Profile of antimicrobial use and potential use of the defined daily dose in neonatology.

One of the measures for monitoring microbial resistance is the calculation of the defined daily dose of antimicrobial agents. For this calculation, the weight of an adult of 70 kg is used as a standard, so that application in neonatology is not possible. The aim of this study is to describe the use profile and calculate the defined daily dose (DDD) of antimicrobials in a neonatal intensive care unit (NICU) of a public hospital in the interior of Bahia, Brazil. From March 2020 to December 2021, the medical records of 712 newborns admitted to a NICU between September 2018 and June 2020 were analyzed. A total of 410 newborns diagnosed with neonatal sepsis were included. The most used antimicrobials per patient were gentamicin (408/410; 99.5%), ampicillin (407; 99.3%), amikacin (29; 7.1%) and oxacillin (21; 5.1%), with a mean (SD) treatment duration of 9.8 (3.9) days. The most commonly used combination of antimicrobials was ampicillin with gentamicin, which was used in 406 patients (99.0%). The values for neonatal DDDs were on average 26 times lower than those for adult DDDs. The neonatal DDDs were similar to those observed in other studies. Ampicilin and cefepime were the antimicrobials for which the greatest differences were observed in neonatal DDDs compared with adult DDDs, which differed mainly between maintenance doses, reflecting the lack of international standards in neonatology. Standardization of DDDs as a surveillance measure has the potential to clarify the pattern of antimicrobial use in neonatal patients worldwide and, in particular, to prevent indiscriminate use and bacterial resistance.

Extensive mycetoma in forearm, chest and neck due to Nocardia mexicana.

INTRODUCTION: Mycetoma is a chronic granulomatous inflammatory disease of the subcutaneous tissue, which affects deep structures and bone. Most cases of actinomycetoma are caused by members of the genus Nocardia. CASE PRESENTATION: Here we report the case of a 43-year-old male who presented a disseminated mycetoma on the forearm, chest and neck, characterized by enlarged and erythematous lesions through which seropurulent material drains, and numerous atrophic scars. Molecular identification was performed by 16S gene amplification and sequencing. Nocardia mexicana was identified with 100% identity. Trimethoprim-sulfamethoxazole, diaminodiphenyl sulfone and amikacin was a successful treatment after 6 months. CONCLUSIONS: Nocardia mexicana is a rare organism that causes mycetoma. We report a case of extensive mycetoma on the forearm with spread to the neck and thorax associated with manipulation of the mouth of a calf.

In vitro evaluation of human intravenous immunoglobulin in combination with antimicrobials and human serum against multidrug-resistant isolates of Acinetobacter baumannii.

The high incidence of multidrug-resistant (MDR) Acinetobacter baumannii has been a challenge for health worldwide, due to the reduction of therapeutic options, making the use of antimicrobial combinations necessary for the treatment, such as meropenem, amikacin, and colistin. Antibodies against bacterial species, mainly immunoglobulins G (IgG), are produced for acting as effector mechanisms (neutralization, opsonization, phagocytosis, and complement system activation). Some studies have demonstrated promising results of IgG in combination with antimicrobial preparations against bacterial infections, in which the direct action of IgG has restored the immune system balance. Serious problem caused by the increase of MDR A. baumannii isolates results in a constant search for therapeutic alternatives to defeat these infections. However, this study aims to verify in vitro the phagocytosis rate of the A. baumannii-infected human monocytes, as well as to analyze possible morphological changes induced by intravenous immunoglobulin G (IVIG) with human serum in association with antimicrobials. The phagocytosis rate and bacterial cell binding capacity of IVIG were determined for two A. baumannii isolates submitted to 4 mg/mL of human IVIG alone and in combination with different sub-minimum inhibitory concentrations (sub-MICs) of meropenem, amikacin, and colistin and processed for indirect immunofluorescence. Subsequently, these isolates were resubmitted and coupled with human serum and processed for scanning electron microscopy. There was no statistical difference for phagocytosis rates in the isolates tested. Bacterial isolates showed alterations in cell morphology when exposed to IVIG/human serum alone and in combination with antimicrobials such as alteration in shape, wrinkling, membrane depression, and especially cell rupture with extravasation of cytoplasmic material. The isolates visually differed in the IVIG binding to the bacterial cell, with higher fluorescence intensity, which corresponds to the highest IVIG binding, in the isolate more sensitive to meropenem, amikacin, and colistin. No differences between treatments were observed in the IVIG binding to the bacterial cell. The combined action of IVIG with meropenem, amikacin, and colistin against A. baumannii MDR isolates induced several bacterial cell damages. And when associated with human serum, a massive destruction of cells can be observed. These results may suggest the analysis of the use of IgG preparations for the treatment of A. baumannii MDR infections.

Failure to predict amikacin elimination in critically ill patients with cancer based on the estimated glomerular filtration rate: applying PBPK approach in a therapeutic drug monitoring study.

PURPOSE: The aim of this work was to integrate the Therapeutic Drug Monitoring (TDM) with the model-informed precision dosing (MIPD) approach, using Physiologically-based Pharmacokinetic/Pharmacodynamic (PBPK/PD) modelling and simulation, to explore the relationship between amikacin exposure and estimated glomerular filtration rate (GFR) in critically ill patients with cancer. METHODS: In the TDM study, samples from 51 critically-ill patients with cancer treated with amikacin were analysed. Patients were stratified according to renal function based on GFR status. A full-body PBPK model with 12 organs model was developed using Simcyp V. 21, including steady-state volume of distribution of 0.21 L/kg and renal clearance of 6.9 L/h in healthy adults. PK parameters evaluated were within the 2-fold error range. RESULTS: During the validation step, predicted vs observed amikacin clearance values after single infusion dose in patients with normal renal function, mild and moderate renal impairment were 7.6 vs 8.1 L/h (7.5 mg/kg dose); 3.8 vs 4.5 L/h (1500 mg dose) and 2.2 vs 3.1 L/h (25 mg/kg dose), respectively. However, predicted vs observed amikacin clearance after a single dose infusion of 1400 mg in critically-ill patients with cancer were 1.46 vs 1.63 (P = 0.6406) L/h (severe), 2.83 vs 1.08 (P < 0.05) L/h (moderate), 4.23 vs 2.49 (P = 0.0625) L/h (mild) and 7.41 vs 3.36 (P < 0.05) L/h (normal renal function). CONCLUSION: This study demonstrated that estimated GFR did not predict amikacin elimination in critically-ill patients with cancer. Further studies are necessary to find amikacin PK covariates to optimize the pharmacotherapy in this population. Therefore, TDM of amikacin is imperative in cancer patients.

Use of bedaquiline in spinal osteomyelitis and soft tissue abscess caused by multidrug-resistant Mycobacterium tuberculosis: A case report.

INTRODUCTION: Spinal Tuberculosis (STB) represents between 1% and 2% of total tuberculosis cases. STB management remains challenging; the first-line approach consists of medical treatment, while surgery is reserved for patients with complications. No data regarding STB treatment with bedaquiline-containing regimens are available in the literature. CASE DESCRIPTION: Herein, we report the case of a 21-year-old man from Côte d'Ivoire with a multidrug resistance STB with subcutaneous abscess. After approval of the hospital off-label drug committee, we started bedaquiline 400 mg daily for two weeks, followed by 200 mg three times per week, for 22 weeks, associated with linezolid 600 mg daily, rifabutin 450 mg daily, and amikacin 750 mg daily (interrupted after eight weeks). During treatment, we performed a weekly EKG. No QT prolongation was shown, but inverted T waves appeared, requiring several cardiological consultations and cardiac MRI, but no cardiac dysfunction was found. After 24 weeks, bedaquiline was replaced with moxifloxacin 400 mg daily. The patient continued treatment for another year. We performed another computer tomography at the end of treatment, confirming the cure. DISCUSSION: A salvage regimen containing bedaquiline proved effective in treating multidrug-resistance tuberculosis spinal infection without causing severe adverse effects. However, further studies are needed to evaluate better bedaquiline bone penetration and the correct duration of treatment with bedaquiline in MDR spinal tuberculosis.

Características microbiológicas de los pacientes con úlcera del pie diabético / Microbiologic characteristics of patients with diabetic foot ulceration

RESUMEN Introducción: Las infecciones de las úlceras del pie diabético son comunes, complejas, de alto costo y constituyen la principal causa de amputación no traumática de las extremidades inferiores. Objetivo: Identificar los microorganismos aislados para estimar tanto la sensibilidad a los antibióticos como la coincidencia entre el tratamiento empírico y los resultados microbiológicos en pacientes con úlceras del pie diabético. Métodos: Se realizó una investigación descriptiva-retrospectiva. La población de estudio estuvo constituida por 210 pacientes ingresados en el Hospital Universitario Clínico Quirúrgico "Comandante Faustino Pérez Hernández" de Matanzas entre junio de 2017 y junio de 2020. Las variables de salida fueron la frecuencia y el tipo de germen, la cantidad de gérmenes por úlcera, la sensibilidad para cada tipo de antibiótico, y el porcentaje de coincidencia entre el tratamiento empírico y el resultado microbiológico. Resultados: Se identificaron 259 gérmenes y se observaron 1,23 gérmenes por úlcera. El 62,5 por ciento de los gérmenes encontrados fueron Gram negativos, pero el germen más representado fue el Staphylococcus aureus. El 58,8 por ciento de los Staphylococcus aureus se mostraron resistentes a la meticillin. La vancomicina y el linezolid resultaron efectivos en el 100 por ciento de los Gram positivos. La amikacina fue el antibiótico más efectivo para los Gram negativos. Se observó coincidencia entre el tratamiento empírico y el resultado del antibiograma en el 27,6 por ciento de los pacientes. Conclusiones: Resulta necesario un apropiado diagnóstico microbiológico de las úlceras del pie diabético para identificar los gérmenes presentes en las lesiones y diseñar algoritmos de terapia antimicrobiana adecuados(AU)

ABSTRACT Introduction: Diabetic foot ulcer infections are common, complex, high cost and are the leading cause of non-traumatic lower extremity amputation. Objective: To identify the microorganisms isolated to estimate both the sensitivity to antibiotics and the coincidence between empirical treatment and microbiological results in patients with diabetic foot ulcers. Methods: A descriptive-retrospective investigation was performed. The study population consisted of 210 patients admitted to the University Hospital "Comandante Faustino Pérez Hernández" of Matanzas between June 2017 and June 2020. The output variables were the frequency and type of germ, the number of germs per ulcer, the sensitivity for each type of antibiotic, and the percentage of coincidence between the empirical treatment and the microbiological result. Results: A total of 259 germs were identified and 1.23 germs per ulcer were observed. The 62.5 percent of the germs found were Gram negative, but the most represented germ was Staphylococcus aureus. Of the Staphylococcus aureus, 58.8 percentwere resistant to methicillin. Vancomycin and linezolid were effective in 100 percent of Gram positives. Amikacin was the most effective antibiotic for Gram-negatives. Agreement between empirical treatment and antibiogram result was observed in 27.6 percent of patients. Conclusions: An appropriate microbiological diagnosis of diabetic foot ulcers is necessary to identify the germs present in the lesions and to design adequate antimicrobial therapy algorithms(AU)

Amikacin for the treatment of carbapenem-resistant Klebsiella pneumoniae infections: clinical efficacy and toxicity.

Infections by carbapenem-resistant Klebsiella pneumoniae (CRKp) are an increasing global threat with limited therapeutic options. Our objective was to evaluate clinical and microbiological outcomes of patients treated with amikacin for CRKp infections. We did a retrospective cohort of patients > 18 years old, with CRKp infections treated with amikacin in two tertiary care hospitals in Porto Alegre, Brazil. The impact of clinical factors, antibiotic treatment, and amikacin minimum inhibitory concentration (MIC) on patients' 30-day mortality was assessed. Microbiological clearance and nephrotoxicity (assessed by RIFLE score) were evaluated as secondary outcomes. A Cox regression analysis was done for mortality. We included 84 patients for analysis. Twenty-nine (34.5%) patients died in 30 days. Amikacin MIC values ranged from 0.125 to 8 µg/mL and did not influence on mortality, regardless of the prescribed dose of this antibiotic (P = 0.24). Bacterial clearance occurred in 17 (58.6%) of 29 patients who collected subsequent cultures. Two (16.6%) of the 12 persistently positive cultures changed the amikacin susceptibility profile from susceptible to intermediate. Twenty-nine (37.2%) patients developed acute kidney injury (AKI): risk 13, injury 11, and failure 5. Risk factors for AKI were higher baseline eGFR (P < 0.01) and combination therapy with colistin (P = 0.02). Comparing patients who received combination with colistin vs polymyxin B, AKI occurred in 60.0% vs 20.6%, respectively, P < 0.01. Fifteen of the 16 (16.6%) patients who developed renal injury or failure were receiving colistin. In conclusion, amikacin was an effective treatment for CRKp infections. Within susceptible range, amikacin MIC values did not influence on clinical outcomes. Combination therapy of amikacin and colistin was highly nephrotoxic and should be used with caution.

Gérmenes bacterianos aislados con frecuencia en úlceras flebostáticas de pacientes ingresados / Bacterial germs frequently isolated in phlebostatic ulcers of admitted patients

Introducción: Las úlceras flebostáticas constituyen una patología importante en la práctica médica diaria en todos los niveles de asistenciales; después del dolor y del edema, las úlceras de los miembros inferiores representan el tercer problema más común en las consulta de angiología. Objetivo: Caracterizar los gérmenes bacterianos aislados con frecuencia en las úlceras flebostáticas de los pacientes ingresados. Métodos: Se realizó un estudio descriptivo retrospectivo de corte transversal en 60 pacientes ingresados por diagnóstico de úlceras flebostáticas entre julio de 2016 y junio de 2017. A todos se les hizo cultivo microbiológico de la lesión con el respectivo antibiograma. Se tuvieron en cuenta las variables: tipo de úlcera flebostática, gérmenes bacterianos aislados, antibióticos analizados in vitro y patrón de sensibilidad antibiótica. Se calcularon las frecuencias absolutas y relativas. Resultados: Se encontró un predominio de úlceras varicosas (67 por ciento). El germen bacteriano que más se aisló fue Pseudomas spp. (41,7 por ciento), con más frecuencia en las úlceras varicosas que en las postrombóticas (47,5 por ciento vs. 30 por ciento). Los mejores porcentajes de sensibilidad in vitro se mostraron ante los siguientes antibióticos: Clindamicina (100 por ciento), Tobramicina (79,2 por ciento), Ciprofloxacino (78,4 por ciento), Amikacina (68,4 por ciento), Cotrimoxazol (68,2 por ciento), Cefepime (67,6 por ciento), Doxiciclina (66,7 por ciento), Cloranfenicol (60 por ciento), Meropenem (62,1 por ciento), Penicilina G (57 por ciento) y Aztreonam (55,9 por ciento). Conclusiones: Pseudomas spp. fue el germen bacteriano que más se aisló en los pacientes con úlceras varicosas y postrombóticas; además, se manifestó sensibilidad a 11 de los 23 antibióticos que se probaron in vitro en más del 50 por ciento de los aislados a los que se enfrentaron(AU)

Introduction: Phlebostatic ulcers are an important pathology in daily medical practice at all levels of care; after pain and edema, lower limb ulcers are the third most common problem in angiology consultations. Objective: Characterize frequently isolated bacterial germs in the phlebostatic ulcers of admitted patients. Methods: A descriptive, cross-sectional, retrospective study was conducted in 60 patients admitted due to a diagnosis of phlebostatic ulcers from July 2016 to June 2017. It was made a microbiological cultivation of the lesion with the respective antibiogram to all the patients. Variables were taken into account, like: type of phlebostatic ulcer, isolated bacterial germs, antibiotics tested in vitro and antibiotic sensitivity pattern. The absolute and relative frequencies were calculated. Results: A predominance of varicose ulcers (67 percent) was found. The most isolated bacterial germ was Pseudomasspp. (41.7 percent), and it was more often in varicose ulcers than in post-thrombotic ulcers (47.5 percent vs. 30 percent). The best percentages of in vitro sensitivity were shown against the following antibiotics: Clindamycin (100 percent), Tobramycin (79.2 percent), Ciprofloxacin (78.4 percent), Amikacin (68.4 percent), Cotrimoxazol (68.2 percent), Cefepime (67.6 percent), Doxycycline (66.7 percent), Chloramphenicol (60 percent), Meropenem (62.1 percent), Penicillin G (57 percent), Aztreonam (55.9 percent). Conclusions: Pseudomasspp. was the most isolated bacterial germ in patients with varicose and post-thrombotic ulcers; in addition, sensitivity was present in 11 of the 23 antibiotics that were tested in vitro in more than 50 percent of the isolates they faced(AU)

Caseous stomatitis caused by Pseudomonas aeruginosa in Boa constrictor amarali

Background: Pseudomonas aeruginosa is a bacterium that belongs to the microbiota of snakes, but it may also be anopportunistic pathogen and contaminate humans through fecal contact, bites, and injuries. In snakes, this microorganismmay present high pathogenicity at certain conditions and have been associated with high morbidity and mortality. Reportsof infection of Boa constrictor by this pathogen are rare. Thus, this study aimed to describe the P. aeruginosa oral infection in a snake specimen (Boa constrictor amarali), approaching the isolation and identification of the infectious agentsinvolved, the antimicrobial sensitivity and resistance, and the therapeutic protocol adopted.Case: A free-living adult female specimen of Boa constrictor amarali (Amarals boa), with no described previous history was rescued in an urban area by the Environmental Police. Clinical evaluations showed structures of caseous aspectin the oral cavity, with hyperemia spots in the mucosa. Samples of these lesions were sent for mycological examination,and fungal forms were not found. Samples were collected for isolation and culture. The antimicrobial susceptibility of theisolated microorganisms was determined by the modified Kirby-Bauer disk diffusion method. P. aeruginosa was isolatedand showed susceptibility to amikacin, gentamicin, and polymyxin-B; intermediate susceptibility to azithromycin, and ciprofloxacin; and resistance to cephalexin, ceftiofur, chloramphenicol, and enrofloxacin. The treatment consisted of cleaningof the oral cavity, local infiltration of lidocaine for debridement of the caseous area that were later cauterized with iodine.Systemic antibiotic therapy was used, with intramuscular administration of amikacin (5 mg/kg) for the first dose and (2.5mg/kg) for the other doses with intervals of 72 h, and oral administration of metronidazole...(AU)

Caseous stomatitis caused by Pseudomonas aeruginosa in Boa constrictor amarali

Background: Pseudomonas aeruginosa is a bacterium that belongs to the microbiota of snakes, but it may also be anopportunistic pathogen and contaminate humans through fecal contact, bites, and injuries. In snakes, this microorganismmay present high pathogenicity at certain conditions and have been associated with high morbidity and mortality. Reportsof infection of Boa constrictor by this pathogen are rare. Thus, this study aimed to describe the P. aeruginosa oral infection in a snake specimen (Boa constrictor amarali), approaching the isolation and identification of the infectious agentsinvolved, the antimicrobial sensitivity and resistance, and the therapeutic protocol adopted.Case: A free-living adult female specimen of Boa constrictor amarali (Amaral’s boa), with no described previous history was rescued in an urban area by the Environmental Police. Clinical evaluations showed structures of caseous aspectin the oral cavity, with hyperemia spots in the mucosa. Samples of these lesions were sent for mycological examination,and fungal forms were not found. Samples were collected for isolation and culture. The antimicrobial susceptibility of theisolated microorganisms was determined by the modified Kirby-Bauer disk diffusion method. P. aeruginosa was isolatedand showed susceptibility to amikacin, gentamicin, and polymyxin-B; intermediate susceptibility to azithromycin, and ciprofloxacin; and resistance to cephalexin, ceftiofur, chloramphenicol, and enrofloxacin. The treatment consisted of cleaningof the oral cavity, local infiltration of lidocaine for debridement of the caseous area that were later cauterized with iodine.Systemic antibiotic therapy was used, with intramuscular administration of amikacin (5 mg/kg) for the first dose and (2.5mg/kg) for the other doses with intervals of 72 h, and oral administration of metronidazole...

Bedaquilina para pacientes com tuberculose resistentes à rifampicina, multirresistentes e extensivamente resistentes a medicamentos / Bedaquiline for tuberculosis-resistant patients rifampicin, multi-resistant and extensively resistant to medicines

INTRODUÇÃO: A tuberculose (TB), conhecida anteriormente como tísica, é uma doença que pode ser causada por sete espécies do gênero do complexo Mycobacterium sendo a mais importante, do ponto de vista de saúde pública, a M. tuberculosis. Globalmente cerca de 10 milhões de pessoas tiveram TB no ano de 2018. No Brasil, em 2018, foram diagnosticados 72.788 casos novos de TB o que representa uma incidência de 34,8 casos por 100 mil habitantes. A TB pode ser classificada como pulmonar e extrapulmonar, sendo a primeira forma mais prevalente. Além disso, a TB pode ser classificada conforme a resistência à medicamentos, tais como: RR-TB, MDR-TB e XDR-TB. PERGUNTA DE PESQUISA: A bedaquilina (BDQ) associada ao tratamento padrão para pacientes adultos com RR-TB, MDR-TB ou XDR-TB, é mais eficaz, efetiva e segura comparado ao tratamento padrão utilizado pelo SUS (levofloxacino, moxifloxacino, amicacina, capreomicina, etionamida, terizidona, linezolida, clofazimina, pirazinamida, etambutol, isoniazida, rifampicina e paraminossalicílico) ou placebo? TECNOLOGIA: Bedaquilina (Sirturo®). EVIDÊNCIAS CIENTÍFICAS: A revisão sistematizada recuperou nove estudos (uma revisão sistemática [RS] com meta-análise em rede [network meta-analysis - NMA], um ensaio clínico randomizado [ECR] com dois relatos e sete estudos de coorte [seis retrospectivas e uma prospectiva]). A RS, com NMA, avaliou a BDQ em comparação aos medicamentos delamanida, metronidazol, moxifloxacino e levofloxacino. A RS avaliou os desfechos conversão de cultura do escarro e aceitabilidade, e não foram verificados resultados estatisticamente significantes. Os estudos de coorte avaliaram a BDQ em comparação aos mais diversos tratamentos disponíveis para RR-TB, MDR-TB e XDR-TB. As coortes avaliaram os seguintes desfechos: sobrevida sucesso no tratamento, tratamento completo, cura, conversão da cultura do escarro e mortalidade. Os resultados não foram estatisticamente significantes na meta-análise de modelo de efeitos randomizados para todos os desfechos avaliados, porém os resultados dos efeitos fixos demostraram resultados estatisticamente significantes favorecendo o tratamento com BDQ em comparação ao tratamento sem BDQ. Vale salientar que foram realizadas análises de subgrupos com o ECR, TMC207, que avaliou eficácia e segurança da BDQ associado ao tratamento padrão em comparação ao grupo placebo associado ao tratamento padrão em até 120 semanas para os desfechos de conversão da cultura do escarro, cura e segurança (mortalidade), porém não mudaram a direção dos resultados nas duas modelagem da meta-análise. AVALIAÇÃO ECONÔMICA (AE): Os tratamentos com BDQ comparado aos tratamentos do SUS mostraram-se dominados na avaliação de custo-efetividade, para o desfecho paciente curado. Assim, os tratamentos do SUS para RR-TB, MDR-TB e XDR-TB dominaram todos os tratamentos com BDQ, ou seja, todos os tratamentos com BDQ foram menos efetivos e mais caros que os tratamentos do SUS para obter a cura dos indivíduos com RR-TB, MDR-TB e XDR-TB. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO (AIO): A AIO, para os pacientes com RR-TB, variou entre um custo incremental R$ 936 mil no caso base a uma economia de -R$ 1 milhão ao final do quinto ano no cenário alternativo; para MDR-TB variou entre uma economia de -R$44 mil no caso base a um gasto de R$ 110 mil ao final do quinto ano no cenário alternativo; e para XDR-TB variou entre um custo incremental de R$ 188 mil no caso base a R$ 4 mil no cenário alternativo ao final do quinto ano. MONITORAMENTO DO HORIZONTE TECNOLÓGICO (MHT): Cinco medicamentos foram detectados no MHT para pacientes com MDR-TB e XDR-TB (canamicina, cicloserina, sutezolida, pretomanide e protionamida). CONSIDERAÇÕES FINAIS: Há resultados conflitantes nas evidências encontradas no relatório. O ECR, analisado como de alto risco de viés (Risk of Bias 2.0) mostrou que a BDQ associada ao tratamento padrão é eficaz em comparação ao grupo de tratamento placebo associado ao tratamento padrão, porém com maior número de mortes e episódios de náusea em comparação ao grupo de tratamento sem a BDQ. Os resultados da RS, com NMA, de qualidade moderada, não demonstraram diferenças estatisticamente significantes entre as tecnologias avaliadas. Os resultados das meta-análises dos estudos de coorte de baixa qualidade metodológica (Newcastle-Ottawa Scale), em combinação com o ECR da BDQ, foram demonstrados em efeitos fixos e randomizados. Os desfechos sucesso no tratamento, tratamento completo, cura, conversão da cultura do escarro e mortalidade não foram estatisticamente significantes no modelo de efeito randomizados na meta-análise. No entanto, foram estatisticamente significantes no modelo de efeito fixos da metaanálise, e favoreceram o tratamento com BDQ em comparação aos pacientes não tratados sem BDQ. A AE demonstrou que os tratamentos com BDQ foram dominados em relação aos tratamentos disponibilizados no SUS sem BDQ, para o desfecho paciente tratado, sendo, portanto, mais custosos e menos efetivos. A AIO, para pacientes com RR-TB, variou entre R$ 936 mil no caso base a uma economia de -R$ 1 milhão no cenário alternativo ao final do quinto ano, para MDRTB variou entre uma economia de -R$44 mil no caso base a um custo de R$ 110 mil ao final do quinto ano no cenário alternativo e para XDR-TB variou entre um custo adicional de R$ 188 mil no caso base a um custo adicional de R$ 4 mil ao final do quinto ano no cenário alternativo. RECOMENDAÇÃO PRELIMINAR DA CONITEC: A Conitec, em sua 87ª reunião ordinária, realizada nos dias 03 e 04 de junho de 2020, deliberou que a matéria fosse disponibilizada em consulta pública com recomendação preliminar favorável à incorporação no SUS da bedaquilina para pacientes com tuberculose resistente à rifampicina (RR-TB), a tuberculose multirresistente (MDR-TB) e para tuberculose extensivamente resistente a medicamentos (XDR-TB), condicionada ao monitoramento e apresentação dos dados de vida real, efetividade e segurança, da utilização da bedaquilina pela população brasileira e conforme critérios estabelecidos em protocolo do Ministério da Saúde. CONSULTA PÚBLICA: A Consulta Pública nº 24/2020 foi realizada entre os dias 22/06/2020 a 13/07/2020. Foram recebidas 66 contribuições no total, das quais 19 (29%) foram pelo formulário para contribuições técnico-científicas e 47 (71%) pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Das 19 contribuições de cunho técnico-científico, 95% submeteram a contribuição com opinião concordando totalmente com a recomendação preliminar da comissão. Apenas uma contribuição discordou da recomendação preliminar da Conitec, mas foi uma contribuição equivocada e se tratava de outro tema de consulta pública, portanto, foi excluída da análise. Das 47 contribuições recebidas sobre experiência ou opinião, apenas 15 foram analisadas, pois 32 estavam em branco, se tratavam de outro tema ou foram preenchidas inadequadamente. As 15 contribuições remanescentes concordaram 100% com a decisão preliminar da comissão. Após a apreciação das contribuições encaminhadas na consulta pública nº 24/2020, o plenário da Conitec considerou que: I) Foi apresentado um novo preço de USD 340 da bedaquilina pela Johnson & Johnson, sendo proposto um desconto de 15% no preço utilizado no relatório de recomendação preliminar (USD 400); II) Foram enviadas novas estimativas de incidência para pacientes com tuberculose multirresistente, bem como evidência de possíveis limitações na análise de impacto orçamentário; III) A nova análise de impacto orçamentário, utilizando os novos parâmetros enviados na consulta pública, aponta para economia de recursos na população com tuberculose multirresistente e um custo incremental com tuberculose resistente à rifampicina e tuberculose extensivamente resistente no cenário sem taxa de difusão gradual da bedaquilina (100% no primeiro ano de incorporação). No entanto, ao adotarmos o cenário com taxa difusão gradual da bedaquilina, 30% no primeiro ano de incorporação a 70% no quinto ano, os resultados mudam e proporcionam economia de recursos para pacientes com tuberculose resistente à rifampicina e um custo incremental para pacientes com tuberculose multirresistente e tuberculose extensivamente resistente. RECOMENDAÇÃO FINAL DA CONITEC: Os membros da Conitec presentes na 89ª reunião ordinária, no dia 05 de agosto de 2020, deliberaram por unanimidade recomendar a incorporação da bedaquilina para pacientes com tuberculose resistentes à rifampicina, multirresistentes e extensivamente resistente a medicamentos, condicionado a apresentação de dados de vida real e conforme preconizado pelo Ministério da Saúde. Foi assinado o Registro de Deliberação nº 538/2020. DECISÃO: Incorporar a bedaquilina para pacientes com tuberculose resistentes à rifampicina, multirresistentes e extensivamente resistente a medicamentos, condicionado a apresentação de dados de vida real e conforme preconizado pelo Ministério da Saúde, no âmbito do Sistema Único de Saúde - SUS, conforme Portaria nº 36, publicada no Diário Oficial da União nº 168, seção 1, página 77, em 01 de setembro de 2020.

Infecciones del tracto urinario en neonatos sin explicación. Hiperbilirrubinemia: Prevalencia y predictivo factores de riesgo / Urinary tract infections in unexplained neonatal hyperbilirubinemia: Prevalence and predictive risk factors

Introduction: Urinary tract infections (UTIs) are widespread clinical disorder among early neonates. Neonates with UTIs were susceptible to higher rates of morbidity and mortality, particularly when presented with hyperbilirubinemia. Early diagnosis may help in complete recoveryrather than being threatened in terms of complications. The study aimed at determining the prevalence and predictive risk factors of UTIs in neonates with an unexplained hyperbilirubinemia. Method: A cross-sectional study was carried out in the NICU of Aswan University Hospital, Egypt from August 2018 to February 2019. The study was conducted on 140 newborns who were diagnosed with indirect hyperbilirubinemia in the first 4 weeks of life after exclusion of unrelated criteria. Demographic and clinical data were collected by an interview questionnaire. Biochemical markers including bilirubin level, CBC, urine analysis and urine cultures and sensitivity were determined. Results: The prevalence rate of UTIs in the studied newborns was 25%. Escherichia -coli was the dominant organism isolated. Amikacin was the most common antibiotic sensitive to the isolates. There was a significant difference between the UTI positive and negative neonates in the univariate analysis regarding some studied variables. While, an increase in the number of WBCs in the blood (OR = 6.90, P = 0.001), small for gestational age (OR = 4.07, P = 0.021), prolonged phototherapy (OR = 3.50, P = 0.034), and presence of maternal complications (OR = 2.92, P = 0.001) were statistically associated with a positive urine culture in multivariate analysis. Conclusions and recommendations: The prevalence rate of UTIs was 25%. The study indicated the importance of routine screening of UTI (urine culture) as part of the clinical assessment of unexplained hyperbilirubinemia in neonates with an increase in the number of WBCs in their blood, small for gestational age, prolonged duration of phototherapy, and neonates born from mothers who had a history of obstetric complications

Comparison of two different anti-infectious approaches after high-dose chemotherapy and autologous stem cell transplantation for hematologic malignancies in a 12-year period in British Hospital, Uruguay.

Autologous stem cell transplant (ASCT) is a widely used and safe procedure to treat mostly hematologic diseases. These patients are at risk of infectious complications, which represents a major cause of morbidity and it is the second cause of mortality. This retrospective 12-year analysis of the incidence, type, and severity of infections in 266 consecutive unselected ASCT patients at our institution provides novel information addressing this issue. We included 266 ASCT procedures. Patients included in the 2006-2013 period are referred to as group 1 (ciprofloxacin prophylaxis and ceftazidime-amikacin as empirical antibiotics), and those in the 2013-2017 period are group 2 (levofloxacin prophylaxis and meropenem as empirical antibiotics). The incidence of febrile neutropenia was 72% in group 1 and 86.2% in group 2 (p = 0.004). The majority of infectious episodes were associated with fever of unknown origin: 55% in group 1 and 59% in group 2. Febrile of unknown origin episodes were 82.6% in group 1 and 80% in group 2. Significant differences between both groups were found in age, hypogammaglobulinemia, and advanced disease at ASCT. No differences were found between groups regarding the most common agent documented in positive blood cultures (Gram+ were 66.6% in group 1 and 69% in group 2 (p = 0.68)). Mortality within 100 days of transplant was low, 1.87%. Regardless of the prophylactic regimen used, most patients experience febrile episodes in the ASCT setting, fever of unknown origin is the most common infection complication, and Gram+ agents are prevalent in both groups. Mortality rates were low. According to our results, ASCT is a safe procedure and there is no clear benefit in favor of levofloxacin versus ciprofloxacin prophylaxis. Both anti-infectious approaches are acceptable, yielding similar outcomes.

Population Pharmacokinetics of Amikacin Administered Once Daily in Patients with Different Renal Functions.

The aim of this work was to evaluate the pharmacokinetics of amikacin in Mexican patients with different renal functions receiving once-daily dosing regimens and the influence of clinical and demographical covariates that may influence the optimization of this antibiotic. A prospective study was performed in a total of 63 patients with at least one determination of amikacin plasma concentration. Population pharmacokinetic (PK) parameters were estimated by nonlinear mixed-effects modeling; validations were performed for dosing recommendation purposes based on PK/pharmacodynamic simulations. The concentration-versus-time data were best described by a one-compartment open model with proportional interindividual variability associated with amikacin clearance (CL) and volume of distribution (V); residual error followed a homoscedastic trend. Creatinine clearance (CLCR) and ideal body weight (IBW) demonstrated significant influence on amikacin CL and V, respectively. The final model [CL (liters/h) = 7.1 × (CLCR/130)0.84 and V (liters) = 20.3 × (IBW/68)2.9] showed a mean prediction error of 0.11 mg/liter (95% confidence interval, -3.34, 3.55) in the validation performed in a different group of patients with similar characteristics. There is a wide variability in amikacin PK parameters in Mexican patients. This leads to inadequate dosing regimens, especially in patients with augmented renal clearance (CLCR of >130 ml/min). Optimization based on the final population PK model in Mexican patients may be useful, since reliability and clinical applicability have been demonstrated in this study.

Piperacillin/tazobactam plus amikacin vs. piperacilin/tazobactam: treatment for children with febrile neutropenia / Piperacilina/tazobactam más amikacina vs. piperacilina/tazobactam: tratamiento en niños con neutropenia febril

Background: Pediatric patients with febrile neutropenia usually receive a combination of broad spectrum antimicrobials. Treatment without aminoglycoside seems to have advantages. Objective: To compare the efficacy of piperacillin/tazobactam plus amikacin versus piperacillin/tazobactam. Methods: Randomized, open label, controlled clinical trial. Sample size for an efficacy of 55%, and delta of 25%; 80 episodes were required for each group. Selection criteria were patients with febrile neutropenia, candidates to receive parenteral antimicrobial treatment; they were randomized to one of two groups, piperacillin/tazobactam plus amikacin (Group A), or piperacillin/tazobactam (Group B). The outcomes were failure, adverse events and death. Mantel-Haenszel chi squaretest and exact Fisher test were used. Reduction of relative and absolute risk (RRR and ARR), 95% confidence intervals (CI 95%) and number needed to treat (NNT) were calculated. Results: 88 Episodes were analyzed in group A and 76 in group B. There was no statistical difference in general characteristics of patients or type of infections. There was not significant statistical difference in: failure 31.8% group A, 30.2% group B (RR 1.05, CI 95% 0.66-1.66, p = 0.86), or adverse events (one in each group). The RRR was 1.5%, and ARR 2%, with a NNT of 67. Conclusion: Piperacillin/tazobactam without amikacin was as effective as combination therapy in pediatric patients with febrile neutropenia.

Introducción: los pacientes pediátricos con neutropenia febril habitualmente reciben una combinación de antimicrobianos de amplio espectro. La terapia sin aminoglucósido parece tener ventajas. Objetivo: comparar la eficacia de piperacilina/tazobactam más amikacina frente a la de piperacilina/tazobactam. Métodos: ensayo clínico controlado aleatorizado. Tamaño de muestra para una eficacia de 55%, y delta de 25%; se calcularon 80 episodios por grupo. Fueron seleccionados pacientes con neutropenia febril, candidatos a recibir antimicrobiano parenteral; se aleatorizaron a recibir piperacilina/tazobactam más amikacina (grupo A) o piperacilina/tazobactam (grupo B). Los desenlaces fueron falla, eventos adversos y muerte. Se emplearon las pruebas Chi cuadrada de Mantel-Haenszel y exacta de Fisher. Se calculó la reducción de riesgo relativo y absoluto (RRR y RRA), intervalos de confianza 95% (IC 95%) y número necesario a tratar (NNT). Resultados: se analizaron 88 episodios en el grupo A y 76 en el grupo B. No hubo diferencias estadísticas en características generales ni en el tipo de infecciones. No se encontró diferencia significativa en: falla 31.8% grupo A, 30.2% grupo B (RR 1.05, IC 95% 0.66-1.66, p = 0.86), ni en los eventos adversos (uno en cada grupo). La RRR fue de 1.5%, RRA de 2%, con un NNT de 67. Conclusión: la terapia con piperacilina/tazobactam sin amikacina fue tan efectiva como la terapia combinada para pacientes pediátricos con neutropenia febril.

Population pharmacokinetics of amikacin in patients with pediatric cystic fibrosis.

INTRODUCTION: Amikacin is commonly used in patients with pediatric cystic fibrosis (CF) for the treatment of pulmonary exacerbations. Amikacin efficacy is related to maximum plasma concentration/minimum inhibitory concentration (Cmax/MIC) ratio >8. Pharmacokinetic data in patients with pediatric CF are scarce. The aim of this study was to develop a population pharmacokinetic (PopPK) model describing amikacin disposition in patients with pediatric CF. METHODS: CF patients under 18 years of age with pulmonary exacerbation who received amikacin were enrolled. Patients received different amikacin regimens (30 mg-1 kg-1 day-1 every 8, 12, or 24 hours) depending on the patient's status and hospital protocols. Amikacin serum levels were obtained for therapeutic drug monitoring. PopPK model was developed using MONOLIX Suite-2018R1 (Lixoft). RESULTS: A total of 39 patients (114 amikacin concentrations) were included in this study. Population estimates for the elimination rate constant (k) and the volume of distribution (V) were 0.541 hours-1 and 0.451 L/kg, respectively. Between-subject and between-occasion variability were 53% and 16.5% for k and 31% and 22% for V, respectively. Bodyweight was a significant covariate associated with V. Based on simulations, almost 70% of the patients receiving 30 mg-1 kg-1 day-1 every 24 hours would achieve a Cmax/MIC ratio >8 which is an appropriate therapeutic goal while no patient in the other two groups (Q8 and Q12) would achieve that objective. CONCLUSIONS: The regimen of 30 mg-1 kg-1 day-1 every 24 hours more adequately fulfilled the therapeutic target for amikacin. Although all our patients had good clinical results and a good adverse-events profile, further studies are necessary to redefine the optimal treatment strategy.

Multirresistencia de Escherichia coli y Klebsiella pneumoniae provenientes de pacientes con infección del tracto urinario adquirida en la comunidad / Escherichia coli and Klebsiellap neumoniae multiresistance from patients with urinary tract infection acquired in the community

Introducción: El incremento de la multirresistencia bacteriana constituye un problema de salud pública a nivel internacional. Objetivos: Determinar la susceptibilidad antimicrobiana y los patrones de multirresistencia en cepas de Escherichia coli y Klebsiella pneumoniae aisladas de urocultivos. Métodos: Se realizó un estudio descriptivo retrospectivo en el Centro Municipal de Higiene, Epidemiología y Microbiología, municipio Güines, provincia Mayabeque, Cuba, en el periodo comprendido de enero a diciembre de 2017. El estudio incluyó 250 cepas de Escherichia coli y 62 de Klebsiella pneumoniae aisladas e identificadas de muestras de orina de pacientes con infección del tracto urinario adquirida en la comunidad. La susceptibilidad antimicrobiana fue evaluada con el método de difusión en agar empleado la técnica de Kirby Bauer. Resultados: En Escherichia coli se observó niveles de resistencia superiores al 60 por ciento a los antimicrobianos ácido nalidíxico, cefotaxima, trimetoprim - sulfametoxazol y ceftazidima. La nitrofurantoína y la amikacina presentaron 88,8 por ciento y 83,8 por ciento de efectividad, respectivamente. Se apreció en Klebsiella pneumoniae altos valores de resistencia a ceftazidima, trimetoprim - sulfametoxazol y ácido nalidíxico. Amikacina, presentó niveles de sensibilidad de un 71 por ciento. La resistencia a las cefalosporinas de tercera generación se detectó en 78 (31,2 por ciento) de Escherichia coli y 26 (41,9 por ciento) de Klebsiella pneumoniae. De los aislados de Escherichia coli 143 (57,2 por ciento) y Klebsiella pneumoniae 35 (56,4 por ciento) presentaron multidrogoresistencia. Conclusiones: Existe la circulación de cepas resistentes a cefalosporinas de tercera generación y multidrogorresistentes causantes de infecciones de las vías urinarias adquiridas en la comunidad y se informa sobre los antibióticos (nitrofurantoína y amikacina) que podrían ser utilizados para combatirlas de forma empírica en esta área geográfica(AU)

Introduction: The increase of bacterial multiresistance constitutes a public health problem at the international level. Objectives: To determine antimicrobial sensitivity and multiresistance patterns in strains of Escherichia coli and Klebsiellapneumoniae isolated from urine cultures. Methods: A retrospective, descriptive study was conducted at the Municipal Center for Hygiene, Epidemiology and Microbiology, Güines municipality, Mayabeque Province, Cuba, in the period from January to December, 2017. The study included 250 Escherichia coli and 62 Klebsiellapneumoniae strains isolated and identified from urine samples from patients with urinary tract infection acquired in the community. Antimicrobial sensitivity was evaluated with the method of diffusion in agar using Kirby Bauer´s technique. Results: In Escherichia coli, resistance levels higher than the 60% were observed in antimicrobial nalidixic acid, cefotaxime, trimethoprim-sulfamethoxazole and ceftazidime. Nitrofurantoin and amikacin presented 88.8 percent and 83.8 percent of effectiveness, respectively. High values of resistance to ceftazidime, trimethoprim-sulfamethoxazole and nalidixic acid were present in Klebsiellapneumoniae. Amikacin presented sensitivity levels of 71 percent. Resistance to third-generation cephalosporins was detected in 78 (31.2 percent) of Escherichia coli and 26 (41.9 percent) Klebsiellapneumoniae. From the Escherichia coli and Klebsiellapneumoniae isolates, 143 (57.2 percent) and 35 (56.4 percent),respectively, presented multidrug resistance. Conclusions: There is circulation of strains which are resistant to third generation cephalosporins and multidrug resistants that cause urinary tract infections acquired in the community and there are reports on antibiotics (nitrofurantoin and amikacin) that might be used to combat them empirically in this geographical area(AU)

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.