PRESIDENTE
Eduardo Savio
SECRETARIO CIENTÍFICO
Julio Medina
Comité de Resistencia a Antibacterianos
Asociación Panamericana de Infectología
Punta del Este, 7 de Abril de 2011 –Día Mundial de la Salud
Auspiciado por: APUA, OPS y API
Esta declaración es consiguiente a la Declaración de Guadalajara del 1º de Mayo de 2001.
La resistencia bacteriana se ha agudizado en esta última década (2001-2011) dificultando la elección de antibacterianos (comúnmente llamados antibióticos), tanto para el tratamiento de infecciones adquiridas en la comunidad, como para aquellas originadas en el ámbito hospitalario.
En los últimos años se han incrementado las infecciones por bacterias multi-resistentes, también conocidas por la prensa como las “superbacterias”, causantes de una elevada mortalidad.
La resistencia bacteriana representa ya una amenaza para la salud pública de América Latina. Por este motivo, expertos en enfermedades infecciosas de la región hacen un llamado a que gobiernos, industria, profesionales de la salud y la sociedad civil realicen acciones concertadas para contener la resistencia a los
antibacterianos y salvaguardar estos importantes medicamentos para las futuras generaciones.
Fundamentos
Infecciones Hospitalarias
En este ámbito, el riesgo de adquirir infecciones producidas por cepas multi-resistentes o extremadamente resistentes se incrementa en función de: El indudable desarrollo técnico y científico que ha llevado a mejoras en las posibilidades de vida, especialmente en prematuros, personas de la tercera edad y en pacientes con diferentes compromisos, determinando una población hospitalaria con mayor riesgo de morbilidad y mortalidad. El lapso de internación de los pacientes. El incremento de maniobras invasivas (Ej.: ventilación mecánica o colocación de catéteres urinarios, intravenosos o intraarteriales) especialmente en las unidades de cuidados intensivos. El incremento de la colocación de elementos protésicos (reemplazos óseos, marcapasos, “stents” coronarios, etc.) Incremento en medios hospitalarios de bacilos gram-negativos con múltiples mecanismos de resistencia (betalactamasas de espectro extendido, hiperproductores de betalactamasas cromosómicas y especialmente nuevas y múltiples carbapenemasas que afectan a uno de los últimos recursos en antibióticos disponibles: los carbapenemes (ej. imipenem, meropenem…). El preocupante incremento de la resistencia a fluoroquinolonas (ej.ciprofloxacina, etc.) en Acinetobacter baumannii-calcoaceticus, Pseudomonas aeruginosa y recientemente en Klebsiella pneumoniae. Entre los gram-positivos, el aumento de resistencia a vancomicina y nuevos antibióticos como linezolid o daptomicina, en estafilococos y enterococos, principales causantes de infecciones graves de alta morbilidad y mortalidad en el medio hospitalario.
Infecciones en la Comunidad
En los últimos años se han incrementado las infecciones por estas bacterias multi-resistentes en la comunidad en pacientes sin relación con el medio hospitalario. El ejemplo más conspicuo son las cepas de Staphylococcus aureus adquiridas en la comunidad que son genéticamente diferentes de las clásicas productoras de infecciones hospitalarias y pueden causar desde infecciones de piel hasta graves lesiones pulmonares o en otros órganos nobles.
Existen otros ejemplos de microorganismos comunitarios resistentes a los antibacterianos empleados para el tratamiento de las infecciones más frecuentes: El incremento en la frecuencia de aislamiento de bacilos gram-negativos resistentes en pacientes comunitarios. Preocupa la pérdida de actividad de las fluoroquinolonas para infecciones urinarias y respiratorias. Es también preocupante la aparición de infecciones por Clostridium difficile, principal productor de diarreas por uso y/o abuso de antibióticos. El notable incremento de la resistencia a macrólidos y azálidos en neumococos (una de las causas más frecuente de infecciones respiratorias) y otros gram-positivos.
Acciones necesarias hacia un cambio
Si bien la resistencia a los antibióticos es una preocupación global, en el contexto de América Latina se suman varios problemas que acentúan su gravedad: La permanente escasez en muchos países de recursos provenientes de los presupuestos nacionales para salud, lo que es reflejado por la carencia en número y calidad de recursos estructurales, humanos (médicos, microbiólogos, enfermeros, farmacéuticos, etc.) y de gestión. La pobreza que continúa siendo dramática y con ella un problema grave para la transmisión de infecciones debido principalmente al
hacinamiento, que no solamente ocurre en el ámbito domiciliario, sino muchas veces en el propio hospital. Además, la falta de recursos para adquirir los antibióticos es uno de los factores que se asocia con la interrupción precoz de los tratamientos y la dosificación sub-óptima, ambos asociados con el incremento de la resistencia bacteriana. Déficit en la información y formación especializada en enfermedades infecciosas, microbiología y epidemiología. Necesidad de facilitar cursos de formación académica de buenas prácticas clínicas para personal médico, de laboratorio, de enfermería y administrativos. Pocos hospitales cuentan con un servicio de epidemiología hospitalaria y personal con la formación adecuada. La ausencia en la mayor parte de nuestros hospitales de Comités de Infecciones y/o los de Uso Racional de Antibióticos , que son indispensables para el uso correcto y racional de antibióticos en un hospital, siendo imprescindible que funcionen en coordinación en un marco formal y productivo, así como debidamente reconocidos y respaldados por la Autoridad Sanitaria local.
Relación con Agropecuaria y Veterinaria
En los países de América Latina con alto nivel de producción ganadera y de granja no hay vigilancia suficiente sobre el abuso de antibióticos usados en forma masiva con fines no terapéuticos. Las encuestas recientes en América Latina evidencian un aumento en el consumo de antibióticos dirigidos a mascotas recetados por veterinarios. El empleo excesivo de algunos antibióticos como rufloxacina y enrofloxacina dio lugar a E.coli resistentes a todas las fluoroquinolonas. Deberían incrementarse las acciones conjuntas entre el sector agropecuario, médicos veterinarios y los dedicados a medicina humana. Es importante establecer criterios sobre el tiempo del tratamiento y las clases de antibióticos permitidos para uso en animales, de forma que se reduzca la resistencia a antibióticos de importancia crítica para la medicina humana.
El problema de las migraciones y viajes
Las corrientes migratorias desde centros rurales de un mismo país o países vecinos hacia grandes centros urbanos producen: El traslado de bacterias y otros microorganismos de frecuencia y con resistencia regional a dichos centros. La exposición de los migrantes a la adquisición de genes codificados de resistencia que abundan en las grandes ciudades por el uso excesivo de antibacterianos.
La adquisición y portación de viajeros provenientes de distintos países del mismo u otros continentes de bacterias con genes de resistencia que no existían en el país que reside el viajero, es otra de las causas que incrementa la resistencia a los antibióticos.
Calidad de Laboratorios de Microbiología
Sin perjuicio de las evaluaciones de resistencia realizadas por algunos programas de control de resistencia internacionales, éstas no cubren la mayor parte de laboratorios de un país y sus resultados pueden no reflejar la realidad local.
Es necesario estimular a las Sociedades de Infectología y Microbiología locales a realizar encuestas y controles de calidad externos a los fines de garantizar la calidad de las pruebas de sensibilidad a los antibacterianos y sería conveniente que los Ministerios de Salud respaldaran estas medidas creando mecanismos eficientes para difundir la información obtenida sobre la resistencia, con el fin de mejorar la prescripción médica y la gestión en servicios de salud, incluyendo educación médica, guías de tratamiento, formularios hospitalarios y listados nacionales de medicamentos.
Vigilancia y control de la utilización de antibacterianos
A pesar de que algunos países lograron controlar la venta de antibacterianos sin receta, el problema sigue sin resolverse en muchos países de nuestro continente. Hacer énfasis sobre la regulación sanitaria de los países, promover la legislación sobre la prescripción de antibióticos y dispensación exclusivamente con receta y en farmacias, sancionando a los responsables de los canales de comercialización que no la cumplen. Estimular la vigilancia del consumo de antibióticos a nivel nacional.
Calidad
Estimular el fortalecimiento de las entidades reguladoras nacionales para el control de la calidad de los antibióticos, incluyendo en éstos la potencia y bioequivalencia de las formulaciones originales, copias y genéricos, en los casos que corresponda.
Vacunación
Debe promoverse la vacunación contra neumococos, Haemophilus influenzae y meningococos para disminuir su incidencia, y así disminuir la emergencia de resistencia en los mismos
Información Hacer cumplir estándares éticos coherentes en toda la región para la relación entre la industria farmacéutica y el personal de salud, con el fin de promover el uso prudente de los antibióticos. Aumentar la calidad y nivel de la información dirigida al público sobre el problema de la resistencia a los antibióticos, y la necesidad de consumirlos sólo con prescripción médica y cumplir el tratamiento indicado. Para ello es necesario involucrar activamente al sector médico y farmacéutico, los Ministerios de Salud y principalmente a los medios de comunicación.
Este año, el Día Mundial de la Salud fue dedicado al problema de la resistencia a antibacterianos, lo cual puede representar una buena oportunidad para dar ímpetu a las acciones necesarias para contener este grave problema en América Latina.
API José María Casellas
APUA Aníbal Sosa
OPS Pilar Ramón-Pardo
Past President API Sergio Cimerman
Agradecemos la colaboración de los revisores de esta declaración, Dres Mirta Quinteros, Gabriel Gutkind, Gabriel Levy Hara, Hélio Vasconcellos Lopes, Juana Ortellado, María Isabel Fernández, Anahí Dreser y Gabriela Tomé
viernes, 10 de junio de 2011
jueves, 9 de junio de 2011
Brote de Escherichia coli productor de toxina Shiga O104:H4 en Alemania
Eurosurveillance. Volúmen 16, Nº 22, 2 junio de 2011
(http://www.eurosurveillance.org)
• Descripción del brote
Desde principios de mayo de 2011, se notificaron 470 casos de síndrome urémico hemolítico (SUH) al Instituto Robert Koch (RKI) de Alemania.
Del total de los casos, 273 (58%) tuvieron confirmación de laboratorio de su asociación con la infección de STEC.
Los casos de SUH fueron notificados en todos los estados de Alemania, pero la mayor frecuencia (66%) se observó en 5 estados del norte del país. Posteriormente, casos de SUH fueron comunicados por Dinamarca, Gran Bretaña, Francia, Holanda, Noruega, Austria, España, Suecia, Suiza y Estados Unidos. La mayoría de los casos registrados fuera de Alemania tuvieron como vínculo epidemiológico el viaje a ese país.
La curva epidemiológica muestra 1-2 casos de SUH entre 1 al 8 de mayo, incrementándose la incidencia en los días siguientes, alcanzándose el máximo el día 19 de mayo con 39 casos de SUH notificados. Actualmente, si bien continúa la notificación de casos, se observa un descenso marcado en la incidencia.
La mayoría de los pacientes fueron mayores de 20 años (88%) y de sexo femenino (71%). De las 13 muertes producidas, 9 tuvieron SUH y las restantes confirmación de la infección de STEC por laboratorio.
• Descripción de la cepa
La cepa STEC asociada al brote corresponde al serotipo O104:H4, toxina Shiga 2 (stx2)-positiva, intimina (eae)-negativa, enterohemolisina (ehxA)-negativa. La misma es resistente a telurito de potasio, por lo tanto desarrolla en placas de agar CT-SMAC y tiene actividad de β-glucuronidasa.
La cepa presentó además los siguientes factores de virulencia correspondientes a la categoría de Escherichia coli enteroagregativa (EAEC): aatA (gen transportador de proteínas ABC); aggR (gen regulador de los genes del plásmido Vir); aap (gen de la proteína secretada - dispersina); aggA (gen de la subunidad fimbrial AAF/I); aggC (gen del operón de la fimbria AAF/I).
La cepa es resistente a los siguientes antibióticos: Ampicilina, Amoxicilina/Äc. clávulánico, Piperacilina/Sulbactam, Piperacilina/Tazobactam, Cefuroxima, Cefuroxima-Axetil, Cefoxitina, Cefotaxima, Ceftacidima, Cefpodoxima, Estreptomicina, Ac. Nalidíxico, Tetraciclina, Trimetoprima/Sulfametoxazol. La cepa además presenta β-lactamasa TEM-1+.
Por MLST correspondió al siguiente tipo: ST678 (adk6, fumC6, gyrB 5, icd 136, mdh 9, purA 7, RecA 7)
El genoma de cepa implicada en el brote ha sido secuenciado (disponible en ftp://ftp.genomics.org.cn/pub/Ecoli_TY-2482) y presenta un tamaño de aproximadamente 5.2 Mb. El análisis de la secuencia indicó que esta bacteria es un STEC del serogrupo O104 que tiene un 93% de similitud con la cepa EAEC 55989, la cual fue aislada en la República Central de África y reconocida como causal de casos severos de diarrea. La nueva cepa ha adquirido, por transferencia horizontal, secuencias específicas que parecen ser similares a aquellas involucradas en los mecanismos de patogenicidad de la colitis hemorrágica y del síndrome urémico hemolítico.
• Resultados preliminares del estudio caso-control
Los resultados preliminares del estudio epidemiológico caso-control, realizado por el RKI y las autoridades de salud de Hamburgo, muestran que los pacientes afectados en el presente brote consumieron significativamente más tomates crudos, pepinos, y lechuga, que los controles pareados. Sin embargo, otros alimentos no pueden ser excluidos como fuentes de infección.
El RKI y las autoridades de salud de Hamburgo, recomendaron un mayor cuidado en el manejo de frutas y vegetales, y para el área afectada del norte de Alemania, no consumir tomates crudos, pepinos y lechugas, además de las prácticas higiénicas habituales. Es de vital importancia que todas aquellas personas con diarrea, cumplan con prácticas estrictas de higiene de manos, especialmente si están en contacto con niños pequeños o individuos inmunocomprometidos, además de buenas prácticas de higiene en el manejo de los alimentos.
• Situación en Argentina
Ante el alerta por la situación del brote en Alemania y su diseminación a otros países, se fortalecerá la vigilancia de las infecciones por STEC en todo el país a través de la Red Nacional de Diarreas y Patógenos Bacterianos de Transmisión Alimentaria y las Unidades Centinela de SUH. En ese marco, el Ministerio de Salud de la Nación recomienda la importancia de la higiene personal, la utilización de agua segura y el cuidado en la elaboración de los alimentos, como herramientas al alcance de todos para prevenir enfermedades. Para tal fin, ha elaborado un sitio web http://aguasegura.msal.gov.ar/ con consejos y recomendaciones para que todas las personas puedan aplicar en su vida cotidiana y mantenerse saludables.
Servicio Fisiopatogenia, INEI-ANLIS “Dr. Carlos G. Malbrán”, 3 de junio de 2011.
Contacto: Dra. Marta Rivas mrivas@anlis.gov.ar; Bqca. Isabel Chinen ichinen@anlis.gov.ar
Tools for Tracking Antibiotic Resistance
Naomi Lubick
Posted: 05/23/2011; Environmental Health Perspectives. 2011;119(5):a214-a217. © 2011 National Institute of Environmental Health Sciences
Abstract and Introduction
Introduction
When a team of researchers from Sweden first started measuring chemicals in a river near Patancheru, India, they found shocking concentrations of drugs flowing downstream—for example, levels of the potent antibiotic ciprofloxacin greater than those found in the blood of humans taking the drug. A major source of these drugs was treated wastewater from pharmaceutical manufacturing plants that was discharged into the river and surrounding environs, as Joakim Larsson and his colleagues from the University of Gothenburg reported several years ago.[1] An update published in PLoS ONE [2] now links the drugs with downstream development of microbes with genetic resistance to multiple antibiotics typically used to treat human illness.
The researchers found snippets of genetic material in bacteria from river sediments downstream of the treatment plant that conferred resistance not only to ciprofloxacin, a fluoroquinolone, but also to betalactams, aminoglycosides, sulfonamides, and other classes of antibiotics. Several genes that provide resistance to ciprofloxacin and have the ability to transfer between different bacteria were extremely common at some of the sampling sites.[2]
What if the bacteria in Patancheru could develop ways to survive the daily onslaught of ciprofloxacin, most likely over the course of years in their river environment, and ended up passing on their new genetic resistance to pathogenic bacteria that could be a threat to human health? Although Larsson's team has yet to catalog antibiotic resistance in the local population, people in the region are continually exposed to resistant microbes as they use the river water for agriculture and everyday home life. "This is a huge scary experiment in nature," Larsson says.
Just how isolated these kinds of drug "hot spots" are remains unknown, although researchers have pressed for global monitoring of antibiotic use and resistance for the past several decades, across disciplines as diverse as clinical medicine and ecotoxicity. Bringing together these fields reflects the breadth of challenges in tracking antibiotic resistance, but new technologies and ideas hold promise for the near future.
Overcoming a Lack of Coordination
"Misuse of antibiotics is obviously what creates the basic factors that produce drug resistance," says Mario Raviglione, director of the World Health Organization (WHO) department charged with tuberculosis control; this is true in both the developing and developed worlds. And despite educational campaigns by the U.S. Centers for Disease Control and Prevention (CDC)[3] and others aimed at improving clinicians' use of antibiotics, overprescribing remains a problem for multiple reasons.[4] Moreover, patient compliance—for example, taking the full course of prescribed antibiotics—can be lax, which leads to the evolution of more antibiotic-resistant pathogens.
Agricultural use of human drugs adds to the threat of drug resistance. After World War II, antibiotics started to be used for purposes such as growth promotion in livestock. Since then, antibiotics—and in some cases, the genes for resistance to multiple drugs—have been found on industrial cattle, swine, and shrimp farms,[5,6,7,8] measured on chicken skins in grocery stores,[9] and even detected in apple orchards sprayed with drugs originally intended for human use.[10]
For World Health Day in April 2011 the WHO chose the theme of the global spread of antibiotic resistance, marking a little over a decade since the organization first called for patient and doctor guidelines to protect antibiotics from becoming obsolete.[11] A document issued by the WHO in 2001 put forth a series of recommendations for patients and the general community, prescribers and dispensers, hospitals, agricultural enterprises, national governments and health systems, and drug developers and promoters.[12] However, in general "very few countries, if any, have made a comprehensive effort to do any of the measures included in the older guidelines," says Raviglione, who led preparations for World Health Day 2011. "Why are countries not picking them up? Lack of resources? Their health systems are not strong enough? The cost of drugs?"
On 7 April 2011 the organization released updated policy guidance for countries to curb the spread of antibiotic resistance in health care settings.[13] Some of this guidance is aimed at doctors and hospitals, while some is geared toward policy makers and legislators. The simple package of policy recommendations is intended to be easy for countries to adopt, Raviglione says. The WHO-level focus on antibiotic resistance issues also gives health ministers around the world a platform from which to call for funding and research attention at home.
But individual countries cannot handle this issue acting alone. During its 2009 presidency of the European Union, the Swedish government highlighted antibiotic resistance, focusing the conversation on solutions across Europe.[14] For instance, a September 2009 meeting targeted industry, policy makers, and others focused on finding incentives for creating new drugs.[15] Meanwhile, in the United States, the U.S. Food and Drug Administration (FDA) in 2010 issued draft guidance urging the judicious use of medically important antibiotics in livestock.[16] The 2011–2015 Strategic Plan of the National Antimicrobial Resistance Monitoring System, a collaboration between the FDA, CDC, U.S. Department of Agriculture, and state and local health departments, includes efforts to strengthen sampling, reporting, and international and domestic collaborative efforts.[17]
Bills aimed at addressing antibiotic resistance were introduced in 2009 in the House of Representatives[18] and the Senate,[19] but foundered. This year, Louise Slaughter (D–NY) tried again in the House, introducing H.R. 965, the Preservation of Antibiotics for Medical Treatment Act of 2011[20] on March 9. Another bill in the House, H.R. 6331, the Generating Antibiotic Incentives Now Act of 2010,[21] would create incentives to bring new antibiotics to market by speeding up the approval process. These bills have lingered in committee, even as the problem continues to grow globally.
Traveling Wild
The antibiotic drug hot spot in India is not alone: researchers have traced drugs flowing downstream from manufacturers in China and Cuba[22] and from wastewater treatment plants in the United States.[23,24] They also have identified antimicrobial resistance genetic material in treated waste effluent and tap water in Michigan and Ohio,[25,26] and researchers in Sweden recently documented multidrug-resistant Escherichia coli in the waste of migrating birds in the Arctic.[27]
Given the widespread presence of antibiotics in the natural environment,[28] it should not be a surprise that resistance is growing in wild bacteria and microbes—but is that resistance transferable to pathogens relevant to human health? Eventually the answer will most certainly be yes: Bacteria, microbes, and even fungi under stress from high concentrations of drugs might have the ability to replicate DNA snippets and possibly pass them on to other microbial species in the environment, says Dave Ussery, an associate professor of microbial genomics at the Technical University of Denmark. Transported in the integrons, plasmids, and other cellular genetic modules that confer resistance, these snippets can be traded like baseball cards among microbes.[29]
The locations and impacts of reservoirs of antibiotic resistance in the wild remain enigmatic,[30] and not only for humans. Antibiotic drugs and any acquired resistance to them might, for example, affect how microbes communicate with each other through "quorum sensing," a protein signaling feedback loop key to microbial population dynamics.[31]
But until recently, truly wild settings have garnered less interest from researchers, policy makers, and media than agricultural exposures—for example, farmers who handle pigs treated with multiple drugs and then end up with resistant strains on their skin,[32] including methicillin-resistant Staphylococcus aureus.
Researchers from the U.S. Geological Survey led by Dana Kolpin also are looking at animal waste for how much residual concentration of antibiotic it might carry and the potential impacts on microbial life if the manure is spread on agricultural fields or released accidentally. Results of Kolpin's research are not yet available, but a small-scale study by another group tracking resistance genes from biosolids and manure at two soil sites has shown the genes—with resistance for tetracycline and sulfanomides—transfer at different rates depending on soil type.[33]
Kink in the Pipeline
Another worry underlying the issue of resistance is the fact that pharmaceutical companies are not discovering new antibiotics. At least three reasons explain why the pipeline is so empty, says Ingrid Petersson, director of science relations at pharmaceutical company AstraZeneca. First, finding new pathways in microbes or pinpointing proteins to create new antibiotics is difficult, in part because of what could be considered an embarrassment of possibilities with too many unknowns. Second, she says, the regulatory environment is complicated: getting a drug through approval processes takes a long time and costs a lot of money, among other factors. And third, low prices for existing antibiotics—many of which are generics—do not encourage companies to invest in new drugs.
"Existing, older antibiotics are cheaper, which makes it difficult to achieve realistic prices for new antibiotics—prices which would provide a viable return on investment," explains Colin Mackay, director of communication and partnerships for the European Federation of the Pharmaceutical Industries and Associations, a trade organization. "Furthermore, antibiotics are only used acutely, perhaps only for a week to ten days at a time. This adds to the difficulty in making a return on investment. By comparison, treatments for chronic illnesses, say for cardiovascular or musculoskeletal conditions, are used long term, perhaps for the rest of the patient's life."
"Drug development … is one of the most critical things that we are facing," says Otto Cars, the chairman of ReAct (Action on Antibiotic Resistance), an independent think tank, and a professor of infectious diseases at Uppsala University. For gut flora that can shift readily from animal to human hosts—including Gram-negative[34] enterics such as Salmonella, Campylobacter, Klebsiella, E. coli, and Shigella—horizontal gene transfer is "moving rapidly now," he says. "These kinds of infections that Gram-negative bacteria are causing are already untreatable; even in the rich part of the world, there are totally resistant strains," he says. "The drug pipeline is particularly empty for that space."
Nevertheless, some major companies are looking into new antibiotics. For example, AstraZeneca is looking for solutions for multidrug-resistant tuberculosis.[35,36] Companies are investing money, sometimes by acquiring smaller companies that have begun the research or joining in efforts with nonprofits[37] and academic researchers. Petersson notes that the Trans Atlantic Task Force on Antimicrobial Resistance,[38] formed between the European Union and the United States as part of the 2009 EU–US Summit Declaration,[39] will present suggestions at this year's summit meeting for areas of cooperation, including incentives for industry to pursue new drug development.
The WHO, the CDC, and other national, international, and nonprofit organizations are pursuing alternative business models. Government funding, as when a federal agency invests in vaccine research, may be one option, Cars suggests. So-called advanced market commitments—where governments pledge to purchase drugs, thus guaranteeing a market—is another option. In its new policy guidance,[13] the WHO calls for global and national commitments to develop drugs and share information on the national costs of inaction, as well as "push" and "pull" incentives to reduce the inherent risks in the initial phases of research and development and to offset the risks of an uncertain market, respectively.
Crossing Boundaries
Heeding calls[40-42] for better management of the drugs currently available to doctors will require much more attention to trends of resistance. In particular, monitoring is now lacking. "If anything, we don't know enough about developing countries to understand the situation—what resistant bacteria are there? In Europe and the U.S., systems of surveillance are in place, but not in most of Africa or Asia," Raviglione says, referring to health systems, although the same holds true for environmental surveys.
Europe and the United States use far more antibiotics by volume as well as newer antibiotics compared with less affluent countries that typically use fewer and older generations of drugs, Raviglione says. That would indicate such countries might not yet have resistance to latest-generation drugs the same way Europe and the United States do. But there remains concern about the outsourcing of drug production to developing countries, especially India and China, where lax enforcement of regulations could increase the likelihood of unchecked environmental releases of active pharmaceutical ingredients—hence studies such as Larsson's work in Patancheru. The potential for impacts of manufacturing newer antibiotics in developing countries, with possible unwanted environmental releases, has not yet been studied, say the scientists contacted for this story.
Making data internationally available so that teams are tracking the same genes and species in different countries may be one avenue of attack on the issue of antibiotic resistance. Julian Davies, a professor emeritus of microbiology and immunology at the University of British Columbia, and David Graham, an environmental engineer at Newcastle University, have been working on a proposal to bring together members of the medical, environmental, and microbial research communities to address antibiotic resistance issues. If funded, their efforts could result in local centers on every continent working to monitor antibiotic resistance, look for simple solutions to preventing the spread of antibiotic-resistant microbes inside hospitals, and communicate about antibiotic resistance issues at an international scale.
The interdisciplinary breadth needed to address the many issues at hand have led to miscommunications stemming from vocabulary, Graham says. Take the word transmission, he explains: "To a physician or engineer, transmission means migration between individuals at larger scales, whereas to a microbiologist transmission is something at the micro-scale between the bacteria themselves. It took us [the diverse members of the team working on the proposal] awhile to agree upon a common language."
But microbes have few such communication barriers, and they quickly find ways to communicate resistance, as plane transit brings countries—and antibiotic resistance hot spots—closer together. Some of the global aspects of the problem can be illustrated by last year's description of NDM-1, a protein present on plasmids that confers antibiotic resistance to multiple antibiotics.[43] The mechanism of resistance traveled from hospitals in India to the United Kingdom via patients who had visited the subcontinent, presumably for cheap medical treatments, and then returned home. Furthermore, NDM-1 has appeared in tap water and wastewater outside of hospital settings in New Delhi, according to another recent report in The Lancet Infectious Diseases,[44] heightening concerns for local transmission in an urban environment.
Tools for the Trade
Ussery and his colleagues, while working to figure out antibiotic resistance transfer at a basic level, are also developing field tools for tracking antibiotic resistance genes and the microbes that carry them. The team includes computer scientists searching for simple algorithms that will let researchers make fast identifications of resistance gene sequences and resistant microbial species.
Ussery envisions a device on every doctor's desk that could take a swab from a patient and sequence the DNA from that sample. This device, connected to the Internet or with databases preloaded, could use the sequence to identify the microbes present to the genus or even species level, then spot genes they might carry for resistance to certain drugs. The test could potentially even predict the effectiveness of specific drugs in individual patients. That could guide doctors in prescribing treatment or hospitals in determining when to quarantine a patient with a particularly virulent resistant strain of an infectious disease.
"Some machines are now doing single-molecule sequencing [of bacteria] from one cell. The technology is almost there," Ussery says, citing manufacturer Oxford Nanopore's machines that can sequence a microbe from one cell as being close to market-ready.
For tracking antibiotic resistance in the field, these techniques could prove to be a massive boon, but they will have to become much less expensive than current market costs of the machines, comments Davies. The newest so-called third-generation apparatuses for identifying genetic codes in the blink of an eye may cut the cost of reading an entire genome to a tenth or less of current costs, but machines will still cost hundreds of thousands of dollars, he says, backed up by the price tag of Pacific Biosciences' first entry to the market late last year.
Searching for Simple Answers
Even a very expensive diagnostic tool would save a lot of lives, Cars says, and it would also save antibiotics for clinical use: rapid tests used on a daily basis could lead to hospital practices that save time and money while conserving antibiotics for treatment.
But new technologies are not the only tool that will be necessary to address all the threads that intertwine the problem of spreading antibiotic resistance, Cars and others say. Tracking genes in hospitals and the wild, putting policies in place to limit use of antibiotics outside of absolute necessity in a clinical setting—the wish list goes on.
And yet, in some ways, simple solutions seem to be in the offing. U.S. congressmen recently visited Denmark to learn more about that country's successful transition away from antibiotic use for growth promotion in swine.Contrary to stories about how Denmark's agricultural sector crashed after that use of antibiotics completely stopped five years ago, Frank Møller Aarestrup of the Technical University of Denmark and colleagues report the country today continues to increase its exports of pigs without the help of antibiotics, depending solely on improved animal husbandry techniques.[45]
This anecdote underscores the power of seemingly simple policy decisions to make immediate changes with promising consequences. Absent such courageous steps, "it's almost just a matter of time" before antibiotic resistance is transferred to a pathogen that matters for human health, Ussery says.
"It's an enormously frustrating situation," says Davies, who says he feels he and his colleagues talk a lot about the problem without making much headway at the larger scale. In the end, he says, solutions can only come from convincing the general public and lawmakers that the time to act is now.
References
1.Larsson DGJ, et al. Effluent from drug manufactures contains extremely high levels of pharmaceuticals. J Hazard Mat 148(3):751–755 (2007); doi:10.1016/j.jhazmat.2007.07.008.
2.Kristiansson E, et al. Pyrosequencing of antibiotic-contaminated river sediments reveals high levels of resistance and gene transfer elements. PLoS ONE 6(2):e17038 (2011); doi:10.1371/journal.pone.0017038.
3.CDC. Get Smart for Healthcare [website]. Atlanta, GA:U.S. Centers for Disease Control and Prevention (updated 25 Mar 2011). Available: http://tinyurl.com/6jyh49q [accessed 6 Apr 2011].
4.Kuehlein T, et al. Antibiotic prescribing in general practice—the rhythm of the week: a cross-sectional study. J Antimicrob Chemother 65(12):2666–2668 (2010); doi: 10.1093/jac/dkq364.
5.Smith TC, et al. Methicillin-resistant Staphylococcus aureus (MRSA) Strain ST398 is present in Midwestern U.S. swine and swine workers. PLoS ONE 4(1):e4258; doi:10.1371/journal.pone.0004258.
6.Schmidt CW. Swine CAFOs & novel H1N1 flu: separating facts from fears. Environ Health Perspect 117(9):A394–A401 (2009); doi:10.1289/ehp.117–a394.
7.Chapin A, et al. Airborne multidrug-resistant bacteria isolated from a concentrated swine feeding operation. Environ Health Perspect 113(2):137–142; doi:10.1289/ehp.7473.
8.Xuan Le T, et al, Antibiotic resistance in bacteria from shrimp farming in mangrove areas. Sci Total Environ 349(1–3):95–105 (2005); doi:10.1016/j.scitotenv.2005.01.006.
9.Vincent C, et al. Food reservoir for Escherichia coli causing urinary tract infections. Emerg Infect Dis 16(1):88–95 (2010); doi:10.3201/eid1601.091118.
10.Re: U.S. EPA Specific Exemption to the Michigan Department of Agriculture for the Use of Gentamicin, Formulated as the Unregistered Product Agry-Gent 10W, on Apples to Control Fire Blight. Letter from Lois Rossi to Brian Verhougstraete, 24 April 2008. Available: http://tinyurl.com/3e8pcw4 [accessed 6 Apr 2011].
11.WHO. World Health Organization Report on Infectious Diseases 2000. Overcoming Antimicrobial Resistance. A Message From the Director-General, World Health Organization. Geneva, Switzerland:World Health Organization (2000). Available: http://tinyurl.com/69ugd4k [accessed 6 Apr 2011],
12.WHO. WHO Global Strategy for Containment of Antimicrobial Resistance. Executive Summary. Geneva, Switzerland:World Health Organization (2001). Available: http://tinyurl.com/42xdzdx [accessed 6 Apr 2011].
13.WHO. World Health Day 2011: Policy Briefs [website]. Geneva, Switzerland:World Health Organization (2011). Available: http://tinyurl.com/3oypba8 [accessed 6 Apr 2011].
14.Cars O. Antibiotic Resistance Is a Global Public Health Threat That Can Only Be Solved By a World Working Together. Health–EU Newsletter. Brussels, Belgium:Community Public Health Programme, European Union (19 Nov 2009). Available: http://tinyurl.com/44nnyrw [accessed 6 Apr 2011].
15.The Swedish National Board of Health and Welfare. Antimicrobial Resistance—Inspiration and Exchange of Experience from EU Presidencies. Stockholm, Sweden:The Swedish National Board of Health and Welfare (Socialstyrelsen) (2010). Available: http://tinyurl.com/3bbmu5w [accessed 6 Apr 2011].
16.FDA. Draft Guidance #209. The Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals. Rockville, MD:Center for Veterinary Medicine, Food and Drug Administration, U.S. Department of Health and Human Services (28 June 2010). Available: http://tinyurl.com/352ks4e [accessed 6 Apr 2011].
17.FDA. The National Antimicrobial Resistance Monitoring System (NARMS) Strategic Plan 2011–2015. FDA-2010-N-0620. Silver Spring, MD:U.S. Food and Drug Administration, U.S. Department of Health and Human Services (updated 25 Mar 2011).
18.H.R. 1549. Preservation of Antibiotics for Human Treatment Act of 2009. Available: http://tinyurl.com/dm8by3 [accessed 6 Apr 2011].
19.S. 619. Preservation of Antibiotics for Medical Treatment Act of 2009. Available: http://tinyurl.com/4yc2852 [accessed 6 Apr 2011].
20.H.R. 965. Preservation of Antibiotics for Human Treatment Act of 2011. Available: http://tinyurl.com/6hlwzkg [accessed 6 Apr 2011].
21.H.R. 6331. Generating Antibiotic Incentives Now (GAIN) Act of 2010. Available: http://tinyurl.com/3cqfavy [accessed 6 Apr 2011].
22.Graham DW, et al. Antibiotic resistance gene abundances associated with waste discharges to the Almendares River near Havana, Cuba. Environ Sci Technol 45(2):418–424 (2011); doi:10.1021/es102473z.
23.Phillips PJ, et al. Pharmaceutical formulation facilities as sources of opioids and other pharmaceuticals to wastewater treatment plant effluents. Environ Sci Technol 44(13):4910–4916 (2010); doi:10.1021/es100356f.
24.USGS. Manufacturing Facilities Release Pharmaceuticals to the Environment [website]. Washington, DC:Toxic Substances Hydrology Program, U.S. Geological Survey, U.S. Department of the Interior (updated 12 Nov 2010). Available: http://tinyurl.com/3kxjg8x [accessed 6 Apr 2011].
25.Xi C, et al. Prevalence of antibiotic resistance in drinking water treatment and distribution systems. Appl Environ Microbiol 75(17):5714–5718 (2009); doi:10.1128/AEM.00382-09.
26.Zhang Y, et al. Wastewater treatment contributes to selective increase of antibiotic resistance among Acinetobacter spp. Sci Total Environ 407(12):3702–3706 (2009); doi:10.1016/j.scitotenv.2009.02.013.
27.Sjölund M, et al. Dissemination of multidrug-resistant bacteria into the Arctic. Emerg Infect Dis 14(1):70–72 (2008 ); doi:10.3201/eid1401.070704.
28.Rosenblatt-Farrell N. The landscape of antibiotic resistance. Environ Health Perspect 117(6):A244–A250 (2009); doi:10.1289/ehp.117-a244.
29.Aarestrup FM, ed. Antimicrobial Resistance in Bacteria of Animal Origin. Washington, DC:ASM Press (2006).
30.Allen HK, et al. Call of the wild: antibiotic resistance genes in natural environments. Nature Rev Microbiol 8(4):251–259 (2010); doi:10.1038/nrmicro2312.
31.Yim G, et al. The truth about antibiotics. Int J Med Microbiol 296(2–3)163–170 (2006); doi:10.1016/j.ijmm.2006.01.039.
32.Silbergeld EK, et al. Industrial food animal production, antimicrobial resistance, and human health. Annu Rev Public Health 29:151–169 (2008); doi:10.1146/annurev.publhealth.29.020907.090904.
33.Munir M, Xagoraraki I. Levels of antibiotic resistance genes in manure, biosolids, and fertilized soil. J Environ Qual 40(1):248–255 (2011); doi:10.2134/jeq2010.0209.
34.Gram-negative bacteria, with their thinner cell walls, tend to be more likely to develop resistance compared with thicker-walled Gram-positive bacteria.
35.AstraZeneca. Dedicated TB Research [website]. Södertälje, Sweden:AstraZeneca Global (2011). Available: http://tinyurl.com/679gx84 [accessed 6 Apr 2011].
36.AstraZeneca. Bacterial Resistance to Antibiotics is a Global Health Threat. Creative Collaboration is the Key to Successfully Meeting the Challenge [website]. Södertälje, Sweden:AstraZeneca Global (updated 1 Nov 2010). Available: http://tinyurl.com/3hr9tp4 [accessed 6 Apr 2011].
37.Resources for the Future Launches Global Antibiotic Resistance Initiative [press release]. Seattle, WA:Bill & Melinda Gates Foundation (7 Jan 2009). Available: http://tinyurl.com/6cvood4 [accessed 6 Apr 2011].
38.ECDC. Trans Atlantic Task Force on Antimicrobial Resistance—TATFAR [website]. Stockholm, Sweden:European Centre for Disease Prevention and Control (2005-2011). Available: http://tinyurl.com/5sdxlpm [accessed 6 Apr 2011].
39.Swedish Presidency of the European Union [website]. 2009 EU-U.S. Summit Declaration. Stockholm, Sweden:Communications Secretariat for Sweden's EU Presidency, Prime Minister's Office of Sweden (2009). Available: http://tinyurl.com/3u9ndv5 [accessed 6 Apr 2011].
40.ECDC. European Antibiotic Awareness Day [website]. Stockholm, Sweden:European Centre for Disease Prevention and Control (2005-2011). Available: http://tinyurl.com/5to66ko [accessed 6 Apr 2011].
41.ReAct. Antibiotic Awareness Day—Not Only in Europe [press release]. Uppsala, Sweden:ReAct, Uppsala University (22 Dec 2010). Available: http://tinyurl.com/6zmjau9 [accessed 6 Apr 2011].
42.ECDC. ECDC Marks World Health Day 2011 with Situation Update on Antimicrobial Resistance in Europe [press release]. Stockholm, Sweden:European Centre for Disease Prevention and Control (19 Apr 2011). Available: http://tinyurl.com/ykpjtlz [accessed 19 Apr 2011].
43.Kumarasamy KK, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis 10(9):597–602 (2010); doi:10.1016/S1473-3099(10)70143-2.
44.Walsh TR, et al. Dissemination of NDM-1 positive bacteria in the New Delhi environment and its implications for human health: an environmental point prevalence study. Lancet Infect Dis; doi:10.1016/S1473-3099(11)70059-7 [online 6 Apr 2011].
45.Aarestrup FM, et al. Changes in the use of antimicrobials and the effects on productivity of swine farms in Denmark. J Am Vet Med Assoc 71(7):726–733 (2010); doi:10.2460/ajvr.71.7.726.
Posted: 05/23/2011; Environmental Health Perspectives. 2011;119(5):a214-a217. © 2011 National Institute of Environmental Health Sciences
Abstract and Introduction
Introduction
When a team of researchers from Sweden first started measuring chemicals in a river near Patancheru, India, they found shocking concentrations of drugs flowing downstream—for example, levels of the potent antibiotic ciprofloxacin greater than those found in the blood of humans taking the drug. A major source of these drugs was treated wastewater from pharmaceutical manufacturing plants that was discharged into the river and surrounding environs, as Joakim Larsson and his colleagues from the University of Gothenburg reported several years ago.[1] An update published in PLoS ONE [2] now links the drugs with downstream development of microbes with genetic resistance to multiple antibiotics typically used to treat human illness.
The researchers found snippets of genetic material in bacteria from river sediments downstream of the treatment plant that conferred resistance not only to ciprofloxacin, a fluoroquinolone, but also to betalactams, aminoglycosides, sulfonamides, and other classes of antibiotics. Several genes that provide resistance to ciprofloxacin and have the ability to transfer between different bacteria were extremely common at some of the sampling sites.[2]
What if the bacteria in Patancheru could develop ways to survive the daily onslaught of ciprofloxacin, most likely over the course of years in their river environment, and ended up passing on their new genetic resistance to pathogenic bacteria that could be a threat to human health? Although Larsson's team has yet to catalog antibiotic resistance in the local population, people in the region are continually exposed to resistant microbes as they use the river water for agriculture and everyday home life. "This is a huge scary experiment in nature," Larsson says.
Just how isolated these kinds of drug "hot spots" are remains unknown, although researchers have pressed for global monitoring of antibiotic use and resistance for the past several decades, across disciplines as diverse as clinical medicine and ecotoxicity. Bringing together these fields reflects the breadth of challenges in tracking antibiotic resistance, but new technologies and ideas hold promise for the near future.
Overcoming a Lack of Coordination
"Misuse of antibiotics is obviously what creates the basic factors that produce drug resistance," says Mario Raviglione, director of the World Health Organization (WHO) department charged with tuberculosis control; this is true in both the developing and developed worlds. And despite educational campaigns by the U.S. Centers for Disease Control and Prevention (CDC)[3] and others aimed at improving clinicians' use of antibiotics, overprescribing remains a problem for multiple reasons.[4] Moreover, patient compliance—for example, taking the full course of prescribed antibiotics—can be lax, which leads to the evolution of more antibiotic-resistant pathogens.
Agricultural use of human drugs adds to the threat of drug resistance. After World War II, antibiotics started to be used for purposes such as growth promotion in livestock. Since then, antibiotics—and in some cases, the genes for resistance to multiple drugs—have been found on industrial cattle, swine, and shrimp farms,[5,6,7,8] measured on chicken skins in grocery stores,[9] and even detected in apple orchards sprayed with drugs originally intended for human use.[10]
For World Health Day in April 2011 the WHO chose the theme of the global spread of antibiotic resistance, marking a little over a decade since the organization first called for patient and doctor guidelines to protect antibiotics from becoming obsolete.[11] A document issued by the WHO in 2001 put forth a series of recommendations for patients and the general community, prescribers and dispensers, hospitals, agricultural enterprises, national governments and health systems, and drug developers and promoters.[12] However, in general "very few countries, if any, have made a comprehensive effort to do any of the measures included in the older guidelines," says Raviglione, who led preparations for World Health Day 2011. "Why are countries not picking them up? Lack of resources? Their health systems are not strong enough? The cost of drugs?"
On 7 April 2011 the organization released updated policy guidance for countries to curb the spread of antibiotic resistance in health care settings.[13] Some of this guidance is aimed at doctors and hospitals, while some is geared toward policy makers and legislators. The simple package of policy recommendations is intended to be easy for countries to adopt, Raviglione says. The WHO-level focus on antibiotic resistance issues also gives health ministers around the world a platform from which to call for funding and research attention at home.
But individual countries cannot handle this issue acting alone. During its 2009 presidency of the European Union, the Swedish government highlighted antibiotic resistance, focusing the conversation on solutions across Europe.[14] For instance, a September 2009 meeting targeted industry, policy makers, and others focused on finding incentives for creating new drugs.[15] Meanwhile, in the United States, the U.S. Food and Drug Administration (FDA) in 2010 issued draft guidance urging the judicious use of medically important antibiotics in livestock.[16] The 2011–2015 Strategic Plan of the National Antimicrobial Resistance Monitoring System, a collaboration between the FDA, CDC, U.S. Department of Agriculture, and state and local health departments, includes efforts to strengthen sampling, reporting, and international and domestic collaborative efforts.[17]
Bills aimed at addressing antibiotic resistance were introduced in 2009 in the House of Representatives[18] and the Senate,[19] but foundered. This year, Louise Slaughter (D–NY) tried again in the House, introducing H.R. 965, the Preservation of Antibiotics for Medical Treatment Act of 2011[20] on March 9. Another bill in the House, H.R. 6331, the Generating Antibiotic Incentives Now Act of 2010,[21] would create incentives to bring new antibiotics to market by speeding up the approval process. These bills have lingered in committee, even as the problem continues to grow globally.
Traveling Wild
The antibiotic drug hot spot in India is not alone: researchers have traced drugs flowing downstream from manufacturers in China and Cuba[22] and from wastewater treatment plants in the United States.[23,24] They also have identified antimicrobial resistance genetic material in treated waste effluent and tap water in Michigan and Ohio,[25,26] and researchers in Sweden recently documented multidrug-resistant Escherichia coli in the waste of migrating birds in the Arctic.[27]
Given the widespread presence of antibiotics in the natural environment,[28] it should not be a surprise that resistance is growing in wild bacteria and microbes—but is that resistance transferable to pathogens relevant to human health? Eventually the answer will most certainly be yes: Bacteria, microbes, and even fungi under stress from high concentrations of drugs might have the ability to replicate DNA snippets and possibly pass them on to other microbial species in the environment, says Dave Ussery, an associate professor of microbial genomics at the Technical University of Denmark. Transported in the integrons, plasmids, and other cellular genetic modules that confer resistance, these snippets can be traded like baseball cards among microbes.[29]
The locations and impacts of reservoirs of antibiotic resistance in the wild remain enigmatic,[30] and not only for humans. Antibiotic drugs and any acquired resistance to them might, for example, affect how microbes communicate with each other through "quorum sensing," a protein signaling feedback loop key to microbial population dynamics.[31]
But until recently, truly wild settings have garnered less interest from researchers, policy makers, and media than agricultural exposures—for example, farmers who handle pigs treated with multiple drugs and then end up with resistant strains on their skin,[32] including methicillin-resistant Staphylococcus aureus.
Researchers from the U.S. Geological Survey led by Dana Kolpin also are looking at animal waste for how much residual concentration of antibiotic it might carry and the potential impacts on microbial life if the manure is spread on agricultural fields or released accidentally. Results of Kolpin's research are not yet available, but a small-scale study by another group tracking resistance genes from biosolids and manure at two soil sites has shown the genes—with resistance for tetracycline and sulfanomides—transfer at different rates depending on soil type.[33]
Kink in the Pipeline
Another worry underlying the issue of resistance is the fact that pharmaceutical companies are not discovering new antibiotics. At least three reasons explain why the pipeline is so empty, says Ingrid Petersson, director of science relations at pharmaceutical company AstraZeneca. First, finding new pathways in microbes or pinpointing proteins to create new antibiotics is difficult, in part because of what could be considered an embarrassment of possibilities with too many unknowns. Second, she says, the regulatory environment is complicated: getting a drug through approval processes takes a long time and costs a lot of money, among other factors. And third, low prices for existing antibiotics—many of which are generics—do not encourage companies to invest in new drugs.
"Existing, older antibiotics are cheaper, which makes it difficult to achieve realistic prices for new antibiotics—prices which would provide a viable return on investment," explains Colin Mackay, director of communication and partnerships for the European Federation of the Pharmaceutical Industries and Associations, a trade organization. "Furthermore, antibiotics are only used acutely, perhaps only for a week to ten days at a time. This adds to the difficulty in making a return on investment. By comparison, treatments for chronic illnesses, say for cardiovascular or musculoskeletal conditions, are used long term, perhaps for the rest of the patient's life."
"Drug development … is one of the most critical things that we are facing," says Otto Cars, the chairman of ReAct (Action on Antibiotic Resistance), an independent think tank, and a professor of infectious diseases at Uppsala University. For gut flora that can shift readily from animal to human hosts—including Gram-negative[34] enterics such as Salmonella, Campylobacter, Klebsiella, E. coli, and Shigella—horizontal gene transfer is "moving rapidly now," he says. "These kinds of infections that Gram-negative bacteria are causing are already untreatable; even in the rich part of the world, there are totally resistant strains," he says. "The drug pipeline is particularly empty for that space."
Nevertheless, some major companies are looking into new antibiotics. For example, AstraZeneca is looking for solutions for multidrug-resistant tuberculosis.[35,36] Companies are investing money, sometimes by acquiring smaller companies that have begun the research or joining in efforts with nonprofits[37] and academic researchers. Petersson notes that the Trans Atlantic Task Force on Antimicrobial Resistance,[38] formed between the European Union and the United States as part of the 2009 EU–US Summit Declaration,[39] will present suggestions at this year's summit meeting for areas of cooperation, including incentives for industry to pursue new drug development.
The WHO, the CDC, and other national, international, and nonprofit organizations are pursuing alternative business models. Government funding, as when a federal agency invests in vaccine research, may be one option, Cars suggests. So-called advanced market commitments—where governments pledge to purchase drugs, thus guaranteeing a market—is another option. In its new policy guidance,[13] the WHO calls for global and national commitments to develop drugs and share information on the national costs of inaction, as well as "push" and "pull" incentives to reduce the inherent risks in the initial phases of research and development and to offset the risks of an uncertain market, respectively.
Crossing Boundaries
Heeding calls[40-42] for better management of the drugs currently available to doctors will require much more attention to trends of resistance. In particular, monitoring is now lacking. "If anything, we don't know enough about developing countries to understand the situation—what resistant bacteria are there? In Europe and the U.S., systems of surveillance are in place, but not in most of Africa or Asia," Raviglione says, referring to health systems, although the same holds true for environmental surveys.
Europe and the United States use far more antibiotics by volume as well as newer antibiotics compared with less affluent countries that typically use fewer and older generations of drugs, Raviglione says. That would indicate such countries might not yet have resistance to latest-generation drugs the same way Europe and the United States do. But there remains concern about the outsourcing of drug production to developing countries, especially India and China, where lax enforcement of regulations could increase the likelihood of unchecked environmental releases of active pharmaceutical ingredients—hence studies such as Larsson's work in Patancheru. The potential for impacts of manufacturing newer antibiotics in developing countries, with possible unwanted environmental releases, has not yet been studied, say the scientists contacted for this story.
Making data internationally available so that teams are tracking the same genes and species in different countries may be one avenue of attack on the issue of antibiotic resistance. Julian Davies, a professor emeritus of microbiology and immunology at the University of British Columbia, and David Graham, an environmental engineer at Newcastle University, have been working on a proposal to bring together members of the medical, environmental, and microbial research communities to address antibiotic resistance issues. If funded, their efforts could result in local centers on every continent working to monitor antibiotic resistance, look for simple solutions to preventing the spread of antibiotic-resistant microbes inside hospitals, and communicate about antibiotic resistance issues at an international scale.
The interdisciplinary breadth needed to address the many issues at hand have led to miscommunications stemming from vocabulary, Graham says. Take the word transmission, he explains: "To a physician or engineer, transmission means migration between individuals at larger scales, whereas to a microbiologist transmission is something at the micro-scale between the bacteria themselves. It took us [the diverse members of the team working on the proposal] awhile to agree upon a common language."
But microbes have few such communication barriers, and they quickly find ways to communicate resistance, as plane transit brings countries—and antibiotic resistance hot spots—closer together. Some of the global aspects of the problem can be illustrated by last year's description of NDM-1, a protein present on plasmids that confers antibiotic resistance to multiple antibiotics.[43] The mechanism of resistance traveled from hospitals in India to the United Kingdom via patients who had visited the subcontinent, presumably for cheap medical treatments, and then returned home. Furthermore, NDM-1 has appeared in tap water and wastewater outside of hospital settings in New Delhi, according to another recent report in The Lancet Infectious Diseases,[44] heightening concerns for local transmission in an urban environment.
Tools for the Trade
Ussery and his colleagues, while working to figure out antibiotic resistance transfer at a basic level, are also developing field tools for tracking antibiotic resistance genes and the microbes that carry them. The team includes computer scientists searching for simple algorithms that will let researchers make fast identifications of resistance gene sequences and resistant microbial species.
Ussery envisions a device on every doctor's desk that could take a swab from a patient and sequence the DNA from that sample. This device, connected to the Internet or with databases preloaded, could use the sequence to identify the microbes present to the genus or even species level, then spot genes they might carry for resistance to certain drugs. The test could potentially even predict the effectiveness of specific drugs in individual patients. That could guide doctors in prescribing treatment or hospitals in determining when to quarantine a patient with a particularly virulent resistant strain of an infectious disease.
"Some machines are now doing single-molecule sequencing [of bacteria] from one cell. The technology is almost there," Ussery says, citing manufacturer Oxford Nanopore's machines that can sequence a microbe from one cell as being close to market-ready.
For tracking antibiotic resistance in the field, these techniques could prove to be a massive boon, but they will have to become much less expensive than current market costs of the machines, comments Davies. The newest so-called third-generation apparatuses for identifying genetic codes in the blink of an eye may cut the cost of reading an entire genome to a tenth or less of current costs, but machines will still cost hundreds of thousands of dollars, he says, backed up by the price tag of Pacific Biosciences' first entry to the market late last year.
Searching for Simple Answers
Even a very expensive diagnostic tool would save a lot of lives, Cars says, and it would also save antibiotics for clinical use: rapid tests used on a daily basis could lead to hospital practices that save time and money while conserving antibiotics for treatment.
But new technologies are not the only tool that will be necessary to address all the threads that intertwine the problem of spreading antibiotic resistance, Cars and others say. Tracking genes in hospitals and the wild, putting policies in place to limit use of antibiotics outside of absolute necessity in a clinical setting—the wish list goes on.
And yet, in some ways, simple solutions seem to be in the offing. U.S. congressmen recently visited Denmark to learn more about that country's successful transition away from antibiotic use for growth promotion in swine.Contrary to stories about how Denmark's agricultural sector crashed after that use of antibiotics completely stopped five years ago, Frank Møller Aarestrup of the Technical University of Denmark and colleagues report the country today continues to increase its exports of pigs without the help of antibiotics, depending solely on improved animal husbandry techniques.[45]
This anecdote underscores the power of seemingly simple policy decisions to make immediate changes with promising consequences. Absent such courageous steps, "it's almost just a matter of time" before antibiotic resistance is transferred to a pathogen that matters for human health, Ussery says.
"It's an enormously frustrating situation," says Davies, who says he feels he and his colleagues talk a lot about the problem without making much headway at the larger scale. In the end, he says, solutions can only come from convincing the general public and lawmakers that the time to act is now.
References
1.Larsson DGJ, et al. Effluent from drug manufactures contains extremely high levels of pharmaceuticals. J Hazard Mat 148(3):751–755 (2007); doi:10.1016/j.jhazmat.2007.07.008.
2.Kristiansson E, et al. Pyrosequencing of antibiotic-contaminated river sediments reveals high levels of resistance and gene transfer elements. PLoS ONE 6(2):e17038 (2011); doi:10.1371/journal.pone.0017038.
3.CDC. Get Smart for Healthcare [website]. Atlanta, GA:U.S. Centers for Disease Control and Prevention (updated 25 Mar 2011). Available: http://tinyurl.com/6jyh49q [accessed 6 Apr 2011].
4.Kuehlein T, et al. Antibiotic prescribing in general practice—the rhythm of the week: a cross-sectional study. J Antimicrob Chemother 65(12):2666–2668 (2010); doi: 10.1093/jac/dkq364.
5.Smith TC, et al. Methicillin-resistant Staphylococcus aureus (MRSA) Strain ST398 is present in Midwestern U.S. swine and swine workers. PLoS ONE 4(1):e4258; doi:10.1371/journal.pone.0004258.
6.Schmidt CW. Swine CAFOs & novel H1N1 flu: separating facts from fears. Environ Health Perspect 117(9):A394–A401 (2009); doi:10.1289/ehp.117–a394.
7.Chapin A, et al. Airborne multidrug-resistant bacteria isolated from a concentrated swine feeding operation. Environ Health Perspect 113(2):137–142; doi:10.1289/ehp.7473.
8.Xuan Le T, et al, Antibiotic resistance in bacteria from shrimp farming in mangrove areas. Sci Total Environ 349(1–3):95–105 (2005); doi:10.1016/j.scitotenv.2005.01.006.
9.Vincent C, et al. Food reservoir for Escherichia coli causing urinary tract infections. Emerg Infect Dis 16(1):88–95 (2010); doi:10.3201/eid1601.091118.
10.Re: U.S. EPA Specific Exemption to the Michigan Department of Agriculture for the Use of Gentamicin, Formulated as the Unregistered Product Agry-Gent 10W, on Apples to Control Fire Blight. Letter from Lois Rossi to Brian Verhougstraete, 24 April 2008. Available: http://tinyurl.com/3e8pcw4 [accessed 6 Apr 2011].
11.WHO. World Health Organization Report on Infectious Diseases 2000. Overcoming Antimicrobial Resistance. A Message From the Director-General, World Health Organization. Geneva, Switzerland:World Health Organization (2000). Available: http://tinyurl.com/69ugd4k [accessed 6 Apr 2011],
12.WHO. WHO Global Strategy for Containment of Antimicrobial Resistance. Executive Summary. Geneva, Switzerland:World Health Organization (2001). Available: http://tinyurl.com/42xdzdx [accessed 6 Apr 2011].
13.WHO. World Health Day 2011: Policy Briefs [website]. Geneva, Switzerland:World Health Organization (2011). Available: http://tinyurl.com/3oypba8 [accessed 6 Apr 2011].
14.Cars O. Antibiotic Resistance Is a Global Public Health Threat That Can Only Be Solved By a World Working Together. Health–EU Newsletter. Brussels, Belgium:Community Public Health Programme, European Union (19 Nov 2009). Available: http://tinyurl.com/44nnyrw [accessed 6 Apr 2011].
15.The Swedish National Board of Health and Welfare. Antimicrobial Resistance—Inspiration and Exchange of Experience from EU Presidencies. Stockholm, Sweden:The Swedish National Board of Health and Welfare (Socialstyrelsen) (2010). Available: http://tinyurl.com/3bbmu5w [accessed 6 Apr 2011].
16.FDA. Draft Guidance #209. The Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals. Rockville, MD:Center for Veterinary Medicine, Food and Drug Administration, U.S. Department of Health and Human Services (28 June 2010). Available: http://tinyurl.com/352ks4e [accessed 6 Apr 2011].
17.FDA. The National Antimicrobial Resistance Monitoring System (NARMS) Strategic Plan 2011–2015. FDA-2010-N-0620. Silver Spring, MD:U.S. Food and Drug Administration, U.S. Department of Health and Human Services (updated 25 Mar 2011).
18.H.R. 1549. Preservation of Antibiotics for Human Treatment Act of 2009. Available: http://tinyurl.com/dm8by3 [accessed 6 Apr 2011].
19.S. 619. Preservation of Antibiotics for Medical Treatment Act of 2009. Available: http://tinyurl.com/4yc2852 [accessed 6 Apr 2011].
20.H.R. 965. Preservation of Antibiotics for Human Treatment Act of 2011. Available: http://tinyurl.com/6hlwzkg [accessed 6 Apr 2011].
21.H.R. 6331. Generating Antibiotic Incentives Now (GAIN) Act of 2010. Available: http://tinyurl.com/3cqfavy [accessed 6 Apr 2011].
22.Graham DW, et al. Antibiotic resistance gene abundances associated with waste discharges to the Almendares River near Havana, Cuba. Environ Sci Technol 45(2):418–424 (2011); doi:10.1021/es102473z.
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Be on Alert for 'Super Toxic' Bug in Travelers, CDC Says
E coli Infection 'Very Rare' but Deadly
Nancy A. Melville
June 3, 2011 — As health officials in Germany continued to seek the source of a uniquely toxic enterohemorrhagic Escherichia coli outbreak that has claimed the lives of at least 18 people, the Centers for Disease Control and Prevention (CDC) issued a notice to healthcare providers to be on alert for the Shiga toxin–producing E coli O104:H4 (STEC O104:H4) infections among travelers returning from Germany.
While there are some reports of the outbreak stabilizing, the World Health Organization (WHO) confirms that a total of 1823 cases of STEC O104:H4 have been reported, including 520 cases of hemolytic uremic syndrome (HUS), a potentially life-threatening complication of the infection that can cause kidney failure. Twelve HUS cases were fatal, and 6 deaths were reported among non-HUS cases.
The number of countries reporting cases of the STEC O104:H4 poisoning had increased to 11 on Friday. However, all but 1 of the deaths since the outbreak emerged in May have occurred in Germany. The 18th death was reportedly in Sweden and involved a person who had recently returned from Germany.
Symptoms of the strain, which European authorities have called "super-toxic," are notably severe, including stomach cramps, bloody diarrhea, vomiting, and fever. However, fever is not usually high.
Rare but Not Unfamiliar
Four suspected cases of the infection have been reported in the United States, all involving people who had recently traveled to Hamburg, Germany, said Chris Braden, MD, Director of Foodborne, Waterborne, and Environmental Diseases for the CDC, at a press briefing today.
Three of the 4 cases in the United States involved HUS and the patients were hospitalized. "The fourth case did not develop HUS but had bloody diarrhea, and we know there was a Shiga toxin–producing organism involved," he said.
Dr. Braden described the STEC O104:H4 strain as "very rare" but not entirely unfamiliar.
"The CDC is not aware of any confirmed cases of this infection ever reported in the US. However, we have become aware of similar strains in other countries in the past," he said.
The strain attacks the body in a manner unlike other strains of Shiga-producing E coli.
"The strain is different in its genetic markers and in the way it attaches to the lining of the intestine," Dr. Braden added.
Most Victims Female
In addition to causing particularly severe symptoms, the strain is unusual in that most of its victims appear to be women and people over the age of 20.
"It is true that in Germany 60% of the enterohemorrhagic E coli cases and 71% of the HUS cases are female," the WHO confirmed.
The unusual patterns underscore that little is known about the strain's unusual nature, but they could also suggest the source that may be somehow related to the adult female demographic, Dr. Braden said.
"We have a lot to learn about this particular organism. It's possible this organism had a predilection for adults over children, but it's also possible the type of food or produce is being eaten [more] by adult women than others."
Dr. Braden also noted that the duration time from exposure to onset of symptoms is also unique, with incubation times of more than a week to up to 12 days, compared to as little as 5 days commonly seen with other E coli infections.
Most patients' symptoms resolve within 5 to 7 days. However, HUS can develop a week after diarrhea begins.
"The classic triad of findings in HUS is acute renal damage, microangiopathic hemolytic anemia (evidence of schistocytes and helmet cells on peripheral blood smear), and thrombocytopenia," the CDC explained in a statement.
Prime Suspects
After backtracking on an earlier suggestion that the source of the E coli strain could be linked to organic Spanish cucumbers, German officials maintain that cucumbers, tomatoes, and lettuce are top suspects.
In addition, the Robert Koch Institute, Germany's national disease control agency, has advised consumers, particularly those in the northern Germany region around Hamburg, to avoid those vegetables.
The Institute has said that the number of cases appeared to have peaked around May 21 or 22. However, officials cautioned that communication delays may have slowed the reporting of new cases since then. In the meantime, German officials are not letting their guard down.
"We are dealing here in fact with the biggest epidemic caused by bacteria in recent decades," Reinhard Brunkhorst, president of the German Nephrology Society, told reporters in Hamburg this week.
In treating suspected STEC cases, some research has shown that administering antibiotics may in fact increase their risk of developing HUS, but the CDC recommends that clinicians ultimately determine treatment according to each individual patient.
"There may be indications for antibiotics in patients with severe intestinal inflammation if perforation is of concern," the agency said. "Of note, isolates of STEC O104:H4 from patients in Germany have demonstrated resistance to multiple antibiotics."
Detection Guidelines
The agency issued the following additional guidelines for detecting and characterizing STEC infections:
•All stools submitted for testing from patients with acute community-acquired diarrhea should be cultured for STEC O157:H7. These stools should be simultaneously assayed for non-O157 STEC with a test that detects the Shiga toxins or the genes encoding these toxins.
•Clinical laboratories should report and send E coli O157:H7 isolates and Shiga toxin–positive samples to state or local public health laboratories as soon as possible for additional characterization.
•Specimens or enrichment broths in which Shiga toxin or STEC are detected, but from which O157:H7 STEC isolates are not recovered, should be forwarded as soon as possible to a state or local public health laboratory so that non-O157:H7 STEC can be isolated.
•It is often difficult to isolate STEC in stool by the time a patient presents with HUS. Immunomagnetic separation (IMS) has been shown to increase recovery of STEC from HUS patients. For any patient with HUS without a culture-confirmed STEC infection, stool can be sent to a public health laboratory that performs IMS or to the CDC (through a state public health laboratory). In addition, serum can be sent to CDC (through a state public health laboratory) for serologic testing of common STEC serogroups.
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