RESUMO
In Brazil, the production of KPC-type carbapenemases in Enterobacteriales is endemic, leading to widespread use of polymyxins. In the present study, 502 Klebsiella pneumoniae isolates were evaluated for resistance to polymyxins, their genetic determinants and clonality, in addition to the presence of carbapenem resistance genes and evaluation of antimicrobial resistance. Resistance to colistin (polymyxin E) was evaluated through initial selection on EMB agar containing 4% colistin sulfate, followed by Minimal Inhibitory Concentration (MIC) determination by broth microdilution. The susceptibility to 17 antimicrobials was assessed by disk diffusion. The presence of blaKPC, blaNDM and blaOXA-48-like carbapenemases was investigated by phenotypic methods and conventional PCR. Molecular typing was performed by PFGE and MLST. Allelic variants of the mcr gene were screened by PCR and chromosomal mutations in the pmrA, pmrB, phoP, phoQ and mgrB genes were investigated by sequencing. Our work showed a colistin resistance frequency of 29.5% (n = 148/502) in K. pneumoniae isolates. Colistin MICs from 4 to >128 µg/mL were identified (MIC50 = 64 µg/mL; MIC90 >128 µg/mL). All isolates were considered MDR, with the lowest resistance rates observed for amikacin (34.4%), and 19.6% of the isolates were resistant to all tested antimicrobials. The blaKPC gene was identified in 77% of the isolates, in consonance with the high rate of resistance to polymyxins related to its use as a therapeutic alternative. Through XbaI-PFGE, 51 pulsotypes were identified. MLST showed 21 STs, with ST437, ST258 and ST11 (CC11) being the most prevalent, and two new STs were determined: ST4868 and ST4869. The mcr-1 gene was identified in 3 K. pneumoniae isolates. Missense mutations in chromosomal genes were identified, as well as insertion sequences in mgrB. Furthermore, the identification of chromosomal mutations in K. pneumoniae isolates belonging from CC11 ensures its success as a high-risk epidemic clone in Brazil and worldwide.
Assuntos
Antibacterianos , Colistina , Farmacorresistência Bacteriana , Infecções por Klebsiella , Klebsiella pneumoniae , beta-Lactamases , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Brasil , Colistina/farmacologia , Colistina/uso terapêutico , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/genética , Humanos , Infecções por Klebsiella/epidemiologia , Infecções por Klebsiella/genética , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/isolamento & purificação , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus , Polimixinas/efeitos adversos , Polimixinas/farmacologia , Polimixinas/uso terapêutico , beta-Lactamases/genética , beta-Lactamases/uso terapêuticoRESUMO
Polymyxins are antibiotics developed in the 1950s. Polymyxin-induced neurotoxicity has been often described in medical literature. The same cannot be said of nephrotoxicity or tubulopathy in particular. This report describes the case of a patient prescribed polymyxin B to treat a surgical wound infection, which led to significant increases in fractional excretion of calcium, magnesium, and potassium and subsequent persistent decreases in the levels of these ions, with serious consequences for the patient. Severe hypocalcemia, hypomagnesemia, and hypokalemia may occur during treatment with polymyxin. Calcium, magnesium and potassium serum levels must be monitored during treatment to prevent life-threatening conditions.
Assuntos
Injúria Renal Aguda , Hipocalcemia , Hipopotassemia , Injúria Renal Aguda/induzido quimicamente , Humanos , Hipocalcemia/induzido quimicamente , Hipocalcemia/tratamento farmacológico , Hipopotassemia/induzido quimicamente , Magnésio/efeitos adversos , Polimixinas/efeitos adversosRESUMO
Acinetobacter baumannii is an opportunistic pathogen associated with nosocomial and community infections of great clinical relevance. Its ability to rapidly develop resistance to antimicrobials, especially carbapenems, has re-boosted the prescription and use of polymyxins. However, the emergence of strains resistant to these antimicrobials is becoming a critical issue in several regions of the world because very few of currently available antibiotics are effective in these cases. This review summarizes the most up-to-date knowledge about chromosomally encoded and plasmid-mediated polymyxins resistance in A. baumannii. Different mechanisms are employed by A. baumannii to overcome the antibacterial effects of polymyxins. Modification of the outer membrane through phosphoethanolamine addition, loss of lipopolysaccharide, symmetric rupture, metabolic changes affecting osmoprotective amino acids, and overexpression of efflux pumps are involved in this process. Several genetic elements modulate these mechanisms, but only three of them have been described so far in A. baumannii clinical isolates such as mutations in pmrCAB, lpxACD, and lpsB. Elucidation of genotypic profiles and resistance mechanisms are necessary for control and fight against resistance to polymyxins in A. baumannii, thereby protecting this class for future treatment.
Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/genética , Cromossomos Bacterianos , Farmacorresistência Bacteriana Múltipla/genética , Polimixinas/farmacologia , Saúde Pública , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/química , Acinetobacter baumannii/metabolismo , Animais , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Proteínas de Bactérias/genética , Infecção Hospitalar/microbiologia , Etanolaminofosfotransferase/metabolismo , Humanos , Lipídeo A/genética , Lipídeo A/metabolismo , Lipopolissacarídeos/metabolismo , Camundongos , Testes de Sensibilidade Microbiana , Plasmídeos/genética , Polimixinas/efeitos adversos , Polimixinas/uso terapêuticoRESUMO
Polymyxins are polypeptide antibiotics with strong action against Gram-negative bacteria. Their use was almost halted between 1970 and 1980 due to the launching of less toxic compounds. The emergence of multiresistant Gram-negative bacterial strains, mainly in patients hospitalized in intensive care units, and the absence of new antimicrobials effective against these pathogens, renewed interest in polymyxins in recent years. The major adverse effect of this class of antibiotics is nephrotoxicity. Currently, only polymyxins B and E are used in clinical practice. Polymyxin E, the compound more employed and studied, is known as colistin and is used in the form of sodium colistimethate, for the purpose of reducing its nephrotoxicity. There is no consistent data about prevalence of renal injury associated with use of the polymyxins or about the risk factors to develop nephrotoxicity with these antibiotics. The aim of this manuscript is to review the main aspects of polymyxin pharmacodynamics, to provide a better understanding about the mechanism of renal injury associated with them and to compare the different prevalences of renal injury described with the use of these antibiotics.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Antibacterianos/efeitos adversos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Rim/efeitos dos fármacos , Polimixinas/efeitos adversos , Animais , Antibacterianos/farmacocinética , Cães , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Humanos , Polimixinas/farmacocinéticaRESUMO
As polimixinas são antibióticos polipeptídeos com potente ação sobre várias bactérias gram-negativas. O seu uso foi praticamente abandonado entre 1970 e 1980, em virtude do aparecimento de drogas com menor toxicidade. Com o aparecimento de bactéria gram-negativas multirresistentes, principalmente em pacientes internados em unidades de terapia intensiva, e a ausência de novos antimicrobianos para combater esses patógenos, renovou-se o interesse pelas polimixinas nos últimos anos. O principal efeito adverso desta classe de antibióticos é a nefrotoxicidade. Atualmente, somente as polimixinas B e E são utilizadas na prática clínica. A polimixina E é conhecida como colistina e utilizada na forma de colestimetato de sódio com o intuito de reduzir sua nefrotoxicidade, sendo o composto mais utilizado e mais estudado. Não existem dados consistentes sobre a prevalência de leão renal associada ao uso das polimixinas ou sobre os fatores de risco para desenvolvimento de nefrotoxicidade desses antibióticos. A proposta deste artigo é rever os principais aspectos de farmacodinâmica das polimixinas, prover um melhor entendimento dos seus mecanismos de nefrotoxicidade e comparar as diferentes prevalências de lesão renal descritas com o uso desta classe de antibióticos.
Polymyxins are polypeptide antibiotics with strong action against Gram-negative bacteria. Their use was almost halted between 1970 and 1980 due to the launching of less toxic compounds. The emergence of multiresistant Gram-negative bacterial strains, mainly in patients hospitalized in intensive care units, and the absence of new antimicrobials effective against these pathogens, renewed interest in polymyxins in recent years. The major adverse effect of this class of antibiotics is nephrotoxicity. Currently, only polymyxins B and E are used in clinical practice. Polymyxin E, the compound more employed and studied, is known as colistin and is used in the form of sodium colistimethate, for the purpose of reducing its nephrotoxicity. There is no consistent data about prevalence of renal injury associated with use of the polymyxins or about the risk factors to develop nephrotoxicity with these antibiotics. The aim of this manuscript is to review the main aspects of polymyxin pharmacodynamics, to provide a better understanding about the mechanism of renal injury associated with them and to compare the different prevalences of renal injury described with the use of these antibiotics.
Assuntos
Animais , Cães , Humanos , Injúria Renal Aguda/induzido quimicamente , Antibacterianos/efeitos adversos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Rim/efeitos dos fármacos , Polimixinas/efeitos adversos , Antibacterianos/farmacocinética , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Polimixinas/farmacocinéticaRESUMO
BACKGROUND: There has been an increase in worldwide infections caused by carbapenem-resistant Acinetobacter. This poses a therapeutic challenge as few treatment options are available. OBJECTIVES: The aim of this study was to evaluate the efficacy and safety of polymyxins and ampicillin/sulbactam for treating infections caused by carbapenem-resistant Acinetobacter spp. and to evaluate prognostic factors. METHODS: This was a retrospective review of patients from two teaching hospitals who had nosocomial infections caused by carbapenem-resistant Acinetobacter spp. from 1996 to 2004. Diagnosis of infection was based on CDC criteria plus the isolation of Acinetobacter from a usually sterile site or from bronchoalveolar lavage. Urinary tract infections were not included. Data on demographic and clinical features and treatment were collected from medical records. Prognostic factors associated with two outcomes (mortality during treatment and in-hospital mortality) were evaluated. RESULTS: Eighty-two patients received polymyxins and 85 were treated with ampicillin/sulbactam. Multiple logistic regression analysis revealed that independent predictors of mortality during treatment were treatment with polymyxins, higher Acute Physiological and Chronic Health Evaluation II (APACHE II) score, septic shock, delay in starting treatment and renal failure. On multivariate analysis, prognostic factors for in-hospital mortality were older age, septic shock and higher APACHE II score. CONCLUSIONS: This is the first study comparing current therapeutic options for infections due to carbapenem-resistant Acinetobacter. The most important finding of the present study is that ampicillin/sulbactam appears to be more efficacious than polymyxins, which was an independent factor associated with mortality during treatment.