between 1 July 2007 and 30 June 2018, 22 762 (54%) were treated with INSTI-based regimens. Mean age was 38 years, 74% were male, and 19% were Medicaid insured. PWH on INSTIs were 31% more likely to develop new-onset diabetes mellitus/hyperglycemia (hazard ratio HR, 1.31; 95% confidence interval CI, 1.15-1.48) compared with those who initiated non-INSTI-based regimens. When examined individually, the highest risk was associated with elvitegravir (HR, 1.54; 95% CI, 1.32-1.97; P < .001) and the lowest risk with raltegravir (HR, 1.19; 95% CI, 1.03-1.37; P = .02).
INSTI use was associated with increased risk of new-onset diabetes mellitus/hyperglycemia in the 6 months following ART initiation.
Itraconazole is the preferred azole for histoplasmosis in the current Infectious Diseases Society of America guidelines. Voriconazole is increasingly used as treatment for histoplasmosis; it has in ...vitro activity against Histoplasma capsulatum and has shown success in case reports and small case series, but may have a lower barrier to resistance. No comparative studies have been published.
We constructed a single-center, retrospective cohort of adult patients diagnosed with histoplasmosis from 2002 to 2017. Individual charts were reviewed to gather clinical information, including demographics, clinical features, immune status, treatments, and mortality. Patients were categorized based on the choice of azole and use as an initial treatment or as a step-down therapy from amphotericin B. Initial therapies with other azoles were excluded. Mortality was compared using a multivariable Cox proportional hazards with Heaviside function at 42 days.
We identified 261 cases of histoplasmosis from 2002 to 2017. After excluding patients not treated with itraconazole or voriconazole, 194 patients remained. Of these, 175 (90%) patients received itraconazole and 19 (10%) received voriconazole. There were no significant demographic differences between patient populations receiving either azole as their initial azole treatment. Death at 180 days occurred in 41 patients (23.4%) in the itraconazole group and 6 patients (31.6%) in the voriconazole group. Patients on voriconazole had a statistically significant increase in mortality during the first 42 days after initiation of treatment when compared to patients receiving itraconazole (hazard ratio, 4.30; 95% confidence interval, 1.3-13.9; P = .015), when controlled for other risk factors.
Voriconazole in histoplasmosis was associated with increased mortality in the first 42 days when compared to itraconazole.
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