Effectiveness, Tolerability, and Safety of Different Amphotericin B Formulations in Invasive Fungal Infections: A Multicenter, Retrospective, Observational Study.

PURPOSE: Data on the real-life use of amphotericin B lipid complex (ABLC) compared with other available formulations are limited. This study aimed to evaluate the effectiveness, tolerability, and safety of different amphotericin B (AMB) intravenously administered in the context of hospital practice for the treatment of invasive fungal infections (IFI) and to provide new insights into the profile of ABLC. METHODS: This is a multicenter, retrospective, observational study conducted at 10 tertiary Brazilian hospitals. Patients first exposed to any formulation of AMB for treating endemic and opportunistic IFI who had received at least 2 intravenous doses were screened. Retrospective data (from January 2014 to December 2019) were extracted from the patients' medical records. Clinical parameters were examined pre- and post-treatment to determine effectiveness; acute infusion-related side effects (IRSE) and drug interruption to determine tolerability; and adverse events, toxicity, and treatment interruption were stated to analyze safety. FINDINGS: Overall, 1879 medical records of patients were identified. The median (interquartile rate) duration of treatment was 14 (7-21) days. The overall success rate (95% confidence interval [CI]) was 65% (95% CI 60-65). ABLC proved to be effective among AMB formulations with 59% (95% CI 55.6-62.5) within complete response. This was significantly higher in patients who received the drug for a longer period, ≥4 weeks compared to <1 week treatment (P < 0.001). IRSE was observed in 446 (23.7%) patients. Eight cases (1.4%) of severe IRSE in pediatrics and 14 (1.1%) in adults resulted in treatment discontinuation. Regarding safety, 637 (33.9%) patients presented some alteration in creatinine levels during AMB exposure, and 89 (4.74%) had to interrupt or discontinue the drug within the first 14 days of therapy because of renal dysfunction. Overall mortality was 34%. IMPLICATIONS: ABLC is an effective formulation for the treatment of invasive fungal infections, with few adverse events leading to drug discontinuation or lethal outcomes. Furthermore, this real-life study confirmed the comparative safety of AMB lipid formulations versus AMB deoxycholate.

A contemporary investigation of burden and natural history of aspergillosis in people living with HIV/AIDS.

BACKGROUND: Untreated HIV infection can lead to profound immunosuppression and increase susceptibility of people living with HIV/AIDS (PLHA) to aspergillosis. OBJECTIVES: Reporting the burden and natural history of aspergillosis documented in PLHA admitted in five medical centres in Brazil. PATIENTS AND METHODS: Clinical, epidemiological and laboratory data were collected in all sequential cases of proven or probable aspergillosis documented in PLHA hospitalised in five medical centres between 2012 and 2020. RESULTS: We enrolled 25 patients ageing between 23 and 58 years (mean = 39) including 11 patients with invasive aspergillosis (IA) and 14 with chronic pulmonary aspergillosis (CPA). The prevalence rate of aspergillosis was 0.1% of 19.616 PLHA. Overall, 72.7% of patients with IA exhibited CD4 < 100 cells/mL and 42.8% of patients with CPA exhibited CD4 count >200 cells/mL. Most patients had a history of tuberculosis, especially those with CPA (85.7%). IA was documented after a mean of 16.5 days of hospitalisation, mainly in critically ill patients exposed to corticosteroids and broad-spectrum antibiotics. In the CPA group, a positive culture (71.4%) and radiological alterations were the most frequent findings supporting their diagnosis. Episodes of IA were mostly documented by tissue biopsies. Crude mortality rates were 72.7% and 42.8% in patients with IA and CPA, respectively. CONCLUSIONS: Despite being considered an unusual complication in PLHA (0.1%), IA should be considered in patients with profound immunosuppression and pneumonia refractory to conventional therapy. CPA should be investigated in PLHA with chronic deterioration of pulmonary function and previous diagnosis of tuberculosis.

Epidemiology and risk factors for mortality among methicillin-resistant Staphylococcus aureus bacteremic patients in Southern Brazil.

This study aimed to evaluate the epidemiology and 30-day mortality of adult patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. We retrospectively reviewed the demographic and clinical data of adult patients with S. aureus bloodstream infections (BSI), admitted to a tertiary public teaching medical center in Porto Alegre, Southern Brazil, from January 2014 to December 2019. A total of 928 patients with S. aureus BSI were identified in the study period (68.5 per 100,000 patient-years), and the proportion of MRSA isolates was 22% (19-27%). Thus, 199 patients were included in the analyses. The median age was 62 (IQR: 51-74) years, Charlson Comorbidity Index (CCI) median was 5 (IQR: 3-6), the Pitt bacteremia score (PBS) median was 1 (IQR: 1-4), and the most common site of infection was skin and soft tissue (26%). Most infections were hospital-acquired (54%), empirical anti-MRSA treatment was initiated in 34% of the cases, and in 44% vancomycin minimum inhibitory concentration was 1.5mg/L or above. Sixty-two (31.2%) patients died up to 30 days after the bacteremia episode. Patients with more comorbid conditions (higher CCI; aOR 1.222, p = 0.006) and a more severe presentation (higher PBS; aOR 1.726, p<0.001) were independently associated with mortality. Empiric antimicrobial therapy with an anti-MRSA regimen was associated with reduced mortality (aOR 0.319, p = 0.016). Our study identified significant risk factors for 30-day mortality in patients with MRSA BSI in a population with a high incidence of S. aureus bacteremia. Empiric treatment with an anti-MRSA drug was a protective factor. No significant variation in the incidence of S. aureus BSI was recorded throughout the period.

Characteristics, mortality, associated variables with death, and therapeutic response among HIV-positive, solid organ transplant (SOT), and non-HIV-positive/non-transplant (NHNT) patients with cryptococcosis: First multicenter cohort study in Brazil.

Cryptococcosis is traditionally associated with immunocompromised patients but is increasingly being identified in those without the human immunodeficiency virus (HIV) or other immunocompetent individuals. We aim to describe the characteristics, mortality, and associated variables with death among hospitalized patients with cryptococcosis in Brazil. This is the first multicenter retrospective cohort study conducted in seven public tertiary Brazilian hospitals. A total of 384 patients were included; the median age was 39 years and 283 (73.7%) were men. In all, 304 HIV-positive were hosts (79.2%), 16 (4.2%) solid organ transplant (SOT), and 64 (16.7%) non-HIV-positive/non-transplant (NHNT). Central nervous system (CNS) cryptococcosis had a significantly higher number across disease categories, with 313 cases (81.5%). A total of 271 (70.6%) patients were discharged and 113 (29.4%) died during hospitalization. In-hospital mortality among HIV-positive, SOT, and NHNT was 30.3% (92/304), 12.5% (2/16), and 29.7% (19/64), respectively. Induction therapy with conventional amphotericin B (AMB) mainly in combination with fluconazole (234; 84.2%) was the most used. Only 80 (22.3%) patients received an AMB lipid formulation: liposomal (n = 35) and lipid complex (n = 45). Most patients who died belong to the CNS cryptococcosis category (83/113; 73.4%) when compared with the others (P = .017). Multivariate analysis showed that age and disseminated cryptococcosis had a higher risk of death (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.01-1.05; P = .008 and OR, 1.84; 95% CI, 1.01-3.53; P = .048, respectively). Understanding the epidemiology of cryptococcosis in our settings will help to recognize the burden and causes of mortality and identify strategies to improve this scenario.

This multicenter cohort study included 384 hospitalized individuals with cryptococcosis in Brazil. Most individuals were men (74%), HIV-positive (79%), had central nervous system involvement (82%), and received conventional amphotericin plus fluconazole (84%). In-hospital mortality was high (29%).

Combination therapy with polymyxin B for carbapenemase-producing Klebsiella pneumoniae bloodstream infection.

Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP) bloodstream infections (BSIs) are related to high mortality rates, and combination therapy has been associated with lower mortality in patients treated mostly with colistin. There is a paucity of studies addressing polymyxin B (PMB) treatment for KPC-KP infections. This was a retrospective cohort study of patients with monomicrobial KPC-KP BSIs. The primary outcome was 30-day mortality. Antimicrobial therapy was defined as empirical (started within the first 48 h) or definitive (initiated after >48 h) and was evaluated as follows: monotherapy (only one in vitro active agent or combination therapy of one in vitro active agent plus one or more in vitro non-active agents); and combination therapy with two or more in vitro active agents. A total of 82 KPC-KP BSIs were included; 40 patients (48.8%) died in the first 30 days. Mortality of patients treated with the combination of two in vitro active antimicrobial agents, mostly PMB plus amikacin, was significantly lower (37.5%) compared with monotherapy (64.7%) (P= 0.01). Combination therapy [adjusted hazard ratio (aHR) = 0.40, 95% confidence interval (CI) 0.22-0.83; P = 0.01] was independently associated with lower 30-day survival when controlled for non-surgical admission (aHR = 2.33, 95% CI 1.14-4.80; P = 0.02) and use of vasoactive drugs (aHR = 7.37, 95% CI 3.01-18.02; P < 0.01). In conclusion, combination therapy with two in vitro active agents, mostly PMB plus amikacin, showed a survival benefit compared with other regimens.

Characteristics of serogroup 20 S.pneumoniae isolates from Brazil.

BACKGROUND: Although serogroup 20 is not part of any conjugate pneumococcal vaccine, its serotype 20A, but not 20B, belongs to the polysaccharide 23-valent formula. Little is known about its clinical, laboratorial and epidemiological characteristics. METHODS: The purpose of this study was to evaluate the bacterial genotypes (by PFGE and MLST), clinical characteristics of patients (from review of medical records) and antimicrobial susceptibility of serogroup 20 isolates which were recovered from patients with invasive pneumococcal disease (IPD) from 2007 to 2012. Subtyping to determine 20A and 20B types was also performed by sequencing the genes of the cps locus. RESULTS: Sixteen isolates were genotyped and were highly related. All pneumococci were resistant to tetracycline and 31 % were non-susceptible to trimethoprim/sulfamethoxazole. Penicillin MIC ranged from 0.004 to 1 µg/mL and non-susceptibility (MIC ≥ 0.12 µg/mL) was observed in 5/16 isolates (31 %). All isolates belonged to subtype 20B. Most patients were male with a median age of 62 years and presented at least one underlying disease (mostly respiratory conditions). All isolates belonged to ST8889 and to a unique PFGE clone. CONCLUSIONS: A high clonal occurrence of serotype 20B pneumococci recovered from patients with IPD in Brazil was observed. As a non-PCV10 serotype, selective pressure may be responsible for this unusual occurrence of serogroup 20. However, temporal variation effect should not be underestimated; therefore it is an issue that warrants continued monitoring.

Burden of isolation for multidrug-resistant organisms in a tertiary public hospital in Southern Brazil.

We aimed to describe the use of isolation beds between September 2011 and August 2013 at a tertiary hospital located in Southern Brazil. The main cause for isolation was gram-negative carbapenem-resistant bacteria. Huge costs were associated with isolation practices. Considering the high burden on the isolation ward, practice of surveillance cultures and contact isolation should be balanced with other infection control practices.

Anfotericina B: uma revisão sobre suas diferentes formulações, efeitos adversos e toxicidade / Amphotericin B: a review on different formulations, side effects and toxicity

A incidência de infecções fúngicas invasivas tem aumentado, como consequência do contingente cada vez maior de pacientes com imunossupressão. O tratamento de infecções fúngicas com anfotericina B (AmB) está associado a efeitos adversos importantes, como nefrotoxicidade e toxicidade hematológica. Nesta revisão buscou-se abordar os estudos sobre AmB nas diferentes formulações, focando em suas características farmacológicas e toxicidade. Formulações lipídicas de AmB estão associadas a um risco menor de nefrotoxicidade, entretanto ainda há controvérsia sobre diferenças entre as duas formulações lipídicas de AmB disponíveis. Diferenças em relação ao perfil imunomodulatório e ligação a lipoproteínas podem explicar parte das diferenças clínicas existentes entre as formulações de AmB. A maioria dos estudos clínicos que avaliou a nefrotoxicidade associada à AmB em diferentes formulações não utilizou critérios validados para classificação do dano renal, o que dificulta sua comparação. A toxicidade hematológica relacionada ao uso de AmB é um fenômeno descrito desde os primórdios do seu uso clínico, entretanto poucos dados existem sobre sua frequência, fatores de risco e impacto nos desfechos clínicos. Dados precisos, e adequados ao contexto local, sobre a toxicidade de AmB nas suas diferentes formulações são necessários para uma adequada avaliação dos aspectos de farmacoeconomia e custo-efetividade...

Invasive fungal infections have emerged in recent years, as a consequence of increasing numbers of immunosuppressed patients. Treatment of these conditions with amphotericin B (AmB) has been associated with important side effects, such as nephrotoxicity and hematological toxicity. In this review we aimed to assess studies about different formulations of AmB, focusing on pharmacological properties and toxicity. Lipid formulations of AmB have been linked to a lower risk of nephrotoxicity; however, there is still controversy about differences between the two available lipid formulations. Differences in immunomodulatory profile and lipoprotein binding could partly explain clinical inequalities among AmB formulations. Most clinical trials that evaluated AmB-associated nephrotoxicity did not use validated criteria for renal injury classification, impairing comparability. Hematological toxicity associated with AmB treatments is an occurrence described since the beginning of its clinical use; nevertheless, few data exist about its frequency, risk factors, and clinical impact. Clear and more precise information, derived from local studies, is needed to an adequate evaluation about pharmacoeconomic aspects of AmB treatment and cost-effectiveness of lipid formulations...

Perfil dos pacientes colonizados por enterobactérias produtoras de KPC em hospital terciário de Porto Alegre, Brasil / Characteristics of patients colonized by KPC-producing enterobacteriaceae in a tertiary hospital from Porto Alegre, Brazil

Enterobactérias produtoras de carbapenemase do tipo Klebsiella pneumoniae (KPC) são cada vez mais identificadas em pacientes hospitalizados, porém pouco se conhece sobre o perfil e o prognóstico dos pacientes colonizados por elas. Este estudo objetiva avaliar o perfil epidemiológico e a mortalidade total intra-hospitalar dos pacientes colonizados por KPC em um centro de referência. Métodos: Estudo de coorte retrospectivo em adultos colonizados por KPC em internação clínica de novembro/2012 a março/2013 no Hospital Nossa Senhora da Conceição, Porto Alegre (RS). Foram definidos como colonizados pacientes com exame de rastreio (swab) positivo para bactérias produtoras de KPC durante a internação. Resultados: Foram incluídos 75 pacientes, sendo 40 homens, com mediana de 52 anos. O tempo desde o início da internação até a positivação do swab apresentou uma mediana e amplitude interquartil de 18 (9-33) dias, com período de internação de 36 (24-56) dias. Foi identificado uso de cateter central em 93%, sondagem vesical de demora 88%, sondagem nasogástrica/nasoentérica 87%, ventilação mecânica 81% e hemodiálise 40%. Dois terços dos pacientes apresentaram pelo menos um evento infeccioso após a colonização. O escore de Charlson (OR 1,53 por cada ponto; IC95% 1,25-1,97) e diálise prévia (OR 4,35; IC95% 1,39-15,37) foram preditores independentes de mortalidade. Óbito ocorreu em 56% dos pacientes (n=42). Conclusão: Pacientes colonizados por KPC apresentam mortalidade total intra-hospitalar elevada. Comorbidades prévias à colonização foram associadas com mortalidade. O presente estudo não permite definir qual o papel da colonização no desfecho clínico dos pacientes...

Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae have been increasingly identified in hospitalized patients, but little is known about the profile and prognosis of patients colonized by these bacteria. This study aims to assess the epidemiological profile and overall in-hospital mortality of patients colonized by KPC in a reference center. Methods: This is a retrospective cohort study in adult patients colonized by KPC and admitted to clinical units of Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil, between November/2012 and March/2013. Those patients with screening culture test positive for KPC-producing bacteria during hospitalization were defined as colonized. Results: Seventy-five patients were included, 40 of which were males, and the median age was 52 years. The median and interquartile range of time from onset of hospitalization until colonization was 18 [9-33] days, with a median hospital stay of 36 (24-56) days. Considering the other risk factors for colonization, there was a high prevalence in the use of central access catheter (93%), indwelling catheter (88%), nasogastric/enteral tube (87%), mechanical ventilation (81%), and need for hemodialysis (40%). Two thirds of patients had at least one infectious event after colonization. Charlson score (OR 1.53 for each point; 95%CI1.25-1.97) and previous dialysis (OR 4.35; 95%CI1.39-15.37) were independent predictors for mortality. In hospital mortality was 56%. Conclusion: Patients colonized by KPC have high in-hospital overall mortality. Comorbidities were associated with mortality. This study does not enable to define the role of colonization in defining patients’ clinical outcomes...

Prevalência de carbapenemases em enterobactérias resistentes a carbapenêmicos em quatro hospitais terciários de Porto Alegre / Prevalence of carbapenemases in carbapenem-resistant Enterobacteriaceae in four tertiary care hospitals in Porto Alegre

INTRODUÇÃO: A disseminação de Klebsiella pneumoniae carbapenemase (KPC) no Brasil e a recente detecção de bactérias produtoras de New Delhi metalo-β-lactamase (NDM-1) em hospital terciário do sul do Brasil indicam a necessidade da avaliação da presença destas enzimas em enterobactérias resistentes a carbapenêmicos (ERC).OBJETIVO: Avaliar prevalência de carbapenemases nas ERC em quatro hospitais terciários de Porto Alegre, por meio de PCR multiplex em tempo real. MÉTODOS: Estudo descritivo, período de abril a dezembro de 2013. Isolados bacterianos de pacientes internados foram identificados pelo sistema automatizado VITEK 2, com realização do teste de suscetibilidade aos antimicrobianos. Amostras com isolados de ERC foram encaminhadas ao laboratório de referência para análise por PCR em tempo real para identificação de carbapenemases. RESULTADOS: Total de 701 isolados. As ERC predominantes foram K. pneumoniae (47% das amostras positivas) e Enterobacter cloacae (18%). As carbapenemases mais frequentes foram KPC (48%), OXA-48-like (3%) e NDM (2%). Em 47% das amostras não foi identificado o mecanismo de resistência. Isolados originados de culturas de vigilância foram associados com maior positividade para carbapenemases do que isolados de amostras clínicas (p<0,0001). Isolados de ERC pertencentes ao grupo Proteae (Proteus spp., Morganella spp., Providencia spp.) foram associados a menor positividade para carbapenemase do que isolados de outras ERC (p<0,0001). CONCLUSÃO: KPC foi a carbapenemase mais frequentemente detectada. A circulação de uma enzima OXA-48-like foi demonstrada, um achado novo e preocupante. O achado da carbapenemase NDM também é preocupante devido ao seu potencial de disseminação. Esses dados e outros estudos poderão contribuir para um entendimento maior da epidemiologia das ERC.

BACKGROUND: The spread of Klebsiella pneumoniae carbapenemase (KPC) in Brazil and the recent detection of bacteria producing New Delhi metallo-β-lactamase (NDM-1) in a tertiary care hospital in Porto Alegre indicate the need to evaluate the presence of these enzymes in carbapenem-resistant Enterobacteriaceae (CRE). AIM: To evaluate the prevalence of carbapenemases in CRE in four tertiary care hospitals in Porto Alegre using multiplex real-time PCR.METHODS: Descriptive study from April to December 2013. Bacterial isolates from hospitalized patients were identified by VITEK 2 automated system, with antimicrobial susceptibility testing. Samples with CRE isolates were sent to the reference laboratory for analysis using real-time PCR for identification of carbapenemases. RESULTS: Total of 701 isolates. The predominant CRE were K. pneumoniae (46% of positive samples) and Enterobacter cloacae (18%). The most frequent carbapenemases were KPC (48%), OXA-48-like (3%), and NDM-1 (2%). In 47% of the samples no carbapenemase was identified. Isolates originated from surveillance cultures were associated with higher positivity for carbapenemases than isolates from clinical samples (p<0.0001). CRE isolates belonging to the Proteae group (Proteus spp., Morganella spp., Providencia spp.) were associated with less positivity for carbapanemase than isolates of other CRE (p<0.0001). CONCLUSION: KPC was the most frequently detected carbapenemase. The movement of an OXA-48-like enzyme was demonstrated, a novel and worrisome finding. The finding of carbapenemase NDM is also worrisome due to its dissemination potential. These data and further studies may contribute to a better understanding of the epidemiology of CRE.

Continuous infusion of amphotericin B deoxycholate in the treatment of cryptococcal meningoencephalitis: analysis of safety and fungicidal activity.

We measured fungicidal activity of continuous infusion of amphotericin B deoxycholate plus 5'flucytosine using quantitative cultures of cerebrospinal fluid (CSF) obtained from lumbar punctures of human immunodeficiency virus (HIV)-infected patients with neurocryptococcosis during 14 days of treatment. Glomerular renal function was preserved in all patients. Mycological efficacy with progressive reduction in CSF cryptococcal colony-forming units was comparable to standard 4-h infusion of amphotericin B.