Carbapenem-resistant Klebsiella pneumoniae bloodstream infections in haematological malignances and hematopoietic stem cell transplantation: Clinical impact of combination therapy in a 10-year Brazilian cohort.

Bacterial bloodstream infections (BSI) are a common threat among patients with haematological malignancies (HM) and hematopoietic stem cell transplant recipients (HSCT). The purpose of this research was to describe clinical and microbiological aspects of BSI caused by carbapenem-resistant Klebsiella pneumoniae (CRKp) and assess risk factors associated with 30-day mortality in a 10-year cohort of haematological patients. A total of 65 CRKp-BSI episodes occurring in HM patients and HSCT recipients and CRKp-BSI between January 2010 and December 2019 were retrospectively studied. Acute leukemias were the most frequently observed underlying disease (87.7%) and 18 patients (27.7%) received HSCT. Mucosal barrier injury in the gastrointestinal tract was the primary cause of bacteremia (86.1%). Also, 14 individuals (21.6%) had an Invasive Fungal Disease (IFD) throughout the episode. Regarding treatment, in 31 patients (47.7%) empirical therapy was deemed appropriate, whereas 33 (50.8%) patients received a combination therapy. Microbiological data revealed that the majority of isolates (53-58%) had the Polymyxin B co-resistance phenotype, while amikacin resistance was less common (16 samples, or 24.7%). The mortality rates at 14 and 30 days were 32.3% and 36.9%, respectively. In a multivariate Cox regression analysis, prompt appropriate antibiotic administration within three days was associated with a better outcome (Adjusted Hazard Ratio [aHR]: 0.33; 95% Confidence Interval [CI]: 0.14-0.76; p = 0.01), whereas hypotension at presentation (aHR: 3.88; 95% CI: 1.40-10.74; p = 0.01) and concurrent IFD (aHR: 2.97; 95% CI: 1.20-7.37; p = 0.02) were independently associated with death within 30 days. Additionally, a favorable correlation between combination therapy and overall survival was found (aHR: 0.18; 95%CI: 0.06-0.56; p = 0.002). In conclusion, 30-day mortality CRKp-BSI was elevated and most of the isolates were polymyxin B resistant. Early appropriate antimicrobial treatment and the use of combination therapy were linked to a better outcome.

Pharmacodynamic evaluation of suppression of in vitro resistance in Acinetobacter baumannii strains using polymyxin B-based combination therapy.

The emergence of polymyxin resistance in Gram-negative bacteria infections has motivated the use of combination therapy. This study determined the mutant selection window (MSW) of polymyxin B alone and in combination with meropenem and fosfomycin against A. baumannii strains belonging to clonal lineages I and III. To evaluate the inhibition of in vitro drug resistance, we investigate the MSW-derived pharmacodynamic indices associated with resistance to polymyxin B administrated regimens as monotherapy and combination therapy, such as the percentage of each dosage interval that free plasma concentration was within the MSW (%TMSW) and the percentage of each dosage interval that free plasma concentration exceeded the mutant prevention concentration (%T>MPC). The MSW of polymyxin B varied between 1 and 16 µg/mL for polymyxin B-susceptible strains. The triple combination of polymyxin B with meropenem and fosfomycin inhibited the polymyxin B-resistant subpopulation in meropenem-resistant isolates and polymyxin B plus meropenem as a double combination sufficiently inhibited meropenem-intermediate, and susceptible strains. T>MPC 90% was reached for polymyxin B in these combinations, while %TMSW was 0 against all strains. TMSW for meropenem and fosfomycin were also reduced. Effective antimicrobial combinations significantly reduced MSW. The MSW-derived pharmacodynamic indices can be used for the selection of effective combination regimen to combat the polymyxin B-resistant strain.

Polymyxin B broth disk elution: a feasible and accurate methodology to determine polymyxin B susceptibility in Enterobacterales.

Determination of polymyxins susceptibility by clinical laboratories is a nightmare, mainly because of physicochemical properties of the drug. Elution tests have already been proposed for colistin, but not for polymyxin B. We aimed to evaluate accuracy of Polymyxin B broth disk elution (PBDE) to determine the susceptibility to this drug. We evaluated 196 Enterobacterales (45.9% polymyxin B-resistant). PBDE was done in 15-mL cation-adjusted Mueller-Hinton broth where one polymyxin B disk (300 U) was eluted (2 µg/mL). BMD was performed as reference method. Categorical Agreement (CA), Major Error (ME) and Very Major Error (VME) were 99.5%, 0% and 1.11% (one false-negative K. pneumoniae MIC 4 µg/mL), respectively. As some institutions preferably use polymyxin B over colistin and in some countries colistin are not commercially available, to specifically evaluate polymyxin B is important. PBDE proved to be a cheap and easy to perform methodology to evaluate susceptibility to polymyxin B among Enterobacterales.

Dois casos de hiperpigmentação cutânea induzido pela polimixina B / Two cases of skin hyperpigmentation induced by polymyxin B

INTRODUÇÃO: O processo de hiperpigmentação cutânea envolve mecanismos bioquímicos e imunológicos que estimulam a melanogênese e apesar da nefrotoxicidade consistir na reação adversa mais relevante da polimixina B, o antimicrobiano também está associado a esta alteração. RELATO DE CASO: Caso 1: paciente masculino diagnosticado com Linfoma de Hodgkin, que desenvolveu hiperpigmentação cutânea após iniciar tratamento com meropenem, anidulafungina e polimixina B devido a um quadro de choque séptico. Caso 2: paciente masculino admitido na UTI por rebaixamento do nível de consciência e suspeita de IAMCSST, diagnosticado com endocardite e pericardite, que também apresentou hiperpigmentação cutânea durante terapia com anfotericina B e polimixina B. CONCLUSÃO: Após criteriosa avaliação da ordem cronológica e medicamentos utilizados pelos pacientes, concluímos que a polimixina B desencadeou a hiperpigmentação em ambos. Por fim, baseado ao mecanismo desta reação e aos achados científicos, estudos clínicos que possam evidenciar um provável efeito farmacológico com o uso de antagonistas H2 são necessários.

INTRODUCTION: The skin hyperpigmentation process involves biochemical and immunological mechanisms that stimulate melanogenesis and although nephrotoxicity consists of the most relevant adverse reaction of polymyxin B, it is also associated with this changes. CASE REPORT: Case 1: male patient, diagnosed with Hodgkin's Lymphoma, who developed skin hyperpigmentation after starting treatment with meropenem, anidulafungin and polymyxin B due to a septic shock. Case 2: male patient, admitted to the ICU for decreased level of consciousness and suspected STEMI, diagnosed with endocarditis and pericarditis, who also presented skin hyperpigmentation during therapy with amphotericin B and polymyxin B. CONCLUSION: After careful evaluation of chronological order and drugs used by patients, we conclude that polymyxin B caused hyperpigmentation in both patients. Finally, based on the mechanism of this reaction and the scientific findings, clinical studies that may evidence a probable pharmacological effect with the use of H2 antagonists are required.

Clinical Use of Polymyxin B.

Polymyxin B is another clinically available polymyxin that has re-emerged in clinical practice to treat infections caused by multi-drug (MDR) or extensively-drug-resistant (XDR) Gram-negative bacteria (GNB). Its chemical structure is very similar to the structure of polymyxin E (colistin). However, since the latter is administered as a prodrug, there are major pharmacokinetic differences between both polymyxins that may potentially determine different clinical and microbiological outcomes. Studies addressing clinical or microbiological outcomes in patients treated with polymyxin B for MDR or XDR GNB are reviewed in this chapter.

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.

Polymyxin B clinical outcomes: A prospective study of patients undergoing intravenous treatment.

WHAT IS KNOWN AND OBJECTIVE: Polymyxins, especially polymyxin B, has become the last line of therapy against Gram-negative pathogens' carbapenemase producers. However, given increasing use of polymyxin B in clinical settings its therapeutic value has been evaluated worldwide due to its toxic effects. The aim of this study was to assess the efficacy and safety of antimicrobial therapy with polymyxin B in patients with multidrug-resistant bacteria in Brazil. METHODS: This was a prospective cohort study in a 403-bed academic tertiary care centre, located in the countryside of Brazil. Patients receiving polymyxin B intravenous treatment for at least 72 hours were eligible for the study. Antimicrobial susceptibility, adverse reactions and clinical outcomes were submitted for descriptive analysis. Main outcomes measure the following: Patients' conditions following treatment (Treatment Success, Mortality, Treatment Failure, Inadequate Empiric Treatment or Indeterminate Response) and toxicities induced by polymyxin B (nephrotoxicity and skin hyperpigmentation). RESULTS AND DISCUSSION: Among 247 patients, treatment success was achieved in 25.1%, while mortality was observed in 32.8%. Empirical therapy was prescribed for 26.3% of the patients. Nephrotoxicity was reported in 40.5%. The carbapenemase producer, Klebsiella pneumonia, was the bacterium most associated with mortality (22.2%). CONCLUSIONS: Even though polymyxin B is currently the main therapy against carbapenemase producers, its use demands robust criteria to lead to positive clinical outcomes.

Pulp response of rats submitted to bleaching and the use of different anti-inflammatory drugs.

This study aimed to evaluate neuropeptide expression after bleaching treatment using histopathological and immunohistochemical analyses and the effects of hydrocortisone and acetaminophen on pulp inflammation, sine dental bleaching and inflammation first occur, and only then, the treatmentt. Sixty-three rats were divided into three groups (n = 21) according to the pain-relieving therapy used: I-control; II-topical application of Otosporin for 10 min after the bleaching treatment; III-oral administration of paracetamol 30 min before whitening and then every 12h. In all the study groups, placebo gel was applied to the left upper jaw (control) and a 35% H2O2-based whitening gel was applied to the right upper jaw for 45 min. Seven animals from each group were euthanized at different time points: 0h after treatment, 24h, and 48h. After euthanasia, the first molar on each side was analyzed by histology and immunohistochemistry to assess the degree of inflammation and verify the presence of the neuropeptides, substance P (SP) and calcitonin gene-related peptide (CGRP). The data were analyzed using the statistical nonparametric Kruskal-Wallis test followed by Dunn's test for individual comparisons. Extensive areas of necrosis were observed in the groups that received bleaching treatment only, whereas reduced damage were obtained in the group treated with Otosporin. The immunohistochemical analysis showed positive immunolabeling in all groups, including the control, but this was stronger in the groups that received bleaching treatment. The best results were obtained in the group that received treatment with Otosporin. The use of Otosporin after dental bleaching minimized the side effects of this treatment.

Nephrotoxicity prevalence in patients treated with polymyxins: a systematic review with meta-analysis of observational studies.

Colistin and polymyxin B are increasingly reintroduced in clinical practice due to the absence of effective antibiotics for the treatment of emerging infections caused by gram-negative bacteria. The synthesis of current evidence on the characteristics of polymyxins, especially regarding nephrotoxicity, is necessary. This study aims to conduct a systematic review and meta-analysis of cohort-type observational studies in order to identify the prevalence of nephrotoxicity in patients treated with either colistin or polymyxin B. PubMed, Scopus, and DOAJ electronic databases were searched, and manual searches were done. Cohort studies evaluating renal damage (nephrotoxicity) in adult patients caused by colistin or polymyxin B were included. Meta-analyses of the prevalence of nephrotoxicity as well as cumulative meta-analysis and meta-regression were conducted. After the systematic searches, 95 cohorts (n = 7911 patients) were included for analysis. The nephrotoxicity prevalence was 26.7% [confidence interval (CI) 95%: 22.8-30.9%] for colistin and 29.8% (CI 23.8-36.7%) for polymyxin B (P = 0.720). The publication year of the studies, the criteria used to classify renal damage, and the nephrotoxicity as primary or secondary outcome showed a significant influence on the adverse event rates.

Polymyxin B and colistin-the economic burden of nephrotoxicity against multidrug resistant bacteria.

BACKGROUND: Polymyxin B and colistin are nephrotoxic drugs used in the treatment of carbapenem-resistant Enterobacteriaceae. The aim of this study is to evaluate the burden of costs due to polymyxin associated AKI and propose a simulated break-even price for new therapies. METHODS: The pharmacoeconomic model is based on two large cross-sectional studies of polymyxin nephrotoxicity. Total direct costs in patients with and without renal failure were compared. The direct cost of each hemodialysis section (USD82.94) and daily hospital charges (USD934.85) were based on the values used in a major public hospital in the city where the clinical study was performed. The break-even price of new drugs was simulated considering eventual new drugs as effective as polymyxins, but less nephrotoxic in different percentages. Outcomes of patients after hospital discharge were not evaluated. RESULTS: Total direct cost of the group of patients who survived without AKI was significantly lower than total direct cost of the groups either with AKI or the group who died without AKI. There was a tendency of even higher costs in those who died with AKI and dialysis. Direct cost of hemodialysis was not as important as the longer hospitalization after sepsis. Considering daily cost of polymyxin is USD60, drugs with 50% less AKI could be considered cost-beneficial if the daily cost is lower than USD160. CONCLUSIONS: AKI in patients with carbapenem-resistant Enterobacteriaceae treated with polymyxin increases both length of stay in hospital and total costs.

Colistin and polymyxin B for treatment of nosocomial infections in intensive care unit patients: pharmacoeconomic analysis.

Background The emergence and rapid spread of multidrug-resistant gram-negative bacteria related to nosocomial infections is a growing worldwide problem, and polymyxins have become important due to the lack of new antibiotics. Objectives To evaluate the outcomes and pharmacoeconomic impact of using colistin and polymyxin B to treat nosocomial infections. Setting Neurosurgical, cardiovascular, or transplantation intensive care unit (ICU) at the Clinical Hospital of the University of Campinas (São Paulo, Brazil). Method A retrospective cohort study was conduct in patients in the ICU. The renal function was determined daily during treatment by measuring the serum creatinine. A cost minimization analysis was performed to compare the relative costs of treatment with colistin and polymyxin B. Main outcomes measure The outcomes were 30-day mortality and frequency and onset of nephrotoxicity after beginning treatment. Results Fifty-one patients treated with colistin and 51 with polymyxin B were included. 30-day mortality was observed in 25.49% and 33.33% of patients treated with colistin and polymyxin B, respectively; Nephrotoxicity was observed in 43.14% and 54.90% of patients in colistin and polymyxin B groups, respectively; and onset time of nephrotoxicity was 9.86 ± 13.22 days for colistin and 10.68 ± 9.93 days for polymyxin B group. Colistin treatment had a lower cost per patient compared to the cost for polymyxin B treatment (USD $13,389.37 vs. USD $13,639.16, respectively). Conclusion We found no difference between 30-day mortality and nephrotoxicity between groups; however, colistin proved to be the best option from a pharmacoeconomic point of view.

Effect of polymyxin B-containing regimens on renal function for the treatment of carbapenem-resistant Enterobacteriacea mediastinitis

ABSTRACT A retrospective cohort study, were evaluated: polymyxin B plus aminoglycosides or polymyxin B plus other antibiotics. Any degree of acute kidney injury occurred in 26 (86.6%) patients. The median time to acute kidney injury was 6.0 (95% CI 3-14) days in the polymyxin-aminoglycoside containing regimen group, against 27.0 (95% CI 6-42) days in the polymyxin with other antimicrobial combinations group (p = 0.03). Polymyxin B with aminoglycosides group progressed faster to any degree of renal dysfunction.

Effect of polymyxin B-containing regimens on renal function for the treatment of carbapenem-resistant Enterobacteriacea mediastinitis.

A retrospective cohort study, were evaluated: polymyxin B plus aminoglycosides or polymyxin B plus other antibiotics. Any degree of acute kidney injury occurred in 26 (86.6%) patients. The median time to acute kidney injury was 6.0 (95% CI 3-14) days in the polymyxin-aminoglycoside containing regimen group, against 27.0 (95% CI 6-42) days in the polymyxin with other antimicrobial combinations group (p=0.03). Polymyxin B with aminoglycosides group progressed faster to any degree of renal dysfunction.

Emergence of polymyxin B resistance in a polymyxin B-susceptible KPC-producing Klebsiella pneumoniae causing bloodstream infection in a neutropenic patient during polymyxin B therapy.

The emergence of resistance to polymyxins in KPC-producing Klebsiella pneumoniae isolates has been a major clinical problem. This study evaluated the molecular mechanisms associated with polymyxin B (PMB) resistance that emerged in a previously PMB-susceptible KPC-2-producing K. pneumoniae during PMB therapy for a bloodstream infection in a neutropenic patient. The first isolate (PMB-susceptible) was obtained while the patient was receiving meropenem and other isolates were recovered from 2 sets of blood cultures in different dates while the patient was receiving PMB therapy (4 of 6 blood cultures bottles yielded isolates with full PMB resistance). The population analysis profile of the first isolate revealed the growth of resistant subpopulations with PFGE profile distinct from the parental isolate but undistinguishable from those obtained in subsequent days under PMB exposure. Resistant subpopulations were obtained from all parental PMB-susceptible and in one PMB-resistant isolate recovered from the patient. The molecular mechanism observed in the hetero-resistant subpopulations (IS1-like in mgrB-promoter region, increased rstB transcription with no mutation and non-identified mechanism) differed from those found in the PMB-resistant isolates, in which no mutation or transcriptional alterations were detected. This study showed that the mechanism of resistance to PMB that emerged during PMB therapy was not related to those observed in subpopulations selected in vitro from PMB-susceptible isolates recovered from the patient. The absence of mutations in the former isolates may be due to adaptive resistance occurred because of sub-optimal PMB levels as well as amikacin and meropenem used in combination.

[Risk factors for acute kidney injury in patients treated with polymyxin B experience from 139 cases at a tertiary university hospital in Colombia]. / Factores asociados a nefrotoxicidad por polimixina B en un hospital universitario de Neiva, Colombia. 2011-2015.

BACKGROUND: The rise of infections caused by multidrug-resistant Gram negative bacilli (MDR-GNB), added to paucity of newer therapy, have led to increase polymyxin B use, despite adverse renal toxicity profile. AIM: To determine the incidence and risk factors associated to acute kidney injury (AKI) and polymyxin B use, in patients with infections caused by MDR-GNB. METHODS: A retrospective cohort, with a nested case-control study of adults who received polymyxin B for more than 48 hours at a tertiary university hospital in Colombia (2011-2015) was performed. AKI was defined by AKIN criteria. RESULTS: Of 139 patients included in our study, 102 were male with median age of 49 years (IQR:28-64). Sixty-one patients (44%) developed AKI. Independent risk factors for development of AKI included: total polymyxin B daily dose (OR = 2.19, 95% CI, 1.04-4.64); length of stay at ICU (OR = 1.03, 95% CI, 1.00-1.06); nosocomial infection (OR = 6.43, 95% CI, 2.12, -19.47); and vasopressor use (OR = 5.38, 95% CI, 2.40-12.07). Mortality was higher among AKI-patients (58.6%) compared with non-AKI patients (25.6%) (p = 0.001). CONCLUSION: In this study, the rate of AKI associated to polymyxin B use was greater than reported in studies from last decade, and associated with increased mortality. AKI associated to polymyxin B use is likely multifactorial and aggravated by the critically ill state of patients suffering nosocomial infections caused by mdr-gnb.

Medicamentos tópicos para otite externa aguda / Topical medicines for acute external otitis

CONTEXTO: Otite externa aguda é uma inflamação que ocorre na orelha externa ­ pavilhão e canal auditivos. Essa condição clínica é caracterizada pelo acometimento da pele e do tecido subcutâneo, sendo a infecção bacteriana a principal causa. O paciente com essa doença tem inflamação no local, acompanhada de intensa dor e secreção. Além disso, experimenta dificuldades de audição, que deixam de existir com a cura da condição clínica. São alternativas terapêuticas para pacientes com otite externa aguda a assepsia (remoção de cerume e limpeza local), aplicação tópica de antibióticos, anti-inflamatórios esteroides e anestésicos, além da administração por via oral de analgésicos e antibióticos. Há no Brasil diversas apresentações farmacêuticas registradas para o tratamento da otite externa aguda. Contudo, nenhuma delas integra a Relação Nacional de Medicamentos Essenciais ­ RENAME. PERGUNTA: Qual alternativa terapêutica é mais eficaz/efetiva e segura para o tratamento de pacientes com otite externa aguda? EVIDÊNCIAS CIENTÍFICAS: Evidências clínicas: foi realizada revisão sistemática para sintetizar as evidências disponíveis sobre eficácia/efetividade e segurança de alternativas terapêuticas para o tratamento de pacientes com otite externa aguda. Foram incluídos dois estudos que avaliam alternativas terapêuticas disponíveis no Brasil. Um dos estudos aponta que a utilização de ciprofloxacino 2 mg/mL se mostrou mais eficaz em curar a doença em menos tempo que a associação entre polimixina B 10.000 UI, neomicina 3,5 mg/mL, hidrocortisona 10 mg/mL. O outro estudo concluiu que tanto ciprofloxacino 2 mg/mL associado a hidrocortisona 10 mg/mL quanto polimixina B 10.000 UI, neomicina 3,5 mg/mL, hidrocortisona 10 mg/mL são semelhantes em resolver o quadro de dor entre seis e sete dias. Para ampliar a análise, nova seleção de estudos foi feita incluindo a avaliação de medicamentos com equivalentes classes farmacêuticas no Brasil. Foram incluídos doze estudos. Foi notada maior eficácia da utilização de quinolona em relação à associação entre não quinolonas e anti-inflamatório esteroide em relação à cura em sete a dez dias de acompanhamento. Avaliação de custo-efetividade: foi realizada avaliação de custo-efetividade em virtude da diferença na eficácia entre quinolona e a associação entre não quinolonas e anti-inflamatório esteroide. Os preços considerados para as alternativas foram os Preços Fabrica definidos pela Câmara de Regulação do Mercado de Medicamentos ­ CMED. Foi construída árvore de decisão para avaliar o desfecho de cura clínica em sete a dez dias. O custo foi representado pelo valor monetário do medicamento e a efetividade pela cura clínica em sete a dez dias. A razão de custo-efetividade incremental de quinolona em relação à associação entre não quinolonas e anti-inflamatório esteroide foi de R$ 136,25. Esse é o valor necessário para que o tratamento com quinolona proporcione uma cura clínica a mais em relação à associação entre não quinolonas e anti-inflamatório esteroide. Avaliação de Impacto Orçamentário: Compreendendo o período entre os anos de 2017 e 2021, foram consideradas as projeções populacionais calculadas pelo IBGE, as taxas de atendimentos de pacientes com otite externa aguda e a cobertura da atenção básica pelo SUS no Brasil. Considerando a perspectiva de financiamento pelo Componente Básico da Assistência Farmacêutica, além do impacto orçamentário total, foram calculados o impacto orçamentário médio por município e por habitante. O impacto orçamentário total em cinco anos para a potencial incorporação de quinolona foi de R$ 87.362.082,52 e para a da associação entre não quinolonas e anti-inflamatório esteroide foi de R$ 16.373.657,88. Os respectivos valores médios por município foram de R$ 15.684,40 e R$ 2.939,62. O impacto orçamentário médio por habitante foi de R$ 0,4148 para quinolona e R$ 0,0778 para a associação entre não quinolonas e anti-inflamatório esteroide. DISCUSSÃO: São escassos os estudos sobre alternativas terapêuticas disponíveis no Brasil. A avaliação por classes farmacêuticas deve se dar com cautela, haja vista a pequena quantidade de estudos disponíveis e a heterogeneidade entre eles. Por meio da evidência disponível, pouco se sabe sobre os efeitos atribuídos a cada princípio ativo. Para a seleção de medicamentos antimicrobianos, pode ser importante avaliar, em vez de uma infecção isolada, um conjunto de infecções para verificar os potenciais benefícios e riscos de se optar por um determinado medicamento. RECOMENDAÇÃO DA CONITEC: A matéria será disponibilizada em Consulta Pública com recomendação preliminar desfavorável à incorporação de medicamentos tópicos para o tratamento de otite externa aguda. CONSULTA PÚBLICA: Foram recebidas três contribuições técnico-científicas e 2 contribuições de experiência ou opinião. Todas as contribuições técnico-científicas continham argumentação técnico-científica contra a recomendação inicial da Conitec. As contribuições de experiência ou opinião também foram contra a recomendação inicial da Conitec. No geral, houve evidências com potencial de alteração desta recomendação. DELIBERAÇÃO FINAL: Por recomendar a incorporação da associação entre sulfato de polimixina B 10.000 UI, sulfato de neomicina 3,5 mg/mL, fluocinolona acetonida 0,25 mg/mL e cloridrato de lidocaína 20 mg/mL, apresentada em frasco com 5 mL, para otite externa aguda. DECISÃO: Incorporar a associação de sulfato de polimixina B 10.000 UI, sulfato de neomicina 3,5 mg/mL, fluocinolona acetonida 0,25 mg/mL e cloridrato de lidocaína 20 mg/mL, apresentada em frasco com 5 mL, para otite externa aguda no âmbito do Sistema Único de Saúde ­SUS. Decisão dada pela Portaria SCTIE-MS nº 15 publicada no Diário Oficial da União (DOU) nº 58, de 24 de março de 2017, pág. 107.(AU)

Factores asociados a nefrotoxicidad por polimixina B en un hospital universitario de Neiva, Colombia. 2011-2015 / Risk factors for acute kidney injury in patients treated with polymyxin B experience from 139 cases at a tertiary university hospital in Colombia

Background: The rise of infections caused by multidrug-resistant Gram negative bacilli (MDR-GNB), added to paucity of newer therapy, have led to increase polymyxin B use, despite adverse renal toxicity profile. Aim: To determine the incidence and risk factors associated to acute kidney injury (AKI) and polymyxin B use, in patients with infections caused by MDR-GNB. Methods: A retrospective cohort, with a nested case-control study of adults who received polymyxin B for more than 48 hours at a tertiary university hospital in Colombia (2011-2015) was performed. AKI was defined by AKIN criteria. Results: Of 139 patients included in our study, 102 were male with median age of 49 years (IQR:28-64). Sixty-one patients (44%) developed AKI. Independent risk factors for development of AKI included: total polymyxin B daily dose (OR = 2.19, 95% CI, 1.04-4.64); length of stay at ICU (OR = 1.03, 95% CI, 1.00-1.06); nosocomial infection (OR = 6.43, 95% CI, 2.12, -19.47); and vasopressor use (OR = 5.38, 95% CI, 2.40-12.07). Mortality was higher among AKI-patients (58.6%) compared with non-AKI patients (25.6%) (p = 0.001). Conclusion: In this study, the rate of AKI associated to polymyxin B use was greater than reported in studies from last decade, and associated with increased mortality. AKI associated to polymyxin B use is likely multifactorial and aggravated by the critically ill state of patients suffering nosocomial infections caused by mdr-gnb.

Introducción: El surgimiento de infecciones graves causadas por bacilos gramnegativos multi-resistentes (BGN-MR), sumado a la carencia de nuevas opciones terapéuticas efectivas, ha llevado a retomar el uso de polimixina B, a pesar de su perfil de nefrotoxicidad. Objetivo: Determinar la incidencia y factores relacionados con el desarrollo de nefrotoxicidad asociada al uso de polimixina B, en pacientes adultos con infecciones causadas por BGN-MR. Materiales y Métodos: Estudio observacional, analítico, tipo cohorte histórica, con un análisis de casos y controles anidado, realizado en un hospital universitario de tercer nivel de Colombia entre 2011 y 2015, en pacientes que recibieron polimixina B intravenosa por más de 48 h. Resultados: De 139 pacientes incluidos en el estudio, 61 (44%) desarrollaron falla renal aguda por criterios AKIN. Los factores de riesgo independientes para nefrotoxicidad fueron: dosis diaria de polimixina B (OR 2,19; IC 95% 1,04-4,64), días de estancia en UCI (OR 1,03; IC 95% 1,00-1,06), presencia de infección nosocomial (OR 6,43; IC 95% 2,12-19,47) y requerimiento de fármacos vasopresores (OR 5,38; IC 95%: 2,40-12,07). Conclusión: La tasa de nefrotoxicidad observada en pacientes que recibieron polimixina B es considerable; su origen probablemente multifactorial y agravada por estado crítico de pacientes con infecciones nosocomiales por BGN-MR.

Clinical features and mortality of patients on renal replacement therapy receiving polymyxin B.

There are no clinical data for polymyxin B (PMB) in patients on renal replacement therapy (RRT). The aim of this study was to evaluate the characteristics of patients on RRT receiving PMB and to identify predictors of 30-day mortality, with special focus on dosage. A multicentre prospective cohort study including patients aged ≥18 years treated with PMB for ≥48h while on any type of RRT was performed. In total, 88 patients were evaluated, including 34 (38.6%) on continuous venovenous haemodialysis (CVVH) and 54 (61.4%) on intermittent haemodialysis. Most patients (81.8%) received recommended doses between 1.5mg/kg/day and 3.0mg/kg/day. The 30-day mortality was 51.1% (45/88 patients). There was no significant association of dose (in mg/kg) with mortality. A PMB average daily dose ≥200mg was predictive of decreased 30-day mortality in the multivariate model (hazard ratio=0.35, 95% confidence interval 0.14-0.90; P=0.03), whilst CVVH (P=0.04), higher Charlson co-morbidity index (P=0.02) and Acute Physiology and Chronic Health Evaluation (APACHE) II score (P=0.04), and Pseudomonas aeruginosa infection (P=0.001) were independent risk factors for mortality. The results were not changed by the inclusion of patient weight or dose (in mg/kg) in the model, although the latter was significantly correlated with total daily dose. This is the first clinical study to show that higher doses of PMB are associated with lower mortality in patients on RRT.

Dor em urgência odontológica: uso de anti-inflamatórios, corticoides e analgésicos em casos de pulpite aguda irreversível / Pain in dental emergency: anti inflammatory use, steroids and painkillers in cases of irreversible acute pulpitis

O objetivo deste estudo foi avaliar o uso do cetorolaco de trometamina 10mg sublingual 30 minutos antes do procedimento de biopulpectomia em pacientes com pulpite irreversível com relação à dor antes do procedimento e nas 48 horas subsequentes, a quantidade de medicação consumida no pós-operatório e tempo esperado para sua utilização. Também foi avaliada a influência da anestesia intrapulpar, o uso da automedicação analgésica antes da procura pelo atendimento e diferença entre gêneros sobre os níveis de dor pré e pós-operatória. Propôs-se avaliar também a necessidade da presença do antibiótico na medicação intracanal, comparando o Otosporin® com hidrocortisona. Participaram da pesquisa 608 pacientes que procuraram o Setor de Urgência Odontológica da Faculdade de Odontologia de Bauru ou o Setor Odontológico do Pronto Socorro Central da Prefeitura Municipal de Bauru, sendo que 34 completaram de forma adequada o protocolo previsto. Foram divididos em 4 grupos que receberam cetorolaco ou placebo como medicação pré-operatória e Otosporin® ou hidrocortisona como medicação intracanal. Foram anotados os valores de intensidade de dor, em uma escala visual analógica, antes da medicação pré-operatória, antes do atendimento, após o atendimento, 1, 2, 4, 12, 24, 48 horas após e quando houve necessidade de medicação pós-operatória para alívio da dor. Também foi anotado se o paciente havia se automedicado e qual a droga utilizada, se houve necessidade de anestesia intrapulpar, a quantidade de medicação consumida pelo paciente no pós-operatório e o tempo esperado para seu consumo. Dos resultados observou-se que os pacientes que receberam cetorolaco como medicação pré-operatória tiveram uma redução significativa da dor em 30 minutos, quando comparado ao placebo. Foi observado que o tempo necessário para a ingestão de medicamentos pós-operatórios não demonstrou diferença significativa entre os grupos, assim como na quantidade de medicação ingerida. O tempo decorrido entre a primeira e a última dose de medicação pós-operatória também não demonstrou diferença estatística. Com relação a anestesia intrapulpar, 78% dos pacientes necessitaram desta técnica, mas devido ao pequeno tamanho da amostra obtida, não foi possível correlacionar o seu uso com a utilização da medicação pós-operatória. Para os pacientes que se automedicaram previamente, não houve diferença significativa em relação à dor inicial. Quando os gêneros foram comparados, não foi possível observar uma diferença estatística significante entre eles com relação aos parâmetros estudados. Também foram descritos no trabalho os motivos de não inclusão dos 574 pacientes que foram abordados durante a realização deste estudo. Com base nos resultados, conclui-se que o cetorolaco diminuiu expressivamente o nível de dor durante a espera pelo atendimento, porém com relação ao tempo esperado pelo paciente para tomar a primeira dose de medicação pós-operatória, a última dose, a quantidade de comprimidos e a frequência de ingestão não demonstrou a mesma diferença. Também não houve diferença no nível de dor inicial entre os pacientes que se automedicaram e os que não fizeram uso dessa prática. Devido ao pequeno número da amostra, não foi possível encontrar uma correlação entre o uso da técnica anestésica intrapulpar e medicação pós-operatória, sugerindo mais estudos futuros.(AU)

The aim of this study was to evaluate the use of ketorolac tromethamine (10mg sublingual taken 30 minutes before pulpectomy in patients with irreversible pulpitis) in pain reduction immediately before the procedure and the 48 subsequent hours, postoperative consumption of analgesic drugs and time for its use. The influence of intrapulpal anesthesia, the use of analgesic self-medication prior to the demand for care and gender difference on the levels of pre- and postoperative pain was also evaluated. It was also proposed assess the need for antibiotic presence in the intracanal medicament, comparing Otosporin® with hydrocortisone. A total of 608 patients who presented to Dental Urgency Sector from Dental School of Bauru (USP) or Emergency Dental Sector from Bauru City Hall were invited to participate, and 34 completed properly planned protocol. They were distributed in 4 groups that received either ketorolac or placebo as preoperative medication and Otosporin® or hydrocortisone as intracanal medication. The rates of pain intensity were recorded by means of a visual analogue scale before pretreatment medication, immediately before the appointment, 1, 2, 4, 12, 24, 48 hours after the appointment, and when there was taken post medication for postoperative pain relief. It was also recorded if the patient had self medicated and which the drug used and, if there was need intrapulpal anesthesia, amount of ketorolac and rescue medication (paracetamol 750mg) consumed by the patient postoperative time and the waitng time for consumption. The results showed that patients receiving Ketorolac as preoperative medication had a significant reduction of pain in 30 minutes compared to placebo. It was observed that the time required for the intake of postoperative drug showed no significant difference between groups, as well as the amount of medication intake. The time elapsed between the first and last dose of postoperative medication also showed no statistical difference. Concerning intrapulpal anesthesia, 78% of patients required for this technique, but because of the small sample size obtained it was impossible to correlate their use with the use of postoperative medication. For patients who practiced self medication previously, there was no significant difference with respect to initial pain. When genders were compared, it was not possible to observe a statistically significant difference between them regarding the parameters studied. Were also described in the study the reasons of non-inclusion of 574 patients that were addressed during this study. Based on the results, it is concluded that ketorolac significantly decreased the level of pain during the waiting time, but with respect to the time length for the patient to take the first dose of postoperative medication, the last dose, the number of tablets and taken frequency did not show the same difference. There was no difference in the initial level of pain among patients who practiced self medication and those who did not use this practice. Due to the small sample size, it was not possible to find a correlation between the use of the anesthetic technique intrapulpal and postoperative medication, suggesting more future studies.(AU)