Laurie Barclay, MD
May 11, 2010 — Use of proton pump inhibitors (PPIs) is linked to Clostridium difficile infection, according to the results of 2 studies reported in the May 10 issue of the Archives of Internal Medicine. The articles describing this prospective analysis are part of a series about PPIs in the Archives of Internal Medicine entitled "Less Is More."
First Study: Howell and Colleagues
"The incidence and severity of Clostridium difficile infections are increasing," write Michael D. Howell, MD, MPH, and colleagues from Beth Israel Deaconess Medical Center in Boston, Massachusetts. "Acid-suppressive therapy has been suggested as a risk factor for C difficile, but this remains controversial."
In this pharmacoepidemiologic cohort study, the investigators conducted a secondary analysis of prospectively collected data from 101,796 patients who were discharged from a tertiary care medical center during a 5-year period. Acid suppression treatment was the primary exposure of interest, classified by intensity (no acid suppression, histamine2-receptor antagonist [H2RA] treatment, daily PPI use, and PPI use more often than daily).
The risk for nosocomial C difficile infection increased with increasing level of acid suppression. This risk was 0.3% (95% confidence interval [CI], 0.21% - 0.31%) in patients not receiving acid suppressive treatment, 0.6% (95% CI, 0.49% - 0.79%) in those receiving H2RA treatment, 0.9% (95% CI, 0.80% - 0.98%) in those using PPIs daily, and 1.4% (95% CI, 1.15% - 1.71%) in patients using PPIs more often than daily.
The association persisted after adjustment for comorbid conditions, age, antibiotics, and propensity score–based likelihood of receiving no acid suppression treatment. The odds ratio was 1 for no acid suppression (reference), 1.53 for H2RA treatment (95% CI, 1.12 - 2.10), 1.74 for daily PPI use (95% CI, 1.39 - 2.18), and 2.36 for more frequent PPI use (95% CI, 1.79 - 3.11). A matched cohort analysis and nested case-control techniques resulted in similar estimates.
"Increasing levels of pharmacologic acid suppression are associated with increased risks of nosocomial C difficile infection," the study authors write. "This evidence of a dose-response effect provides further support for the potentially causal nature of iatrogenic acid suppression in the development of nosocomial C difficile infection."
Limitations of this study include observational design, possible residual confounding or selection bias, and lack of data about use of acid suppressive medications or antibiotics before admission.
Second Study: Linsky and Colleagues
The second study, by Amy Linsky, MD, from Boston Medical Center in Massachusetts, and colleagues, was a retrospective cohort study using administrative databases of the New England Veterans Healthcare System. From October 1, 2003, through September 30, 2008, there were 1166 inpatients and outpatients treated with metronidazole or vancomycin hydrochloride for incident C difficile infection.
Of these patients, 527 (45.2%) were given oral PPIs within 14 days of diagnosis, and 639 (54.8%) were not. The investigators measured the hazard ratio (HR) for recurrent C difficile infection, which was defined as a positive toxin result in the 15- to 90-day period after incident C difficile infection.
Compared with patients not using PPIs, those using them were more likely to have recurrent C difficile infection (25.2% vs 18.5%), with an adjusted HR of recurrent C difficile infection of 1.42 (95% CI, 1.11 - 1.82), based on Cox proportional survival methods.
Among patients exposed to PPIs, risks for recurrent C difficile infection were highest among those older than 80 years (HR, 1.86; 95% CI, 1.15 - 3.01) and among those given antibiotics not targeting C difficile during follow-up (HR, 1.71; 95% CI, 1.11 - 1.64).
"...PPI use during incident CDI [C difficile infection] treatment was associated with a 42% increased risk of recurrence," the study authors write. "Our findings warrant further studies to examine this association and careful consideration of the indications for prescribing PPIs during treatment of CDI."
Limitations of this study include use of observational databases, possible misclassification of exposure, and potential misclassifications of a positive test result for C difficile toxin alone as a clinically relevant recurrence.
Editorial: Risk Increase Not Modest
In an accompanying editorial, Mitchell H. Katz, MD, from the San Francisco Department of Public Health, San Francisco, California, describes these studies as well as the others described in the series, "Less Is More."
"The increases in the risk of Clostridium difficile infection with PPIs are not at all modest, reflecting the likely importance of gastric acid in protecting against infection from this pathogen," Dr. Katz writes.
"A pharmacoepidemiologic study of more than 1,000,000 hospital discharges in this issue of the Archives demonstrates a dose-response curve between level of acid suppression and C difficile infection.... Another article in this issue extends this association by demonstrating that the use of PPIs during treatment for C difficile infection was associated with a 42% increase in the rate of C difficile recurrence."
The authors of the study by Howell and colleagues have disclosed no relevant financial relationships. The study by Linsky and colleagues was supported by the resources of the Veterans Affairs Cooperative Studies Program and using the facilities of the Veterans Affairs Boston Healthcare System. The authors of the study by Linsky and colleagues have disclosed no relevant financial relationships.
Dr. Katz is an independent consultant for Health Management Associates.
Arch Intern Med. 2010;170:747-748, 772-778, 784
miércoles, 12 de mayo de 2010
lunes, 10 de mayo de 2010
Carbapenemases: A Brief Review for Pediatric Infectious Disease Specialists
Overturf, Gary D. MD
Authors and Disclosures
Posted: 01/28/2010; Pediatr Infect Dis J. 2010;29(1):68-70. © 2010 Lippincott Williams & Wilkins
Abstract and Introduction
Introduction
Carbapenems are increasingly utilized against a variety of infections because of the emergence of bacteria producing extended spectrum beta-lactamases (ESBL) in the Enterobacteriaceae, particularly Escherichia coli, Klebsiella pneumoniae, and other enteric bacteria[1,2] Carbapenems (imipenem, meropenem, ertapenem, and doripenem) are often the drugs of last resort for ESBL producing organisms which are increasingly also resistant to quinolones, aminoglycosides, trimethoprim–sulfamethoxazole and other antibiotics, thereby meeting the definition of multiply drug resistant organisms.[3] In addition, the carbapenems are often relied upon for uniquely resistant isolates of Pseudomonas aeruginosa and Acinetobacter spp. However, the emergence and proliferation of bacteria producing carbapenemases are increasingly being seen in clinical practice, jeopardizing the effective use of carbapenems generating a whole new class of Gram negative "superbugs."
Resistance to carbapenems may not always due to the production of carbapenemases[4] Some resistance among Enterobacteriaceae are caused by the expression of AmpC type enzymes when combined with a limitation to cellular penetration via a porin loss, then carbapenem resistance can occur. In addition, other "conventional" beta-lactamases such as the SHV class of ESBLs with porin loss can also produce a phenotype of carbapenem resistance.[5] However, this discussion will focus on the emerging issue of carbapenemases in clinical isolates and the hazards they pose in laboratory detection and effective clinical treatment of infections.
Carbapenemases
Table 1 outlines the common carbapenemases produced by pathogenic bacteria. These enzymes fall into 3 of the Ambler classes of beta-lactamases, A, B, and D classes and include the Klebsiella pneumoniae carbapenemases (KPC), 4 serine carbapenemases (SME, NMC-A, IMI, and rare GES) and several metallo-beta-lactamases (IMI, VIM).[6,7] A last group of enzymes, OXA, are only weakly active against carbapenems and are largely confined to Pseudomonas and Acinetobacter species, and only rarely in Enterobacteriaceae.[8] It is unknown whether OXA carbapenemases, which are confined to bacterial chromosomes and not present on mobile elements, will emerge as significant causes of resistance in bacteria other than Acinetobacter.
KPC Carbapenemases
These agents are the most commonly occurring class A carbapenemases and yet have been found only recently.[9] Although KPC 1–8 have been described, types 1 and 2 have been subsequently been found to be identical; the rest are variants of the bla KPC genes on conjugative plasmids that often carry other resistance markers such as fluoroquinolone and aminoglycoside resistance. Interspecies transfers of these enzymes have been suggested in studies in some health care facilities. KPC enzymes when present are generally broadly active against all beta-lactams despite the fact that they may test susceptible to some carbapenems (particularly imipenem and meropenem) as well as to cefepime and cephamycins, particularly when using agar dilution methods such as disk testing and Etest.[7] Some automated systems have been associated with this difficulty as well. However, ertapenem resistance generally has been found to be the single most sensitive indicator of carbapenem resistance with KPCs, but when dilution tests are performed, the minimum inhibitory concentration (MIC) of imipenem and meropenem will be found to be elevated, to at least the "intermediate" range of MIC.
KPC enzymes have been most often in K. pneumoniae, but like ESBLs these enzymes are no longer confined to this organism, and KPCs have been found in Klebsiella oxytoca, Salmonella enterica, Citrobacter freundii, Enterobacter aerogenes, Enterobacter Cloacae, and Serratia marcescens.[7] In addition, they have been found in rare isolates of Ps. aeruginosa in Puerto Rico and Colombia. The first KPC isolates (K. pneumoniae) occurred in the United States in North Carolina and are now concentrated in New York, New Jersey, Maryland, Pennsylvania, but now rarely in Florida, Colorado, New Mexico, and California, as well as Missouri, Arkansas, Virginia, and Alabama.[7,10] However, KPCs are now widely distributed worldwide with reports in Israel, China, Greece, South America and India.[6,7]
Serine Carbapenemases
Class A serine carbapenemases are chromosomal enzymes including SME, IMI and NMC-A and plasmid borne enzymes, the GES beta-lactamases.[6,11] Imipenem and cefoxitin induce chromosomal carbapenemases; confering a unique susceptibility profile with resistance to carbapenems, penicillins, and aztreonam but susceptibility to extended spectrum cephalosporins. The activity of these enzymes is susceptible to inhibition by clavulanate, but not sulbactam. The presence of these genetic elements on chromosomes and not on mobile genetic elements, is cited as the reason that intraspecies spread has been rare. These SME group are confined in S. marcescens and the GES enzymes are also rare, but are found as cassettes within integrons on plasmids mostly in Ps. aeruginosa.
Class B Metallo-β-lactamases
Class B Metallo-β-lactamases (MBL) carbapenemases are of the Ambler class B and have a wide spectrum of activity against carbapenems, penicillins and extended spectrum cephalosporins but not aztreonam.[6,7] These enzymes require zinc as a cofactor and they are inhibited by EDTA, a chelator of divalent cations. These enzymes occur in multiple genera of Gram negative bacteria including Enterobacteriaceae as well as non-fermenters. The enzymes are found world wide and like KPCs have spread rapidly, presenting a serious threat because of the their prolific dissemination.[12] The VIM and IMP type of MBLs are the most common. The VIM MBL consist of a family of 14 enzymes, but VIM-2 predominates in most outbreaks
Laboratory Detection of Carbapenemases
Detection of carbapenemase activity in Enterobacteriaceae is a challenge particularly for the most frequent enzymes of the MBL and KPC type (Table 2). These enzymes do not always produce resistant breakpoints for carbapenems, using standardized susceptibility testing methods. Effective treatment and infection control depend upon the rapid and efficient identification of these isolates. Unfortunately, carbapenem susceptibility by reference MIC methods, such as the broth microdilution and agar dilution, are more sensitive than disk diffusion, Etest, and many automated systems.[7] However, although Enterobacteriaceae with KPC generally have higher MICs they may not test into the defined resistant range. MICs of ≥1.0 to 2.0 μ/mL against ertapenem, meropenem, or imipenem has been found to be an effective screen of the likely presence of KPCs, whereas MBLs produce MICs ≥2.0 μg/mL against imipenem or meropenem. Therefore recommendations for testing have suggested that most MBL producers will have MIC for imipenem and meropenem greater than 2.0 μg/mL and have suggested using this as a cutoff or cutoff ranging from 1 to 4 μg/mL as a "screening" dilution for possible carbapenemase production.[13] As mentioned previously still others suggest ertapenem resistance as the most sensitive screen with MICs of >1 to 2 μg/mL as the most accurate way to detect KPC and MBL carbapenemases.
Once a screen criteria, such as a resistant MIC cutoff for ertapenem or imipenem has been selected, there are a number of phenotypic tests which have been developed to detect carbapenemases in Gram negative bacteria. The Modified Hodge Test is a relatively easily performed test on a single agar plate to detect both KPC and MBL enzymes, but it cannot differentiate between them.[14] A standardized inoculum of a lawn of a reference E. coli is utilized against carbapenem disks on the isolates to be tested. Mutiple isolates can be tested on a single agar and multiple antibiotics and it relatively easy to read, but is somewhat subjective. Several versions of an EDTA disk test[7] have been used for detections for MBL carbapenemases including one which utilizes a double sided Etest with imipenem vs. imipenem with EDTA,[15] a ratio of ≥8 between the MIC of the non-EDTA enhanced versus the EDTA enhanced imipenem MIC indicates the presence of a MBL beta-lactamase.
Summary
Carbapenem resistance constitutes a serious threat to the antibiotics available to deal with increasing resistance in Gram negative pathogens infecting neonates, infants, and compromised children with nosocomial infection caused by carbapenemase and ESBL producing bacteria. The dissemination in hospitals and the location of these enzymes on highly mobile genetic elements has contributed to their rapid spread and the frequent cotransfer of multiple other antibiotic resistance factors. The ability to limit the spread of these pathogens will require effective laboratory screening methods to rapidly identify patients infected with these organisms. Although current criteria to screen for these enzymes and methods for confirmation are useful, laboratories will need new tools, perhaps molecular techniques, to make the process rapid and accurate.
Authors and Disclosures
Posted: 01/28/2010; Pediatr Infect Dis J. 2010;29(1):68-70. © 2010 Lippincott Williams & Wilkins
Abstract and Introduction
Introduction
Carbapenems are increasingly utilized against a variety of infections because of the emergence of bacteria producing extended spectrum beta-lactamases (ESBL) in the Enterobacteriaceae, particularly Escherichia coli, Klebsiella pneumoniae, and other enteric bacteria[1,2] Carbapenems (imipenem, meropenem, ertapenem, and doripenem) are often the drugs of last resort for ESBL producing organisms which are increasingly also resistant to quinolones, aminoglycosides, trimethoprim–sulfamethoxazole and other antibiotics, thereby meeting the definition of multiply drug resistant organisms.[3] In addition, the carbapenems are often relied upon for uniquely resistant isolates of Pseudomonas aeruginosa and Acinetobacter spp. However, the emergence and proliferation of bacteria producing carbapenemases are increasingly being seen in clinical practice, jeopardizing the effective use of carbapenems generating a whole new class of Gram negative "superbugs."
Resistance to carbapenems may not always due to the production of carbapenemases[4] Some resistance among Enterobacteriaceae are caused by the expression of AmpC type enzymes when combined with a limitation to cellular penetration via a porin loss, then carbapenem resistance can occur. In addition, other "conventional" beta-lactamases such as the SHV class of ESBLs with porin loss can also produce a phenotype of carbapenem resistance.[5] However, this discussion will focus on the emerging issue of carbapenemases in clinical isolates and the hazards they pose in laboratory detection and effective clinical treatment of infections.
Carbapenemases
Table 1 outlines the common carbapenemases produced by pathogenic bacteria. These enzymes fall into 3 of the Ambler classes of beta-lactamases, A, B, and D classes and include the Klebsiella pneumoniae carbapenemases (KPC), 4 serine carbapenemases (SME, NMC-A, IMI, and rare GES) and several metallo-beta-lactamases (IMI, VIM).[6,7] A last group of enzymes, OXA, are only weakly active against carbapenems and are largely confined to Pseudomonas and Acinetobacter species, and only rarely in Enterobacteriaceae.[8] It is unknown whether OXA carbapenemases, which are confined to bacterial chromosomes and not present on mobile elements, will emerge as significant causes of resistance in bacteria other than Acinetobacter.
KPC Carbapenemases
These agents are the most commonly occurring class A carbapenemases and yet have been found only recently.[9] Although KPC 1–8 have been described, types 1 and 2 have been subsequently been found to be identical; the rest are variants of the bla KPC genes on conjugative plasmids that often carry other resistance markers such as fluoroquinolone and aminoglycoside resistance. Interspecies transfers of these enzymes have been suggested in studies in some health care facilities. KPC enzymes when present are generally broadly active against all beta-lactams despite the fact that they may test susceptible to some carbapenems (particularly imipenem and meropenem) as well as to cefepime and cephamycins, particularly when using agar dilution methods such as disk testing and Etest.[7] Some automated systems have been associated with this difficulty as well. However, ertapenem resistance generally has been found to be the single most sensitive indicator of carbapenem resistance with KPCs, but when dilution tests are performed, the minimum inhibitory concentration (MIC) of imipenem and meropenem will be found to be elevated, to at least the "intermediate" range of MIC.
KPC enzymes have been most often in K. pneumoniae, but like ESBLs these enzymes are no longer confined to this organism, and KPCs have been found in Klebsiella oxytoca, Salmonella enterica, Citrobacter freundii, Enterobacter aerogenes, Enterobacter Cloacae, and Serratia marcescens.[7] In addition, they have been found in rare isolates of Ps. aeruginosa in Puerto Rico and Colombia. The first KPC isolates (K. pneumoniae) occurred in the United States in North Carolina and are now concentrated in New York, New Jersey, Maryland, Pennsylvania, but now rarely in Florida, Colorado, New Mexico, and California, as well as Missouri, Arkansas, Virginia, and Alabama.[7,10] However, KPCs are now widely distributed worldwide with reports in Israel, China, Greece, South America and India.[6,7]
Serine Carbapenemases
Class A serine carbapenemases are chromosomal enzymes including SME, IMI and NMC-A and plasmid borne enzymes, the GES beta-lactamases.[6,11] Imipenem and cefoxitin induce chromosomal carbapenemases; confering a unique susceptibility profile with resistance to carbapenems, penicillins, and aztreonam but susceptibility to extended spectrum cephalosporins. The activity of these enzymes is susceptible to inhibition by clavulanate, but not sulbactam. The presence of these genetic elements on chromosomes and not on mobile genetic elements, is cited as the reason that intraspecies spread has been rare. These SME group are confined in S. marcescens and the GES enzymes are also rare, but are found as cassettes within integrons on plasmids mostly in Ps. aeruginosa.
Class B Metallo-β-lactamases
Class B Metallo-β-lactamases (MBL) carbapenemases are of the Ambler class B and have a wide spectrum of activity against carbapenems, penicillins and extended spectrum cephalosporins but not aztreonam.[6,7] These enzymes require zinc as a cofactor and they are inhibited by EDTA, a chelator of divalent cations. These enzymes occur in multiple genera of Gram negative bacteria including Enterobacteriaceae as well as non-fermenters. The enzymes are found world wide and like KPCs have spread rapidly, presenting a serious threat because of the their prolific dissemination.[12] The VIM and IMP type of MBLs are the most common. The VIM MBL consist of a family of 14 enzymes, but VIM-2 predominates in most outbreaks
Laboratory Detection of Carbapenemases
Detection of carbapenemase activity in Enterobacteriaceae is a challenge particularly for the most frequent enzymes of the MBL and KPC type (Table 2). These enzymes do not always produce resistant breakpoints for carbapenems, using standardized susceptibility testing methods. Effective treatment and infection control depend upon the rapid and efficient identification of these isolates. Unfortunately, carbapenem susceptibility by reference MIC methods, such as the broth microdilution and agar dilution, are more sensitive than disk diffusion, Etest, and many automated systems.[7] However, although Enterobacteriaceae with KPC generally have higher MICs they may not test into the defined resistant range. MICs of ≥1.0 to 2.0 μ/mL against ertapenem, meropenem, or imipenem has been found to be an effective screen of the likely presence of KPCs, whereas MBLs produce MICs ≥2.0 μg/mL against imipenem or meropenem. Therefore recommendations for testing have suggested that most MBL producers will have MIC for imipenem and meropenem greater than 2.0 μg/mL and have suggested using this as a cutoff or cutoff ranging from 1 to 4 μg/mL as a "screening" dilution for possible carbapenemase production.[13] As mentioned previously still others suggest ertapenem resistance as the most sensitive screen with MICs of >1 to 2 μg/mL as the most accurate way to detect KPC and MBL carbapenemases.
Once a screen criteria, such as a resistant MIC cutoff for ertapenem or imipenem has been selected, there are a number of phenotypic tests which have been developed to detect carbapenemases in Gram negative bacteria. The Modified Hodge Test is a relatively easily performed test on a single agar plate to detect both KPC and MBL enzymes, but it cannot differentiate between them.[14] A standardized inoculum of a lawn of a reference E. coli is utilized against carbapenem disks on the isolates to be tested. Mutiple isolates can be tested on a single agar and multiple antibiotics and it relatively easy to read, but is somewhat subjective. Several versions of an EDTA disk test[7] have been used for detections for MBL carbapenemases including one which utilizes a double sided Etest with imipenem vs. imipenem with EDTA,[15] a ratio of ≥8 between the MIC of the non-EDTA enhanced versus the EDTA enhanced imipenem MIC indicates the presence of a MBL beta-lactamase.
Summary
Carbapenem resistance constitutes a serious threat to the antibiotics available to deal with increasing resistance in Gram negative pathogens infecting neonates, infants, and compromised children with nosocomial infection caused by carbapenemase and ESBL producing bacteria. The dissemination in hospitals and the location of these enzymes on highly mobile genetic elements has contributed to their rapid spread and the frequent cotransfer of multiple other antibiotic resistance factors. The ability to limit the spread of these pathogens will require effective laboratory screening methods to rapidly identify patients infected with these organisms. Although current criteria to screen for these enzymes and methods for confirmation are useful, laboratories will need new tools, perhaps molecular techniques, to make the process rapid and accurate.
¿Promover la resistencia?
JOEL LEXCHIN*
* El Dr. Joel Lexchin es médico de urgencia en Toronto, Canadá, y secretario-tesorero del Grupo Médico de Presión para una Comercialización Apropiada. Es también coautor de Drugs of Choice: A Formulary for General Practice.
El número de otoño de 1996 de Health Horizons, revista de la Federación Internacional de la Industria del Medicamento, publicaba un artículo de fondo de dos páginas titulado International Mobilization Against New and Resistant Diseases (Movilización internacional contra las enfermedades nuevas y resistentes). En este artículo se destacaban los esfuerzos realizados por las organizaciones internacionales y la industria farmacéutica para afrontar la amenaza de la creciente resistencia a los antibióticos. El artículo no mencionaba que una parte de la industria puede también intervenir en la promoción de la resistencia bacteriana a los medicamentos actualmente disponibles.
Según una empresa, la ciprofloxacina es una «opción apropiada para sus pacientes [de los médicos] expuestos». Éste era el mensaje de un anuncio que apareció en el número del 3 de octubre de 2000 del Canadian Medical Association Journal. ¿«Apropiada» para quién? Para responder a esa pregunta, los lectores tenían que observar un pequeño asterisco después de la palabra «riesgo» y después mirar en el pie de la página, en donde en letras pequeñas se hallaba la definición. ¿«Apropiada» para qué? Una vez más la respuesta se hallaba en letras pequeñas; la ciprofloxacina debe utilizarse en infecciones de las vías respiratorias «amenazantes». Nunca se definía la palabra amenazante. En el mismo anuncio, la empresa afirmaba que apoyaba el uso apropiado de los antibióticos.
Los anuncios que no dan una información clara o que la dan en letra tan pequeña que requiere el empleo de una lupa, no apoyan el uso apropiado de los medicamentos. El mensaje contenido en el anuncio de la ciprofloxacina es que los médicos deben sentirse libres de utilizar este medicamento como agente de primera línea siempre que estén preocupados por sus pacientes o piensen que sucede algo extraño. La ciprofloxacina es una primera opción apropiada para un número limitado de problemas, pero no para la mayoría de las infecciones de las vías respiratorias. El Programa australiano de prestaciones farmacéuticas limita el uso de este antibiótico en esas situaciones y lo mismo es cierto en algunas provincias canadienses.
Otro reciente anuncio aparecido en una revista canadiense, esta vez de la azitromicina, presentaba un joven lanzador de béisbol, con su cara resuelta, dispuesto a tirar la pelota con el mensaje «fuerte contra la otitis aguda del oído medio, fácil en los niños». En este caso, el mensaje era que los médicos y sus pequeños pacientes necesitan un medicamento potente para tratar la otitis del oído medio y que la azitromicina cubre esa necesidad. Sin embargo, esto no refleja el creciente consenso en el sentido de que la otitis del oído medio, por lo menos en los niños mayores de dos años, no debe tratarse con antibióticos a no ser que el niño no mejore en 48 horas.
Lo que hacen estos anuncios es promover, como opciones de primera línea, el empleo de antibióticos que deben guardarse en reserva y fomentar el uso de antibióticos para enfermedades que probablemente se resolverán sin ninguna intervención. Ambas situaciones constituyen un uso inadecuado de los antibióticos y tienen claramente la posibilidad de conducir a mayor resistencia.
La otra característica común de estos anuncios es que se refieren a antibióticos nuevos y costosos; son los medicamentos que pueden producir altos beneficios para las empresas si se obtiene un elevado volumen de ventas. Lo que los médicos no ven es la publicidad a favor de antibióticos más antiguos y menos costosos, aunque estos medicamentos son los más adecuados. ¿Cuándo fue la última vez en que apareció un anuncio a favor de la penicilina para la faringitis estreptocócica o de la trimetoprima para una infección de las vías urinarias?
Esa situación no está limitada al Canadá e incluso es peor en otras partes del mundo. El Grupo Médico de Presión para una Comercialización Apropiada (MaLAM) ha recibido varios ejemplares de promoción inadecuada de antibióticos en países en desarrollo. Los anuncios aparecidos en 1994 y 1995 en las Filipinas defendían el uso de la lincomicina para las amigdalitis/faringitis y de la clindamicina en las infecciones de las vías respiratorias altas. La causa más probable de tales enfermedades es una infección vírica, en la que los antibióticos son inútiles. Una vez más se anuncian los antibióticos para trastornos que no lo requieren.
En 1997, la publicidad aparecida en la India a favor de la claritromicina utilizaba las palabras «suspensión pediátrica... rapidez,... fuerza,...espectro,...inocuidad» sin ninguna matización. En opinión de MaLAM, habría sido razonable que los lectores de este anuncio interpretaran esas palabras en el sentido de que la claritromicina tiene ventajas clínicamente importantes sobre otros antimicrobianos y que es así el antibiótico de primera opción para las infecciones corrientes de la infancia. Como señala MaLAM, fuentes autorizadas no recomiendan la claritromicina como tratamiento de elección para la otitis media, la faringitis o la sinusitis en los niños. Los paralelos con el ejemplo canadiense de publicidad de la ciprofloxacina son evidentes; los anuncios fomentan el uso excesivo de medicamentos de segunda línea.
Un par de estudios estadounidenses, separados por casi un cuarto de siglo, señalan que la preocupación por la promoción que conduce al mal uso de los antibióticos no es un simple problema teórico. El primero de ellos, publicado a principios del decenio de 1970, mostró que el uso más apropiado del antibiótico cloranfenicol guardaba relación con el uso infrecuente de anuncios de revistas para conocer la utilidad de nuevos medicamentos, y con la desaprobación de los detallistas como fuentes de información de prescripción para los nuevos medicamentos.1 El segundo estudio apareció en 1996. En este caso, los investigadores presentaron un grupo de médicos de atención primaria en tres situaciones, dos de las cuales se referían a enfermedades infecciosas, pidiéndoles que eligieran entre cuatro opciones terapéuticas de igual eficacia, pero de costos muy distintos. Cuanto mayor credibilidad otorgaban los médicos a la información procedente de representantes de ventas, mayor era el costo de la prescripción del médico.2
En muchos casos, los médicos de países en desarrollo carecen de fuentes de información objetivas sobre los antibióticos. Esos médicos confían totalmente en el material de promoción de las empresas, con todos los sesgos que ello supone. A mediados del decenio de 1980, los médicos en ejercicio en un centro de salud periférico en Sri Lanka, en donde eran corrientes la politerapéutica, el tratamiento con múltiples antibióticos y el uso de mezclas de eficacia sin demostrar, dependían totalmente de la información procedente de las empresas farmacéuticas, que veían de modo positivo.3
Las empresas farmacéuticas se están apresurando ahora para obtener antibióticos nuevos y más potentes que combatan la farmacorresistencia, y debemos ver con agrado esos medicamentos. Ahora bien, si la industria es sincera en el deseo de hacer algo acerca de la resistencia, debe comenzar a vigilar más estrechamente sus prácticas de promoción.
Referencias
1. Becker MH, Stolley PD, Lasagna L, McEvilla JD, Sloane LM. Differential education concerning therapeutics and resultant physician prescribing patterns. Journal of Medical Education 1972; 47:118-27.
2. Caudill TS, Johnson MS, Rich EC, McKinney WP. Physicians, pharmaceutical sales representatives, and the cost of prescribing. Archives of Family Medicine 1996; 5:201-6.
3. Tomson G, Angunawela I. Patients, doctors and their drugs: a study at four levels of health care in an area of Sri Lanka. European Journal of Clinical Pharmacology 1990; 39:463-7.
* El Dr. Joel Lexchin es médico de urgencia en Toronto, Canadá, y secretario-tesorero del Grupo Médico de Presión para una Comercialización Apropiada. Es también coautor de Drugs of Choice: A Formulary for General Practice.
El número de otoño de 1996 de Health Horizons, revista de la Federación Internacional de la Industria del Medicamento, publicaba un artículo de fondo de dos páginas titulado International Mobilization Against New and Resistant Diseases (Movilización internacional contra las enfermedades nuevas y resistentes). En este artículo se destacaban los esfuerzos realizados por las organizaciones internacionales y la industria farmacéutica para afrontar la amenaza de la creciente resistencia a los antibióticos. El artículo no mencionaba que una parte de la industria puede también intervenir en la promoción de la resistencia bacteriana a los medicamentos actualmente disponibles.
Según una empresa, la ciprofloxacina es una «opción apropiada para sus pacientes [de los médicos] expuestos». Éste era el mensaje de un anuncio que apareció en el número del 3 de octubre de 2000 del Canadian Medical Association Journal. ¿«Apropiada» para quién? Para responder a esa pregunta, los lectores tenían que observar un pequeño asterisco después de la palabra «riesgo» y después mirar en el pie de la página, en donde en letras pequeñas se hallaba la definición. ¿«Apropiada» para qué? Una vez más la respuesta se hallaba en letras pequeñas; la ciprofloxacina debe utilizarse en infecciones de las vías respiratorias «amenazantes». Nunca se definía la palabra amenazante. En el mismo anuncio, la empresa afirmaba que apoyaba el uso apropiado de los antibióticos.
Los anuncios que no dan una información clara o que la dan en letra tan pequeña que requiere el empleo de una lupa, no apoyan el uso apropiado de los medicamentos. El mensaje contenido en el anuncio de la ciprofloxacina es que los médicos deben sentirse libres de utilizar este medicamento como agente de primera línea siempre que estén preocupados por sus pacientes o piensen que sucede algo extraño. La ciprofloxacina es una primera opción apropiada para un número limitado de problemas, pero no para la mayoría de las infecciones de las vías respiratorias. El Programa australiano de prestaciones farmacéuticas limita el uso de este antibiótico en esas situaciones y lo mismo es cierto en algunas provincias canadienses.
Otro reciente anuncio aparecido en una revista canadiense, esta vez de la azitromicina, presentaba un joven lanzador de béisbol, con su cara resuelta, dispuesto a tirar la pelota con el mensaje «fuerte contra la otitis aguda del oído medio, fácil en los niños». En este caso, el mensaje era que los médicos y sus pequeños pacientes necesitan un medicamento potente para tratar la otitis del oído medio y que la azitromicina cubre esa necesidad. Sin embargo, esto no refleja el creciente consenso en el sentido de que la otitis del oído medio, por lo menos en los niños mayores de dos años, no debe tratarse con antibióticos a no ser que el niño no mejore en 48 horas.
Lo que hacen estos anuncios es promover, como opciones de primera línea, el empleo de antibióticos que deben guardarse en reserva y fomentar el uso de antibióticos para enfermedades que probablemente se resolverán sin ninguna intervención. Ambas situaciones constituyen un uso inadecuado de los antibióticos y tienen claramente la posibilidad de conducir a mayor resistencia.
La otra característica común de estos anuncios es que se refieren a antibióticos nuevos y costosos; son los medicamentos que pueden producir altos beneficios para las empresas si se obtiene un elevado volumen de ventas. Lo que los médicos no ven es la publicidad a favor de antibióticos más antiguos y menos costosos, aunque estos medicamentos son los más adecuados. ¿Cuándo fue la última vez en que apareció un anuncio a favor de la penicilina para la faringitis estreptocócica o de la trimetoprima para una infección de las vías urinarias?
Esa situación no está limitada al Canadá e incluso es peor en otras partes del mundo. El Grupo Médico de Presión para una Comercialización Apropiada (MaLAM) ha recibido varios ejemplares de promoción inadecuada de antibióticos en países en desarrollo. Los anuncios aparecidos en 1994 y 1995 en las Filipinas defendían el uso de la lincomicina para las amigdalitis/faringitis y de la clindamicina en las infecciones de las vías respiratorias altas. La causa más probable de tales enfermedades es una infección vírica, en la que los antibióticos son inútiles. Una vez más se anuncian los antibióticos para trastornos que no lo requieren.
En 1997, la publicidad aparecida en la India a favor de la claritromicina utilizaba las palabras «suspensión pediátrica... rapidez,... fuerza,...espectro,...inocuidad» sin ninguna matización. En opinión de MaLAM, habría sido razonable que los lectores de este anuncio interpretaran esas palabras en el sentido de que la claritromicina tiene ventajas clínicamente importantes sobre otros antimicrobianos y que es así el antibiótico de primera opción para las infecciones corrientes de la infancia. Como señala MaLAM, fuentes autorizadas no recomiendan la claritromicina como tratamiento de elección para la otitis media, la faringitis o la sinusitis en los niños. Los paralelos con el ejemplo canadiense de publicidad de la ciprofloxacina son evidentes; los anuncios fomentan el uso excesivo de medicamentos de segunda línea.
Un par de estudios estadounidenses, separados por casi un cuarto de siglo, señalan que la preocupación por la promoción que conduce al mal uso de los antibióticos no es un simple problema teórico. El primero de ellos, publicado a principios del decenio de 1970, mostró que el uso más apropiado del antibiótico cloranfenicol guardaba relación con el uso infrecuente de anuncios de revistas para conocer la utilidad de nuevos medicamentos, y con la desaprobación de los detallistas como fuentes de información de prescripción para los nuevos medicamentos.1 El segundo estudio apareció en 1996. En este caso, los investigadores presentaron un grupo de médicos de atención primaria en tres situaciones, dos de las cuales se referían a enfermedades infecciosas, pidiéndoles que eligieran entre cuatro opciones terapéuticas de igual eficacia, pero de costos muy distintos. Cuanto mayor credibilidad otorgaban los médicos a la información procedente de representantes de ventas, mayor era el costo de la prescripción del médico.2
En muchos casos, los médicos de países en desarrollo carecen de fuentes de información objetivas sobre los antibióticos. Esos médicos confían totalmente en el material de promoción de las empresas, con todos los sesgos que ello supone. A mediados del decenio de 1980, los médicos en ejercicio en un centro de salud periférico en Sri Lanka, en donde eran corrientes la politerapéutica, el tratamiento con múltiples antibióticos y el uso de mezclas de eficacia sin demostrar, dependían totalmente de la información procedente de las empresas farmacéuticas, que veían de modo positivo.3
Las empresas farmacéuticas se están apresurando ahora para obtener antibióticos nuevos y más potentes que combatan la farmacorresistencia, y debemos ver con agrado esos medicamentos. Ahora bien, si la industria es sincera en el deseo de hacer algo acerca de la resistencia, debe comenzar a vigilar más estrechamente sus prácticas de promoción.
Referencias
1. Becker MH, Stolley PD, Lasagna L, McEvilla JD, Sloane LM. Differential education concerning therapeutics and resultant physician prescribing patterns. Journal of Medical Education 1972; 47:118-27.
2. Caudill TS, Johnson MS, Rich EC, McKinney WP. Physicians, pharmaceutical sales representatives, and the cost of prescribing. Archives of Family Medicine 1996; 5:201-6.
3. Tomson G, Angunawela I. Patients, doctors and their drugs: a study at four levels of health care in an area of Sri Lanka. European Journal of Clinical Pharmacology 1990; 39:463-7.
Characterization of Small ColE-Like Plasmids Mediating Widespread Dissemination of the qnrB19 Gene in Commensal Enterobacteria
Antimicrobial Agents and Chemotherapy, February 2010, p. 678-682, Vol. 54, No. 2
Copyright © 2010, American Society for Microbiology. All Rights Reserved.
Lucia Pallecchi,1 Eleonora Riccobono,1 Samanta Sennati,1 Antonia Mantella,2 Filippo Bartalesi,2 Christian Trigoso,3 Eduardo Gotuzzo,4 Alessandro Bartoloni,2 and Gian Maria Rossolini1,5*
Dipartimento di Biologia Molecolare, Sezione di Microbiologia, Università di Siena,1 Dipartimento dei Servizi, U. O. Microbiologia e Virologia, Azienda Ospedaliera-Universitaria Senese, Siena, Italy,5 Dipartimento Area Critica Medico Chirurgica, Clinica Malattie Infettive, Università di Firenze, Florence, Italy,2 Instituto Nacional de Laboratorios de Salud INLASA, La Paz, Bolivia,3 Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru4
Received 16 August 2009/ Returned for modification 9 November 2009/ Accepted 1 December 2009
In this work, we have characterized two small ColE-like plasmids (pECY6-7, 2.7 kb in size, and pECC14-9, of 3.0 kb), encoding the QnrB19 quinolone resistance determinant, that were carried by several clonally unrelated quinolone-resistant commensal Escherichia coli strains isolated from healthy children living in different urban areas of Peru and Bolivia. The two plasmids are closely related to each other and carry the qnrB19 gene as the sole resistance determinant, located in a conserved genetic context between the plasmid RNAII sequence (which controls plasmid replication) and the plasmid Xer site (involved in plasmid dimer resolution). ISEcp1-like or other putative insertion sequences are not present in the qnrB19-flanking regions or elsewhere on the plasmids. Since we previously observed a high prevalence (54%) of qnrB genes in the metagenomes of commensal enterobacteria from the same population of healthy children, the presence of pECY6-7- and pECC14-9-like plasmids in those qnrB-positive metagenomes was investigated by PCR mapping. Both plasmids were found to be highly prevalent (67% and 16%, respectively) in the qnrB-positive metagenomes, suggesting that dissemination of these small plasmids played a major role in the widespread dissemination of qnrB genes observed in commensal enterobacteria from healthy children living in those areas.
________________________________________
* Corresponding author. Mailing address: Dipartimento di Biologia Molecolare, Sezione di Microbiologia, Università di Siena, Policlinico Santa Maria alle Scotte, 53100 Siena, Italy. Phone: 39 0577 233455. Fax: 39 0577 233870. E-mail: rossolini@unisi.it
Published ahead of print on 14 December 2009.
Copyright © 2010, American Society for Microbiology. All Rights Reserved.
Lucia Pallecchi,1 Eleonora Riccobono,1 Samanta Sennati,1 Antonia Mantella,2 Filippo Bartalesi,2 Christian Trigoso,3 Eduardo Gotuzzo,4 Alessandro Bartoloni,2 and Gian Maria Rossolini1,5*
Dipartimento di Biologia Molecolare, Sezione di Microbiologia, Università di Siena,1 Dipartimento dei Servizi, U. O. Microbiologia e Virologia, Azienda Ospedaliera-Universitaria Senese, Siena, Italy,5 Dipartimento Area Critica Medico Chirurgica, Clinica Malattie Infettive, Università di Firenze, Florence, Italy,2 Instituto Nacional de Laboratorios de Salud INLASA, La Paz, Bolivia,3 Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru4
Received 16 August 2009/ Returned for modification 9 November 2009/ Accepted 1 December 2009
In this work, we have characterized two small ColE-like plasmids (pECY6-7, 2.7 kb in size, and pECC14-9, of 3.0 kb), encoding the QnrB19 quinolone resistance determinant, that were carried by several clonally unrelated quinolone-resistant commensal Escherichia coli strains isolated from healthy children living in different urban areas of Peru and Bolivia. The two plasmids are closely related to each other and carry the qnrB19 gene as the sole resistance determinant, located in a conserved genetic context between the plasmid RNAII sequence (which controls plasmid replication) and the plasmid Xer site (involved in plasmid dimer resolution). ISEcp1-like or other putative insertion sequences are not present in the qnrB19-flanking regions or elsewhere on the plasmids. Since we previously observed a high prevalence (54%) of qnrB genes in the metagenomes of commensal enterobacteria from the same population of healthy children, the presence of pECY6-7- and pECC14-9-like plasmids in those qnrB-positive metagenomes was investigated by PCR mapping. Both plasmids were found to be highly prevalent (67% and 16%, respectively) in the qnrB-positive metagenomes, suggesting that dissemination of these small plasmids played a major role in the widespread dissemination of qnrB genes observed in commensal enterobacteria from healthy children living in those areas.
________________________________________
* Corresponding author. Mailing address: Dipartimento di Biologia Molecolare, Sezione di Microbiologia, Università di Siena, Policlinico Santa Maria alle Scotte, 53100 Siena, Italy. Phone: 39 0577 233455. Fax: 39 0577 233870. E-mail: rossolini@unisi.it
Published ahead of print on 14 December 2009.
Suscribirse a:
Entradas (Atom)
