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Antimicrobial stewardship programs are important for reducing antimicrobial resistance because they can readjust antibiotic prescriptions to local guidelines, switch intravenous to oral administration, and reduce hospitalization times. Pharmacokinetics-pharmacodynamics (PK-PD) empirically based prescriptions and therapeutic drug monitoring (TDM) programs are essential for antimicrobial stewardship, but there is a need to fit protocols according to cost benefits. The cost benefits can be demonstrated by reducing toxicity and hospital stay, decreasing the amount of drug used per day, and preventing relapses in infection. Our aim was to review the data available on whether PK-PD empirically based prescriptions and TDM could improve the cost benefits of an antimicrobial stewardship program to decrease global hospital expenditures.A narrative review based on PubMed search with the relevant studies of vancomycin, aminoglycosides, beta-lactams, and voriconazole.TDM protocols demonstrated important cost benefit for patients treated with vancomycin, aminoglycosides, and voriconazole mainly due to reduce toxicities and decreasing the hospital length of stay. In addition, PK-PD strategies that used infusion modifications to meropenem, piperacillin-tazobactam, ceftazidime, and cefepime, such as extended or continuous infusion, demonstrated important cost benefits, mainly due to reducing daily drug needs and lengths of hospital stays.TDM protocols and PK-PD empirically based prescriptions improve the cost-benefits and decrease the global hospital expenditures.

Background During the COVID-19 pandemic, the burden of nosocomial infections caused by MDR pathogens has caused a shortage of polymyxins. Thus, we evaluated the in vitro synergism and antibiofilm activity of antimicrobial combinations and propose a test kit for synergism against carbapenem-resistant Acinetobacter baumannii (CRAB). Methods Fifty-six CRAB isolates were tested for synergy between meropenem, gentamicin and ampicillin/sulbactam. MICs were determined by broth microdilution. Synergism was tested using chequerboard analysis, followed by a time–kill curve. Additionally, minimum biofilm eradication concentration was determined and the antibiofilm activity of the combinations was evaluated by MTT assay and biomass reduction. A test kit was developed for routine laboratory testing to detect synergism. Results All CRAB isolates were resistant to gentamicin and ampicillin/sulbactam. Chequerboard synergism occurred against 75% of the isolates. Meropenem + ampicillin/sulbactam was the most frequent combination with synergism (69%), followed by ampicillin/sulbactam + gentamicin (64%) and meropenem + gentamicin (51%). All combinations presented only bacteriostatic activity and no bactericidal or antibiofilm effects. The routine laboratory test showed 100% accuracy compared with other in vitro assays. Conclusions Our study demonstrates the potential role of antibiotic combinations against planktonic bacteria. In vitro synergism is possible and can be an alternative treatment for patients with CRAB infection during a polymyxin shortage.

Background This study aimed to evaluate the utility of a commercial kit used to measure serum vancomycin concentrations to determine vancomycin concentrations in cerebrospinal fluid (CSF) samples and evaluate CSF penetration when administered as a continuous high-dose infusion in patients with nosocomial ventriculitis. Methods This study included patients with external ventricular drain infection who were admitted to the intensive care unit between January 2018 and September 2020. After validation, CSF samples from 33 patients were collected. All patients received 30 mg/kg of vancomycin as a loading dose followed by 60 mg/kg as a maintenance dose in continuous infusion; all CSF samples were collected at least 48 hours after the first dose. Results Thirty-three patients were enrolled in this study. The median serum creatinine level was 0.66 mg/dL (0.5-0.92; n = 30), and median creatinine clearance was 119.2 mL/min (64.6-138.4; n = 13). The median serum vancomycin 24-hour area under the curve (AUC24h) was 838 mg*h/L (515-1010). The median CSF vancomycin concentration was 5.20 mg/L (1.95-12.4). Median serum vancomycin concentration was 34.9 mg/L (21.47-42.1), and median CSF/serum ratio was 18.6% (8.4-41.5). Acute renal injury occurred in 21% (n = 7) of the patients by the end of the therapy. In addition, the vancomycin CSF/serum ratio was positively correlated with the median serum creatinine level (r = 0.670; P = 0.004). Conclusions Commercial vancomycin kits used to measure serum samples may be used to evaluate vancomycin concentrations in the CSF. Vancomycin penetration into CSF was 18.6%.

Resumo Objetivo Avaliar a sensibilidade e a especificidade da reação em cadeia de polimerase em tempo real quantitativa (quantitative real-time polymerase chain reaction, qPCR, em inglês) para a triagem do gene rDNA 16S, com a utilização do fluido sonicado de implantes ortopédicos. Métodos Um estudo retrospectivo foi realizado em 73 fluidos sonicados obtidos de pacientes com infecção associada aos implantes ortopédicos. As amostras foram submetidas a cultura convencional e a teste molecular utilizando ionização e dessorção a laser assistida por matriz com espectrometria de massa por tempo de voo (matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, MALDI-TOF MS, em inglês) e qPCR para o gene rDNA 16S. Os valores limiares do ciclo foram usados para definir um ponto de corte para a qPCR do gene rDNA 16S para culturas negativas e positivas. Resultados Não foram observadas diferenças estatísticas entre os grupos de cultura positiva e negativa com base no tempo desde a primeira cirurgia até a infecção (p = 0,958), na idade (p = 0,269), ou nas comorbidades em geral. No entanto, uma diferença estatística foi encontrada entre a duração média do uso de antibióticos antes da remoção do dispositivo (3,41 versus 0,94; p = 0,016). O DNA bacteriano foi identificado em todas as amostras dos fluidos sonicados. Os limiares do ciclo médio de culturas positivas e negativas foram de 25,6 e 27,3, respectivamente (p Conclusão A presença de agentes antimicrobianos por mais de 72 horas diminuiu a positividade da cultura, mas não influenciou os resultados da qPCR. Apesar disso, a amplificação do rDNA 16S pode sobrestimar o diagnóstico de infecção.

INTRODUCTION: Bacteremia is a major cause of morbidity and mortality in hospitalized patients. Predictors of mortality are critical for the management and survival of hospitalized patients. The objective of this study was to determine the factors related to blood culture positivity and the risk factors for mortality in patients whose blood cultures were collected. METHODS: A prospective 2-cohort study (derivation with 784 patients and validation with 380 patients) based on the Pitt bacteremia score for all patients undergoing blood culture collection. The score was obtained from multivariate analysis. The Kaplan–Meier survival curve of the cohort derivation and the cohort validation groups was calculated, and the difference was assessed using a log-rank test. Mortality-related factors were older age, extended hospitalization, > 10% of immature cells in the leukogram, lower mean blood pressure, elevated heart rate, elevated WBC count, and elevated respiratory rate. These continuous variables were dichotomized according to their significance level, and a cut-off limit was created. RESULTS: The area under the ROC curve (AUC) was 0.789. The score was validated in a group of 380 patients who were prospectively evaluated. CONCLUSION: Prolonged hospitalization, body temperature, and elevated heart rate were related to positive blood cultures. The Pitt score can be used to assess the risk of death; however it can be individualized according to the epidemiology of each hospital.

Disseminated histoplasmosis (DH) is endemic in Latin America and the Caribbean where diagnostic tools are restricted. We carried-out a 1-year prospective cohort study at a referral hospital in São Paulo, Brazil. Participants had > or =18 years old, were hospitalized due to any indication and had CD4+ < 200 cells/µl. A urine commercial monoclonal Histoplasma galactomannan enzyme-linked immunosorbent assay (IMMY, Norman, OK, USA) and ‘in house’ Histoplasma blood nested PCR were performed in all cases. Probable/proven DH cases were defined according to international guidelines. Conventional mycological methods were available in routine conditions to investigate suspected DH cases. Treatment of participants followed the institutional routine. One-hundred six participants were included. Median age (interquartile range [IQR]) was 39.5 years (30.0–47.3) and 80 individuals (75.5%) were males. Median (IQR) CD4 cell count was 26.5 (9.4–89.3) cells/mm3. DH was diagnosed in 8/106 patients (7.5%). Antigen assay and/or PCR were positive in 4.7% (5/106) of patients. The antigen assay and/or PCR identified 37.5% (3/8) of DH cases, which had not been diagnosed with conventional mycological methods, but had clinical manifestations compatible with HD. In conclusion, the use of Histoplasma urine antigen and Histoplasma blood PCR guided by CD4 status contributed to the diagnosis of DH in hospitalized individuals. These assays were complementary to conventional mycologic methods and are urgently needed in our setting. Lay Summary In this prospective cohort study carried-out in a referral center in São Paulo, Brazil, we found a high frequency of AIDS-related disseminated histoplasmosis (8/106, 7.5%). We used urine antigen test and blood PCR assay to improve the diagnosis of this opportunistic disease.

Several recent reviews have suggested a role of oxidative stress in the pathophysiology of COVID-19, but its interplay with disease severity has not been revealed yet. In the present study, we aimed to investigate the association between the severity of COVID‐19 and oxidative stress parameters. Clinical data of 77 patients with COVID‐19 admitted to the hospital were analyzed and divided into moderate (n = 44) and severe (n = 33) groups based on their clinical condition. Production of oxidant (hydrogen peroxide) and defense antioxidants (total antioxidant capacity, reduced and oxidized glutathione, glutathione s-transferase), and oxidative damage (malondialdehyde, carbonyl, and sulfhydryl) were assessed using the serum samples. The results revealed that severe patients who presented high serum leukocyte count and CRP level stayed for a longer period in the hospital. However, there was no correlation observed between the oxidative stress parameters and degree of COVID-19 severity in the present study. In conclusion, these results indicate that the disease severity may not be a detrimental factor contributing to the changes in the redox profile of hospitalized patients with COVID-19., Graphical abstract Image 1, Highlights • ROS production and oxidative stress are associated with Sars-Cov-2. • Patients with severe COVID-19 present an elevated inflammatory profile. • Patients with more severe clinical symptoms exhibit a similar redox profile compared to those with less severe symptoms. • COVID-19 severity may not be the detrimental factor contributing to the changes in the redox profile.

Objective:To evaluate the impact of outpatient parenteral antimicrobial therapy (OPAT) on a public hospital in a middle-income country.Design:A retrospective, observational study analyzing the economic data retrieved on the dehospitalization of patients on antibiotic therapy.Setting:Public university trauma hospital.Patients:Data were collected from June 2017 to May 2020. Antibiotic cost, hospital length of stay, and risk of multidrug-resistant (MDR) infection or colonization were reviewed, along with the break-even point at which a balance occurs between OPAT antimicrobial costs and all in-hospital costs. A cumulative risk curve was constructed showing the incidence of MDR during the review period.Results:In total, 225 patients were studied. The implementation of OPAT resulted in a reduction of $156,681 (49.6%), which is equivalent to an average of $696 per patient, as well as a shortened length of stay, from 33.5 to 15.7 days. OPAT reduces the risk of acquiring infection by MDR bacteria by having the final treatments administered outside of the hospital environment. The breakeven curves, comparing the duration of the OPAT to daily medication costs, allowed for the prediction of the time and dollar costs of antibiotic therapy.Conclusions:OPAT presented a significant cost savings, shortened length of stay, and reduced risk of contamination of patients by MDR.

Introduction. The use of automated systems in identification and susceptibility tests can improve antimicrobial therapy, and positively impact clinical outcomes with a decrease in antimicrobial resistance, hospitalization time, costs, and mortality. Aim. The aim of this study was to evaluate the clinical impact of an automated method for identification and susceptibility testing of microbial isolates. Methodology. This was a retrospective cross-sectional study aimed to analyse the results before and after the implementation period of a VITEK 2 system in a Brazilian university hospital. Based on data from medical records, patients with a positive culture of clinical samples from January to July 2017 (conventional method) and from August to December 2017 (automated method) were included in this study. Demographic data, hospitalization time, time interval between culture collection and results, culture results and site, susceptibility profile, minimum inhibitory concentration, and outcome data were evaluated. Chi-square and Fischer’s tests were used in the analysis. Results. Of the total samples, 836 were considered valid by the inclusion criteria, with 219 patients before VITEK 2 system implementation group and 545 in the post-implementation group. The comparison between the two periods showed a reduction of 25 % of the time to culture reports, a decrease of 33.5 to 17.0 days of hospitalization, and a reduction in mortality from 44.3–31.0 %, respectively. Conclusion. The VITEK 2 system provided early access to appropriate antimicrobial therapy for patients and effected a positive clinical impact with a reduction in mortality and hospitalization time.

The liver plays a major role in drug metabolism. Liver transplantation impacts the intrinsic metabolic capability and extrahepatic mechanisms of drug disposition and elimination. Different levels of inflammation and oxidative stress during transplantation, the process of liver regeneration, and the characteristics of the graft alter the amount of functional hepatocytes and activity of liver enzymes. Binding of drugs to plasma proteins is affected by the hyperbilirubinemia status and abnormal synthesis of albumin and alpha-1-acid glycoproteins. Postoperative intensive care complications such as biliary, circulatory, and cardiac also impact drug distribution. Renally eliminated antimicrobials commonly present reduced clearance due to hepatorenal syndrome and the use of nephrotoxic immunosuppressants. In addition, liver transplantation recipients are particularly susceptible to multidrug-resistant infections due to frequent manipulation, multiple hospitalizations, invasive devices, and frequent use of empiric broad-spectrum therapy. The selection of appropriate anti-infective therapy must consider the pathophysiological changes after transplantation that impact the pharmacokinetics and pharmacodynamics of antibiotics and antifungal drugs.

Purpose The aim of this study was to compare pharmacokinetic characteristics between intermittent infusion and continuous infusion of vancomycin for critically ill patients admitted to intensive care units. Methods Intermittent therapy was administered for 60 minutes and prescribed as a loading dose of 30 mg/kg and continued with 15 mg/kg q12 h. Continuous infusion was prescribed as a loading dose of 30 mg/kg followed by 30 mg/kg on constant infusion pump. Blood samples from vancomycin intermittent infusion group were collected 1 h before third dose, 1 h, 8 h and 24 h after third dose infusion. Blood samples from vancomycin continuous infusion group were collected 1 h after loading dose, 12 h, 24 h, 36 h, and 48 h after continuous infusion initiation. Results Median serum concentration of continuous infusion group at 24-hour was 23.59 μg/mL [14.52–28.97], while of intermittent infusion group at 23-hour was 12.30 μg/mL [7.27–18.12] and on 25-hour was 17.58 μg/mL [12.5–22.5]. Medians AUC24–48h were 357.2 mg.h/L and 530.2 mg.h/L for intermittent infusion and continuous infusion groups, respectively (p = 0.559). Conclusion Vancomycin CI reached steady state earlier, which guaranteed therapeutic levels from the first day and made it possible to manage therapeutic drug monitoring faster.

Made available in DSpace on 2022-04-28T19:48:30Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-02-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Ministério da Educação The incidence density trend of the carbapenem-resistant Gram-negative bacteria was analysed in device-associated infections and antimicrobial consumption in 99 critical care facilities in a low/middle-income country, between January 2019 and December 2020. Carbapenem-resistant Acinetobacter baumannii (CRAB) per 1000 patient-days increased in 2020 and this finding had a strong positive correlation with the incidence density of COVID-19 by the Spearman test. Polymyxin consumption also increased in 2020 but without significant correlation with CRAB or COVID-19 incidence density, presumably due to empirical and untargeted prescribing as a consequence of concern about CRAB infections. These findings are a warning to infection control programmes and antimicrobial stewardship. School of Medicine Pontifícia Universidade Católica do Paraná Laboratory of Emerging Infectious Diseases Pontifícia Universidade Católica do Paraná State Health Department of Paraná Universidade Estadual Paulista (UNESP) Hospital Marcelino Champagnat Universidade Estadual Paulista (UNESP)

There have historically been concerns of acute kidney injury (AKI) with the use of aminoglycosides. The present study aimed to compare the AKI incidence and mortality rate between critically ill patients treated with aminoglycoside or meropenem in the intensive care unit setting using a propensity score matching approach. This cross-sectional study was conducted at two university hospitals from January 2011 to October 2017. Clinical and laboratorial data were evaluated to exclude potential confounders and to calculate the Charlson index. AKI was classified according to the Acute Kidney Injury Network criteria. All tests were two-tailed, and a p value ≤ 0.05 was considered significant in the univariate and multivariate analyses. We included 494 patients, 95 and 399 of whom used meropenem and aminoglycoside, respectively. Patients in the subgroup that used meropenem were matched with controls (aminoglycoside). Among the 494 patients, 120 developed any grade of AKI (24.2%). After propensity score matching, there were no significant differences in AKI incidence and mortality rate between the aminoglycoside and meropenem groups (p = 0.324 and 0.464, respectively). Patients on the aminoglycoside regimen neither presented a higher AKI incidence nor mortality rate when compared with those on the meropenem regimen. Aminoglycosides may be a safe option for the treatment of critically ill patients on carbapenem sparing antimicrobial stewardship programs.

Background Antimicrobial stewardship programs have been used widely in hospital settings due to the rise of resistant bacteria, antibiotic toxicities, and costs. Nevertheless, few efforts are done to prevent the rising antimicrobial resistance in community settings. The aim of our study was to evaluate the antimicrobial resistance from Enterobacterales community- and hospital-acquired infections in Southern Brazil. Methods A total of 272 Enterobacterales isolates (i.e., Escherichia coli, Klebsiella spp., Citrobacter spp., Enterobacter spp., Serratia spp., Proteus spp., and Providencia) were collected from 2018 and 2019. Broth microdilution method was used to determine minimum inhibitory concentrations for ceftriaxone, cefepime, levofloxacin, amikacin and ertapenem. Molecular evaluation of beta-lactamases (ESBLs, AmpC, and KPC) was also performed. Results Ninety-three, and a hundred and seventy-nine isolates were from community- and hospital-acquired infections, respectively. Similar MIC distribution was found between community and hospital settings (Table 1). Levofloxacin MIC of 8mg/L occurred in 38.7% (n=36) and 30.7% (n=55) of isolates from community- and hospital-acquired infections, respectively (Figure 1). Ceftriaxone MIC of 16mg/L occurred in 39.7%(n=37) and 39.1% (n=70) of isolates from community- and hospital-acquired infections, respectively (Figure 1). At last, cefepime MIC of 32mg/L occurred in 22% (n=21) and 25% (n=46) of isolates from community- and hospital-acquired infections, respectively. The following beta-lactamases were found in isolates from community-acquired group, ACT-MIR, CTX-M, SHV and TEM; while beta-lactamases from the hospital-acquired group were ACT-MIR, CMY II, KPC-2, CTX-M, SHV and TEM. Table 1. Enterobacterales ceftriaxone, cefepime, levofloxacin, amikacin and ertapenem minimum inhibitory concentrations (mg/L) distribution from community- and hospital-settings. Figure 1. Enterobacterales ceftriaxone and levofloxacin minimum inhibitory concentrations (mg/L) distribution from community- and hospital-settings. Conclusion Similar antimicrobials resistances were found in Enterobacterales from community- and hospital-acquired infections. New anti-infective agents are needed urgently to treat pathogens from the community-acquired infections and hospitals that have resistance to the first line regimen. Additionally, community antimicrobial stewardship programs are required. Disclosures All Authors: No reported disclosures

Background: Brazil is facing a surge in COVID-19 infection, with heterogeneous regional spread associated with varying infection and death rates across the country’s states. This study aimed to thoroughly analyze the association of death with demographic characteristics, symptoms, and comorbidities at three levels of COVID-19 severity—in non-hospitalized, non-ICU-ward, and ICU-ward patients—in a state-wide context in South Brazil. Methods: We selected 221,414 cases in the state of Parana diagnosed by positive RT-PCR tests, defining outcome based on electronic medical records including demographic characteristics (sex, age, HDI), description of symptoms (114,025 cases with at least one symptom—SY group), and comorbidities (116,229 cases with at least one comorbidity—CM group). Logistic regression was performed to test the association between deaths with demographic characteristics and categorical variables in three levels of medical intervention within the SY and CM groups. Findings: Registered ICU deaths ranged between 68·62% (SY) and 69·6% (CM). Males presented increased mortality among non-hospitalized patients (SY: OR=1·81, 95% CI=1·51–2·17; CM: OR=1.97, 95% CI=1·66–2·34) and non-ICU patients (SY: OR=1·24, 95% CI=1·07–1·45; CM: OR=1·35, 95% CI=1·15–1·57). Lower human development index (HDI) was associated with increased mortality in non-hospitalized patients (SY: OR=0·01, 95% CI=0·02–0·08, CM: OR=0·02, 95% CI=0·01– 0·11). A higher mortality rate occurred in patients older than 40 years (non-hospitalized OR=25·65, 95% CI=8·17–155·36, non-ICU OR=5·05, 95% CI=1·87–20·75, and ICU OR=3·91, 95% CI=1·27–14·58), with strong association in elderly SY and CM adults. The main symptoms associated with increased mortality were dyspnoea in non-hospitalized (OR=3·71, 95% CI=3·10–4·44), non-ICU (OR=2·47, 95% CI=2·11–2·90), and ICU patients (OR=1·43, 95% CI=1·16–1·77). In all patients, diabetes, heart, neurological, and kidney diseases were associated with death (e.g., in non-hospitalized patients: OR=2·12, 95% CI=1·72–2·60; OR=1·84, 95% CI=1·47–2·29; OR=2·18, 95% CI=1·46–3·17 OR=2·00, 95% CI=1·20–3·19, respectively). Interpretation: The demographic characteristics “male sex” and “age > 40 years” were unequivocally associated with death and with lower HDI in non-hospitalized patients. Other categorical variables—dyspnoea, diabetes, heart disease, neurological disease, and kidney disease—were associated with most patients’ mortality. Our study highlights the importance of these predictors for the implementation of public healthcare policy in response to the pandemic. Funding: Araucaria Foundation – FAAP-PR, State Secretariat of Science, Technology and Higher Education – SETI –PR. ABWB currently receives a research productivity scholarship from CNPq (314288/2018-0). Declaration of Interests: We declare no competing interests. Ethics Approval Statement: The study received the ethical approval number CAAE 39108020.0.0000.0107, registered on the Plataforma Brasil – Comissao Nacional de Etica em Pesquisa database (https://plataformabrasil.saude.gov.br).

Highlights • Inflammatory innate immunity can be described as prognostic factors. • The balancing between Th1 and Th2 response can be associated with mortality in patients with moderate to severe COVID-19 infection. • IFN-γ was an independent risk factor associated with mortality in patients with SARS-Cov2., Background Innate and adaptive immune responses have been evaluated in infected patients with COVID-19. The severity of the disease has been supposed to be associated with some profile not reported with other bacterial and viral pneumonia. We proposed a study in patients with moderate to severe COVID-19 infection to evaluate the interleukin patterns and its role as prognosis factors. Methods A prospective cohort with moderate and severe cases of COVID-19 infection from June to July 2020. Blood samples from patients were collected regularly to evaluate IFN-γ, TNF-α, IL-4, IL-6, and IL-10. Clinical, laboratory, radiological data, and outcomes were recorded. The outcome variable was in-hospital death, survival, mechanical ventilation, and admission at the intensive care unit. Data are presented in median and interquartile range [IQR]. Results We evaluated the Th1 and Th2 responses according to evolution, distinguishing possible predictive markers. The IFN-γ median of 323 pg/mL [IQR 166−570] was found in patients who died and 208 pg/mL [IQR 155−392] in the survival group (p = 0.017). IFN-γ was also higher in the early stages of the disease (394 pg/mL [IQR 229–575] against 162 pg/mL [IQR 117–259], p < 0.001). IL-4 that was increased in late-stage (182 pg/mL [IQR 162–199] against 131 pg/mL [IQR 124–152], p < 0.001) but not associated with mortality. Also, death was also related to male gender (relative risk = 1.5 [95 % confidence interval = 1.1−2.0]). Conclusion Our results suggest that the activation of the host immune response between Th1 or Th2 in COVID-19 infection may be related to the final result between discharge or death. This implies an attempt to control cytokines, such as IFN-γ, with combined therapies for clinical treatment.

There is an urgent need to identify optimal antiviral therapies for COVID-19 caused by SARS-CoV-2. We have conducted a rapid and comprehensive review of relevant pharmacological evidence, focusing on (1) the pharmacokinetics (PK) of potential antiviral therapies; (2) coronavirus-specific pharmacodynamics (PD); (3) PK and PD interactions between proposed combination therapies; (4) pharmacology of major supportive therapies; and (5) anticipated drug–drug interactions (DDIs). We found promising in vitro evidence for remdesivir, (hydroxy)chloroquine and favipiravir against SARS-CoV-2; potential clinical benefit in SARS-CoV-2 with remdesivir, the combination of lopinavir/ritonavir (LPV/r) plus ribavirin; and strong evidence for LPV/r plus ribavirin against Middle East Respiratory Syndrome (MERS) for post-exposure prophylaxis in healthcare workers. Despite these emerging data, robust controlled clinical trials assessing patient-centred outcomes remain imperative and clinical data have already reduced expectations with regard to some drugs. Any therapy should be used with caution in the light of potential drug interactions and the uncertainty of optimal doses for treating mild versus serious infections., SCOPUS: re.j, info:eu-repo/semantics/published

Brazil is witnessing a massive increase of COVID‐19 cases and may face some difficulties, not only regarding to other respiratory pathogens, but also to other relevant issues parallelly occurring, for instance, the beggining of autumn and winter seasons, which provides a longer period with high transmissibility of respiratory viroses. Additionally, Brazil is localized in a geographical tropical area with relevant arboviral diseases, where Dengue fever presented highest incidence during March‐June, mainly at Southeast and Midwest regions, where probably it will occur overlapping curves of arboviruses and COVID‐19, which will overload our public health system. The main affected áreas by COVID‐19 in Brazil were the same that presented 66% of the Dengue fever cases in Brazil. Moreover, it is importante to highlight the difficulty found to distinguish Dengue fever and COVID‐19 and its implications, which present similar laboratorial and clinical characteristics. Besides that, it has been pointed out false‐positive results in serological tests for Dengue fever, which later were confirmed as COVID‐19. These issues demand urgent attention,once they culminate in serious and devastating impacts in the Brazilian health system, public health, and social conditions. This article is protected by copyright. All rights reserved.

This study investigated the potential of five miRNA candidates for cerebral toxoplasmosis/HIV co-infection (CT/HIV) biomarkers. miR-155-5p, miR-146a-5p, miR-21-5p, miR-125b-5p and miR-29c-3p were tested in 79 plasma divided into groups: 32 CT/HIV patients; 27 individuals with asymptomatic toxoplasmosis (AT); and 20 individuals seronegative for toxoplasmosis (NC). From each was collected peripheral blood/EDTA for laboratory diagnosis. Blood cells for DNA extractions (molecular diagnosis), plasma for RNA extractions (gene expression) and ELISA (serological diagnosis). miRNA expression was performed by qPCR, and values were expressed in Relative Quantification (RQ). Among the five miRNAs, miR-21-5p and miR-146a-5p were up-expressed in CT/HIV group when compared with AT and NC groups. RQ means for miR-21-5p and miR-146a-5p in CT/HIV group were 3.829 and 2.500, while in AT group, were 1.815 and 1.661, respectively. Differences between 3 groups were statistically significant (Kruskal-Wallis ANOVA test), as well as CT/HIV and AT groups (Mann-Whitney test). Plasma of CT/HIV and AT groups expressed similar levels of miR-29c-3p, miR-155-5p and miR-125b-5p. As NC group was different of CT/HIV and AT groups, differences between three groups were statistically significant (Kruskal-Wallis ANOVA test). No difference was shown between CT/HIV and AT groups (Mann-Whitney test). These results suggest the host miRNAs modulation by Toxoplasma gondii.

Consumption of carbapenem has increased due to extended-spectrum beta-lactamase-producing bacteria spreading. Ertapenem has been suggested as a not carbapenem-resistance inducer. We performed a scoping review of carbapenem-sparing stewardship with ertapenem and its impact on the antibiotic resistance of Gram-negative bacilli. We searched PubMed for studies that used ertapenem as a strategy to reduce resistance to carbapenems and included epidemiologic studies with this strategy to evaluate susceptibility patterns to cephalosporins, quinolones, and carbapenems in Gram-negative-bacilli. The search period included only studies in English, up to February 2018. From 1294 articles, 12 studies were included, mostly from the Americas. Enterobacteriaceae resistance to quinolones and cephalosporins was evaluated in 6 studies and carbapenem resistance in 4 studies. Group 2 carbapenem (imipenem/meropenem/doripenem) resistance on A. baumannii was evaluated in 6 studies. All studies evaluated P. aeruginosa resistance to Group 2 carbapenem. Resistance profiles of Enterobacteriaceae and P. aeruginosa to Group 2 carbapenems were not associated with ertapenem consumption. The resistance rate of A. baumannii to Group 2 carbapenems after ertapenem introduction was not clear due to a lack of studies without bias. In summary, ertapenem as a strategy to spare use of Group 2 carbapenems may be an option to stewardship programs without increasing resistance of Enterobacteriaceae and P. aeruginosa. More studies are needed to evaluate the influence of ertapenem on A. baumannii.

Pseudozyma spp. are described as environmental yeasts but have also been identified as rare human pathogens found in immunocompromised patients. This systematic review details the clinical manifestations, diagnostic methodology, and empirical anti-fungal therapy for this rare yeast. PubMed, LILACS, Scielo, and Web of Science databases were searched for articles about Pseudozyma spp. infections from inception to June 2019. Inclusion criteria were any published studies that included patients with Pseudozyma spp. infection. Infections were identified using criteria set forth by the European Organization for Research and Treatment of Cancer, and were further classified according to clinical, laboratory, or radiologic findings, microbiologic confirmation, and response to therapy. Eleven articles were included with 15 patients. Oncological and/or hematological disorders were the most reported risk factors. Nontraditional microbiological methods correctly identified Pseudozyma spp., whereas traditional methods failed to identify fungal genus. Species were identified by sequencing, and most demonstrated a higher minimal inhibitory concentration (MIC) for fluconazole and echinocandins. MICs for itraconazole, voriconazole, and posaconazole varied by species. All isolates were susceptible to amphotericin B, which was the most used treatment. Pseudozyma spp. infections usually present with fever and are diagnosed by blood culture. Most species studied appeared to be resistant to fluconazole and echinocandin. Voriconazole, posaconazole, and amphotericin were effective in treating P. aphidis. However, more studies are needed to evaluate voriconazole and posaconazole in species other than P. aphidis.

Introduction: Ceftriaxone has been recommended as a first-line treatment for various infections; however, the doses for pneumonia have not been a consensus in randomized clinical trials. To compare ceftriaxone 1 g daily efficacy to other ceftriaxone dosing regimens in community-acquired pneumonia. Area covered: We performed a systematic review and meta-analysis on PubMed, Web of Science, Scopus, and LILACS. Randomized controlled trials of ceftriaxone in community-acquired pneumonia were included. Outcomes included clinical cure in modified intention-to-treatment, clinically and microbiologically evaluable patients. Expert opinion: Ceftriaxone dosages of 1 g daily are as safe and effective as other antibiotic regimens for community-acquired pneumonia. Twenty-four articles fulfilled the inclusion criteria. Twelve studies evaluated ceftriaxone regimens at a dosage of 2 g daily and 12 studies evaluated ceftriaxone at a dosage of 1 g daily. The odds-ratio of clinical cure in the modified intention-to-treatment patients administered either ceftriaxone (4666 patients) or a comparator (4411 patients) was 0.98 (95% CI [0.82-1.17]). Comparator regimens showed similar efficacy to ceftriaxone regimens of 1 g daily, with an odds ratio of 1.03 (95% CI [0.88-1.20]). Dosages higher than ceftriaxone 1 g daily did not result in improved clinical outcomes for community-acquired pneumonia patients (OR 1.02, 95% CI [0.91-1.14]).

Summary In Brazil, all patients who fulfill the criteria for AIDS have had free access to antiretroviral therapy since 1996. We performed this cross-sectional study to evaluate the causes of death among 643 HIV-infected patients over three non-consecutive years (2000, 2006, and 2010), using their epidemiological, clinical, and laboratory data. The causes of death were classified as AIDS-defining or non-AIDS-defining conditions. We observed a progressive increase in the prevalence of HIV infection over the study period, although there was also a decrease in the mortality rate for various groups, and especially among pediatric patients. An AIDS-defining condition was recorded as the cause of death for approximately 30% of the patients. There was also a high frequency (>70%) of infectious and parasitic diseases, including opportunistic infections, and the most common diagnoses were septicemia, pneumonia, tuberculosis, and pneumocystosis. Acute respiratory failure was the underlying cause of death in 30% of these cases. Despite advances in HIV therapy, the mortality rate remains high in Brazil. As few Brazilian studies have investigated HIV/AIDS-related mortality, it is important to evaluate and improve the mortality notification databases, in order to provide information regarding the effects of HIV and to guide the implementation of appropriate healthcare measures.

Aim This study analyzed microvesicles and exosomes, called as extracellular vesicles (EVs) excreted in serum and cerebrospinal fluid (CSF) from patients with cerebral or gestational toxoplasmosis. Methods Clinical samples from 83 individuals were divided into four groups. Group I, 20 sera from healthy individuals and pregnant women (seronegative for toxoplasmosis); group II, 21 sera from seropositive patients for toxoplasmosis (cerebral or gestational forms); group III, 26 CSF samples from patients with cerebral toxoplasmosis/HIV co-infection (CT/HIV) (seropositive for toxoplasmosis); and group IV, 16 CSF samples from seronegative patients for toxoplasmosis, but with HIV infection and other opportunistic infections (OI/HIV). Serum and CSF samples were ultracentrifuged to recover EVs. Next, vesicle size and concentration were characterized by Nanoparticle Tracking Analysis (NTA). Results Concentrations of serum-derived EVs from toxoplasmosis patients (mean: 2.4 x 1010 EVs/mL) were statically higher than of non-infected individuals (mean: 5.9 x 109 EVs/mL). Concentrations of CSF-derived EVs were almost similar in both groups. CT/HIV (mean: 2.9 x 109 EVs/mL) and OI/HIV (mean: 4.8 x 109 EVs/mL). Analyses by NTA confirmed that CSF-derived EVs and serum-derived EVs had size and shape similar to microvesicles and exosomes. The mean size of EVs was similar in serum and CSF. Thus, the concentration, and not size was able distinguish patients with toxoplasmosis than healthy individuals. Presence of exosomes was also confirmed by transmission electron microscopy and evidence of tetraspanins CD63 and CD9 in immunoblotting. Relative expressions of miR-146a-5p, miR-155-5p, miR-21-5p, miR-29c-3p and miR-125b-5p were estimated in exosomal miRNA extracted of EVs. Serum-derived EVs from group II (cerebral and gestational toxoplasmosis) up-expressed miR-125b-5p and miR-146a-5p. CSF-derived EVs from CT/HIV patients) up-expressed miR-155-5p and miR-21-5p and were unable to express miR-29c-3p. Conclusion These data suggest the participation of EVs and exosomal miRNAs in unbalance of immune response as elevation of TNF-α, IL-6; and downregulation of IFN-γ in cerebral and gestational forms of toxoplasmosis.

Various infectious diseases can hyper-stimulate the immune system, causing hemophagocytic syndrome (HPS). Little is known regarding the accuracy of diagnostic criteria and epidemiological triggering factors in the acquired immunodeficiency syndrome (AIDS) setting. We investigated the major infectious disease triggers of HPS in patients living with human immunodeficiency virus (HIV)/AIDS and determined the accuracy of bone marrow aspiration (BMA). The inclusion criteria were (i) confirmed HIV diagnosis, (ii) bone marrow aspiration, and (iii) a minimum of four HPS criteria. Patients were further classified into those with four presumed HPS criteria, or ≥ 5 confirmed criteria. The disease triggers, accuracy of bone marrow aspiration, and prognosis markers were examined. Presumed HPS was observed in 15/36 patients (41%), and confirmed HPS in 58% (n = 21). The major etiological triggers were infection with Mycobacterium (34%), Cytomegalovirus (14%), Cryptococcus neoformans (11%), and hematological or tumoral disease (11%). BMA demonstrated 93% specificity on screening diagnosis (odds ratio [OR] 12.7, 95% confidence interval [CI] 1.4–115.1, P = 0.01). Ferritin > 5000 ng/mL correlated with probability of death in univariate analysis (OR 6.00, 95% CI 1.33–27.05, P = 0.02). Ferritin performance as test of death probability presented area under the curve as 0.74 (95% CI 0.56–0.91, P = 0.016). However, neither cluster of differentiation for lymphocyte count nor HIV viral load correlated with patient deaths. Mycobacterium spp. and Cytomegalovirus were the main factors triggering HPS, followed by Cryptococcus neoformans, and hematological and tumoral diseases. High ferritin levels were associated with increased death probability. High specificity was noted with BMA.

Background Carbapenem-resistant Acinetobacter baumannii infection is a concern in developing countries due to high incidence, few therapeutic options, and increasing costs. Objective Characterize and analyze the antibiotic susceptibility patterns of carbapenem-resistant A. baumannii isolates and evaluate clinical data of meningitis and bacteremia caused by this microorganism. Methods Twenty-six A. baumannii isolates from 23 patients were identified by MALDI-TOF and automated methods and genotyped using pulsed field genotyping electrophoresis. Clinical data and outcomes were evaluated. Susceptibility of isolates to colistin, tigecycline, meropenem, imipenem, and doxycycline was determined. Results Mortality due to A. baumannii infections was 73.91%; all patients with meningitis and 7/8 patients with ventilator-associated pneumonia died. All isolates were susceptibility to polymyxin (100%; MIC50, MIC90: 1 μg/mL, 1 μg/mL) and colistin (100%; MIC50, MIC90: 2 μg/mL, 2 μg/mL), and 92% were susceptible to tigecycline (MIC50, MIC90: 1 μg/mL, 1 μg/mL) and doxycycline (MIC50, MIC90: 2 μg/mL, 2 μg/mL). blaOXA-23 was identified in 24 isolates. Molecular typing showed 8 different patterns: 13 isolates belonged to pattern A (50%). Conclusion Carbapenem-resistant A. baumannii infections mortality is high. Alternative antimicrobial therapy (doxycycline) for selected patients with carbapenem-resistant A. baumannii infection should be considered.