Resistencia antimicrobiana en el siglo XXI: ¿hacia una era postantibiótica? / Antimicrobial resistance in the 21st century: towards a post-antibiotic era? / Resistência antimicrobiana no século XXI: rumo a uma era pós-antibiótica?

Resumen Desde el descubrimiento de la penicilina por Alexander Fleming en 1928, inició una era caracterizada por el desarrollo de diferentes grupos de antibióticos que permitieron el tratamiento adecuado de infecciones graves ocasionadas por bacterias que afectaban la población mundial. Sin embargo, de manera casi simultánea al desarrollo de cada clase de antibióticos, se desencadenó la emergencia de bacterias resistentes, debido en parte al uso extendido e inadecuado de estos medicamentos. Como consecuencia, el manejo de las infecciones bacterianas se ha complicado cada vez más y en la actualidad las opciones de tratamiento son pocas, sumado a que el desarrollo de nuevos antimicrobianos ha dejado de ser atractivo para la industria farmacéutica. Esta situación ha conducido a que la Organización Mundial de la Salud advierta sobre la llegada de una era postantibiótica, donde infecciones comunes o anteriormente de fácil tratamiento pueden ocasionar muertes como resultado de la resistencia bacteriana a los diferentes grupos de antibióticos. Por lo anterior, surgen preguntas sobre cómo pudo ser originada esta situación y qué soluciones son necesarias para evitar la temida era, preguntas que tratan de ser respondidas en el presente ensayo, mediante el abordaje de aspectos relacionados no solo con los microorganismos, sino también con contextos sociales, económicos e incluso políticos, que influyen en el aumento de la resistencia antimicrobiana y dificultan su control.

Abstract Alexander Fleming's discovery of penicillin in 1928 marked the beginning of an era characterized by the development of different groups of antibiotics that allowed the proper treatment of serious infections caused by bacteria that affected the world population. However, the development of each class of antibiotics almost simultaneously triggered the emergence of resistant bacteria, due in part to the widespread and inappropriate use of these medicines. As a result, managing bacterial infections has become increasingly complicated and currently there are few treatment options, added to the fact that the development of new antimicrobials is no longer attractive to the pharmaceutical industry. This situation has led the World Health Organization to warn of the arrival of a post-antibiotic era, where common or previously easily treated infections could cause deaths as a result of bacterial resistance to several groups of antibiotics. Therefore, questions arise about how this situation could have come to be and what solutions are needed to avoid the dreaded post-antibiotic era, questions that we attempt to answer in this paper by addressing aspects related not only to microorganisms, but also to social, economic and even political contexts, which influence the increase of antimicrobial resistance and hinder its control.

Resumo Desde a descoberta da penicilina por Alexander Fleming em 1928, iniciou-se uma era caracterizada pelo desenvolvimento de diferentes grupos de antibióticos que permitiram o tratamento adequado de infecções graves causadas por bactérias que afetavam a população mundial. No entanto, quase simultaneamente ao desenvolvimento de cada classe de antibióticos, foi desencadeado o surgimento de bactérias resistentes, devido parcialmente ao uso generalizado e inadequado desses medicamentos. Como consequência, o tratamento de infecções bacterianas tornou-se cada vez mais complicado e atualmente existem poucas opções para fazê-lo, além de que o desenvolvimento de novos antimicrobianos deixou de ser atrativo para a indústria farmacêutica. Essa situação levou a Organização Mundial da Saúde a alertar sobre a chegada de uma era pós-antibiótica, na qual as infecções comuns ou previamente tratadas com facilidade podem causar mortes como resultado da resistência bacteriana a diferentes grupos de antibióticos. Portanto, surgem questões sobre como se originou essa situação e quais soluções são necessárias para evitar a era temida. Este ensaio tenta responder essas questões, abordando aspectos relacionados não apenas aos microrganismos, mas também aos contextos sociais, econômicos e até políticos, que influenciam o aumento da resistência antimicrobiana e dificultam seu controle.

Time-kill assay and post-antibiotic effect of acetone extract from the stem bark of Canarium odontophyllum against Methicillin-resistant Staphylococcus aureus Mu50 strain

Canarium odontophyllum Miq. is an indigenous fruit found in Sarawak, Malaysia. Methicillin-resistant Staphylococcusaureus (MRSA) is a deadly pathogen that causes to hospital (health-care-acquired MRSA [HA-MRSA]) and community(CA-MRSA) infections worldwide. Vancomycin has been the therapeutic drug of choice against MRSA, but unfortunatelythis pathogen has developed some degree of resistance to vancomycin. This research aimed to evaluate the antimicrobialactivity of the stem bark extract of C. odontophyllum against MRSA Mu50 strain. The minimum inhibitory concentration(MIC) and minimum bactericidal concentration (MBC) of extract and vancomycin against MRSA were determined usingbroth microdilution method and streak plate method. The rate of killing by the extract against Mu50 strain was determinedusing time-kill assay (TKA) at ×1 MIC, ×2 MIC, ×4 MIC, and ×8 MIC of the extract. The post-antibiotic effect (PAE) timeof extract ×10 MIC against MRSA was also investigated. The extract exhibited bacteriostatic effect against MRSA Mu50strain with MIC and MBC values of 1.563 mg/ml and 3.125 mg/ml, respectively. From TKA analysis, the extract was notcapable of killing the Mu50 strain at ×1 MIC and ×2 MIC, but it displayed bactericidal activity at higher concentrationstested. Interestingly, the acetone stem bark extract of C. odontophyllum at ×4 MIC showed comparable time-killingkinetic with the standard antibiotic in the study. The PAE time of the extract was 3.6 ± 0.51 h against MRSA Mu50compared to vancomycin at 2.4 ± 0.68 h. In conclusion, the stem bark acetone extract from C. odontophyllum demonstratedconcentration-dependent bactericidal effect with prolonged PAE time against MRSA Mu50 strain.

Colistín en la era post-antibiótica / Colistin in the post-antibiotic era

One of the most important features of the post-antibiotic era in the late 20th century is the resurgence of colistin for the treatment of extensively drug resistant gram-negative bacteria (XDR). Colistin is a narrow spectrum anti-biotic, active against microorganisms with clinical significance such as Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae. Nowadays its toxicity is lower, partly explained by better pharmaceuticals and management of the critically ill patients. However, there has been much confusion regarding the dosage of the drug, its name and labeling, therefore, experts have recommended using a common language about this polymyxin. The lack of PK/PD studies for colistin is perhaps the main weakness of this area of knowledge, even though the before mentioned approach has contributed with new ways to manage and calculate the dose of this antimicrobial. Indeed, the efficiency of colistin in association with a second agent in reducing mortality has not been demonstrated.

El resurgimiento de colistín para el tratamiento de bacilos gramnegativos extensamente resistentes a antimicrobianos a fines del siglo pasado es una de las características más importantes de la era post-antimicrobiana. Su espectro es reducido y cubre microorganismos con importancia clínica como Acinetobacter baumannii, Pseudomonas aeruginosa y Klebsiella pneumoniae. En contraste a lo que se vio en el pasado, la toxicidad descrita en la actualidad es menor, en parte explicado por las mejores preparaciones farmacéuticas y la optimización del manejo del paciente crítico. Mucha confusión se ha generado respecto a la dosificación del fármaco, debido a la distinta denominación, etiquetado y sugerencias de los laboratorios, a pesar de que el compuesto es el mismo. Por lo anterior, el llamado de los expertos es a utilizar un lenguaje común para referirnos a esta polimixina. Los estudios modernos de PK/PD han contribuido con nuevas formas de administrar y calcular las dosis de este antimicrobiano; no obstante, falta mucho por desarrollar en esta área que se posiciona como su gran debilidad. A pesar que la terapia combinada se sustenta sobre una base teórica lógica, no se ha demostrado que la asociación de colistín con un segundo agente logre disminuir la mortalidad.

Postantibiotic Effects of Photodynamic Therapy Using Erythrosine and Light Emitting Diode on Streptococcus mutans

Dental caries, the most common oral disease, is a multifactorial disease caused by interactions among bacteria within the dental plaque, food, and saliva, resulting in tooth destruction. Streptococcus mutans has been strongly implicated as the causative organism in dental caries and is frequently isolated from human dental plaque. Photodynamic therapy (PDT) is a technique that involves the activation of photosensitizer by light in the presence of tissue oxygen, resulting in the production of reactive radicals capable of inducing cell death. Postantibiotic effect (PAE) is defined as the duration of suppressed bacterial growth following brief exposure to an antibiotic. In this study, the in vitro PAE of PDT using erythrosine and light emitting diode on S. mutans ATCC 25175 was investigated. The PAE of PDT for 1 s irradiation and 3 s irradiation were 1.65 h and 2.1 h, respectively. The present study thus confirmed PAE of PDT using erythrosine on S. mutans.

In vitro pharmacodynamic properties of colistin methanesulfonate and amikacin against Pseudomonas aeruginosa.

Purpose: In vitro pharmacodynamic properties of colistin methanesulfonate and amikacin were investigated by studying time-kill kinetics and post-antibiotic effect (PAE) against strains of Pseudomonas aeruginosa isolated from patients with cystic fibrosis. Method: Synergy was investigated at 0.5×, 1× and 5× MIC of antibiotics using time-kill curve method. PAEs were determined by the standard viable counting method where bacteria in the logarithmic phase of growth were exposed for 1 h to the antibiotics at 1× or 20× MIC, alone and in combinations. Synergy and additive effects were detected at 1×MIC, at 24 h. Results: Some of the strains produced an earlier synergistic effect at 12 h. No antagonism was observed. Colistin methanesulfonate and amikacin produced PAEs 1.16 ± 0.10 to 2.25 ± 0.16 h and 0.96 ± 0.15 to 2.69±0.32 h, respectively. When the antibiotics were used in combination the PAEs were prolonged to a value of 3.88±0.25 h. Consequently, the Conclusions: Findings of this study may play useful role in selecting the appropriate combinations when a single agent is inadequate, and may have important information for optimizing the dose intervals.

Postantibiotic effects and postantibiotic sub-MIC effects of tilmicosin, erythromycin and tiamulin on erythromycin-resistant Streptococcus suis

The postantibiotic effects (PAEs) and postantibiotic sub-MIC effects (PA SMEs) of tilmicosin, erythromycin and tiamulin on erythromycin-susceptible and erythromycin-resistant strains of Streptococcus suis (M phenotype) were investigated in vitro. Tilmicosin and tiamulin induced significantly longer PAE and PA SME against both erythromycin-susceptible and erythromycin-resistant strains than did erythromycin. The durations of PAE and PA SMEs were proportional to the concentrations of drugs used for exposure. The PA SMEs were substantially longer than PAEs on S. suis (P<0.05) regardless of the antimicrobial used for exposure. The results indicated that the PAE and PA SME could help in the design of efficient control strategies for infection especially caused by erythromycin-resistant S. suis and that they may provide additional valuable information for the rational drug use in clinical practice.

Cell surface hydrophobicity and adherence of a strain of group B streptococci during the post-antibiotic effect of penicillin / Hidrofobicidade de superfície celular e aderência de uma estirpe de estreptococos do grupo B durante o efeito pós-antibiótico da penicilina

The minimum inhibitory concentration and post-antibiotic effects of an antimicrobial agent are parameters to be taken into consideration when determining its dosage schedules. The in vitro post-antibiotic effects on cell surface hydrophobicity and bacterial adherence were examined in one strain of group B streptococci. Exposure of the microorganism for 2 h at 37 °C to 1 x MIC of penicillin induced a PAE of 1.1 h. The cell surface charge of the Streptococcus was altered significantly during the post-antibiotic phase as shown by its ability to bind to xylene: hydrophobicity was decreased. Bacterial adherence to human buccal epithelial cells was also reduced. The results of the present investigation indicate that studies designed to determine therapeutic regimens should evaluate the clinical significance of aspects of bacterial physiology during the post-antibiotic period.

A concentração mínima inibitória e os efeitos pós-antibióticos (EPA) de um agente antimicrobiano são parâmetros que devem ser levados em consideração quando da determinação do esquema de dosagem. Os efeitos pós-antibióticos in vitro na hidrofobicidade de superfície celular e na aderência foram pesquisados em uma amostra de estreptococos do grupo B. A exposição do microrganismo por 2 h a 37 °C a 1 x CMI de penicilina induziu um EPA de 1,1 h. A carga da superfície celular da bactéria foi alterada significativamente durante a fase pós-antibiótica revelada através da capacidade de ligação ao xileno, indicada pela diminuição da hidrofobicidade. A aderência bacteriana às células epiteliais bucais humanas também foi reduzida. Os resultados da investigação demonstram que estudos clínicos destinados a determinar regimes terapêuticos deveriam incluir o conhecimento da fisiologia bacteriana durante o período pós-antibiótico.

Investigation of morphological characteristics, membrance potential and membance patency in Escherichia coli following ciprofloxacin exposure / 中国临床药理学与治疗学

AIM: To study the changes of bacterial ultrastructure, membrance potential and membrance patency of Escherichia coli during the postantibiotic effect after exposure to gatifloxacin and ciprofloxacin in order to investigate the mechanisms of PAE. METHODS: During the Postantibiotic effect after exposure to gatifloxacin and ciprofloxacin, the aliquots were taken from the bacterial culture at regular intervals. Then the fluorescence microscope was used to observe changes in bacterial ultrastructure and at the same time we studied the changes of membrance potential and membrance patency in Escherichia coli during the postantibiotic effect by flow cytometry in conjunction with fluorescent probes. RESULTS: The PAE phase characterized by filament formation after exposure to gatifloxacin by fluorescence microscopy,yet no significant changes in membrance potential and membrance patency of Escherichia coli were observed. CONCLUSION: Gatifloxacin and ciprofloxacin can induce filamentation, and this change is indifferent with membrance potential and membrance patency of Escherichia coli.