- Email: [email protected]
Antibiotic resistance: The new apocalypse?
C O M M E N T
Events
resistance: the new apocalypse?
A
nt bmtlC e'~
0
•
Caroline Ash
p
erhaps not yet. Nevertheless, in the 1990s the public perception of the threat from new infectious agents has been fuelled by fear of AIDS, Ebola virus, Salmonella and mad-cow disease. A problem that is more likely to affect us personally is infection by antibiotic-resistant bacteria. Yet, few countries have any policy about regulating the use of antibiotics for human or agricultural use, few data are collected in a systematic way on the incidence of antibiotic resistance and there is no global surveillance. What there is, however, is increasing recognition among the scientific community of the global nature of this growing problem. Alexander Fleming was aware of the potential for bacteria adapting to avoid antibiotics, and the past 50 years have seen an extraordinary evolutionary 'experiment' in progress. Stuart Levy (Tufts University, Boston, MA, USA) presented the notion that antibiotics are societal drugs and that antibiotic resistance is an ecological problem. Antibiotic resistance has occurred by two distinct genetic mechanisms: (1) endogenous mutation, for example multiple drug resistance in Mycobacterium tuberculosis, and (2) the acquisition of resistance genes, for example aminoglycosidemodifying enzymes (Julian Davies, University of British Columbia, Vancouver, Canada). The origin of mobile resistance genes could be the antibiotic-producing organisms themselves; DNA can be detected in antibiotics prepared by fermentation. An interesting possibility is that antibiotics act almost as aphrodisiacs to stimulate conjugative transposition and, thus, facilitate the spread of plasmids that may contain drug-resistance genes. Of major concern is the nearuniversal use of antibiotics as growth promoters for the livestock
Ciba Foundation Symposium No. 207, Antibiotic resistance: origins, evolution, selection and spread. Held at the WeUcome Centre for Medical Science, London, UK, 19 July 1996. [email protected]
industry and the potential this has for the selection and transmission of antibiotic resistance. What is disturbing is the apparent lack of recognition by the industries involved of the relatively small benefit (3-4% growth gains) and the potentially serious consequences of persistent use of glycoside antibiotics, like avoparcin, for this purpose. Avoparcin resistance confers cross-resistance to glycosides such as vancomycin, which is the last effective antibiotic in human use for multiply resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Avoparcin use has led to a reservoir of transferable vanA-mediated glycopeptide resistance in Enterococcus faecalis. This organism can be transferred to humans in meat products and has been found in
HI: S0966-842X(96)30028-0
Copyright © 1996 Elsevier Science Ltd. All rights reserved. 0966 842X/96/$15.00
TRENDS,N
MIC
ROBIOLO
Y
371
VOL. 4
NO.
human faecal samples (Wolfgang Witte, Robert Koch Institute, Wernigerode, Germany). Bill Noble and colleagues have experimentally transferred vanA from E. faecalis to S. aureus (Ref. 1). Although this was achieved with difficulty in vitro, it seems that it will only be a matter of time before it happpens in nature. It is puzzling that it appears such a difficult transposition to make. The mechanisms by which antibiotic-resistance genes move between organisms are complex, ancient and fascinating. One strategy used by strains of S. aureus is to place resistance genes onto the chromosome, thus producing more stable multiple drug resistance (Ron Skurray, University of Sydney, Australia). Ruth Hall (CSIRO, Sydney, Australia) described the intricacies of the nested sets of mobile elements that, under selection, can arrange and rearrange to adapt an organism to survive multiple antibiotics. At the first level are gene cassettes, consisting of a single gene and a 59-bp recombination site. Gene cassettes move by means of site-specific recombinases (integrases) that are encoded by an integron. Several gene cassettes can be taken into an integron site. There are three integron families and gene cassettes can move between them. Class 1 integrons can themselves be mobile and are also found on plasmids or within other transposons, as well as on chromosomes. Integron mobility dictates gene-cassette transfer between species. Although integration occurs at a very low frequency (10-7), this is obviously sufficient, and, once it has happened, it can spread very rapidly and is not lost when the selective pressure is removed. How stable is antibiotic resistance? It appears that there is little physiological cost to becoming drug resistant and what there is, is
10
OCTOBE
1996
C O M M E N T
compensated for by increased fitness (Bruce Levin, Emory University, Atlanta, GA, USA). By modelling resistance to two drugs, and together with the immune response, which of course acts on both sensitive and resistant organisms, it can be seen that selection favours some degree of resistance over sensitivity. Levin models antibiotic resistance arising from poor compliance or premature halting of drug treatment. Other important factors in selecting for resistance are variability in tissue and cellular distribution of an antibiotic in the context of the tendency for infections to compartmentalize. Classic examples are provided by M. tuberculosis and malaria, but all infections
compartmentalize to some extent. Some drugs act better in different compartments than others; the prodrug pyranizamide is used for M. tuberculosis living in the acid vacuoles of macrophages, but other tuberculosis drugs are ineffective against this stage. Therefore, it is important that a variety of antibiotics is used against this organism, otherwise it will be able to escape the effects of the drug and recolonize from a 'protected' compartment. As it is improbable that we will eliminate antibiotic resistance, it is vital that we buy time for the development of new antibiotics by the considered and responsible use of antibiotics. Penti Huovinen (University of Turku, Finland) demon-
strated just how effective community-based control of the use of erythromycin can be in reducing the incidence of resistant cases. This sort of programme needs to be accompanied by improved diagnostics and identification of the organisms causing an infection at the time of treatment, so that the most appropriate drug can be chosen. Additional measures include national and international policies for education, surveillance and use; there is currently no need to deny treatment to any patient. Reference
1 Noble,W.C.,Visari,Z. and Cree,R.G.A. (1992) FEMSMicrobiol. Lett. 93, 195-198
Oral pathogens as contributors systemic infections
to
Haroun N. Shah, Saheer E. Gharbia, David M.A. Andrews, Jonathan C. Williams, Nina Mehta and Kishor Gulabivala he mucosal surfaces of the oral cavity, gingival crevice and teeth provide selective habitats for a large and varied collection of specialized microbial communities. Constant changes in environmental influences dictate changes in the relative abundance between the species. The tooth provides a unique environment for bacteria in disease and health. The bulk of the tooth consists of dentine, a rigid structure that encapsulates the dental pulp, a soft connective tissue. The space occupied by the pulp usually follows the shape of the tooth but in the roots this space becomes very complex and convoluted and is known as the root canal system. The dentine is permeated by millions of tiny tubules that radiate outward from the pulp to its periphery and, in health, contain the cellular processes of specialized cells, the odontoblasts, which are bathed in a serum-derived fluid and
T
Overview of a conference held at the Eastman Dental Institute and Hospital for Oral Health Care Sciences and the Royal College of Surgeons of England, London, UK, 7-8 March 1996. H.N. Shah*, S.E. Gharbia, D.M.A. Andrews, J.C. Williams and N. Mehta are in the Dept of Microbiology,, and K. Gulahivala is in the Dept of Conservative Dentistry, Eastman Dental Institute, UniversiB, of London, 256 Gray's Inn Road, London, UK W C I X 8LD. *tel: +44 171 915 1052, fax: +44 171 915 1127, e-maih [email protected]
secrete the dentine. The dentine is covered on the outer surface by hard and less permeable tissues, constituting enamel in the crown region and cementum in the root region. The cementum attaches one end of the collagenous fibres that are also embedded in the investing bone and coronally in the gingival tissue,
Copyright © 1996 Elscvier Science Ltd. All rights reserved. 0966 842X/96/$15.00
,N
372
Vo,
4
iN{). 1 0
forming the periodontal ligament. This suspends the tooth and has viscoelastic properties. In health, the mucosal, gingival, dental and pulpal tissues provide effective barriers to bacterial invasion. However, during disease, ulceration of the mucosa, loss of attachment of periodontal tissues, loss of enamel or cementum and the necrosis of the dental pulp provide selective habitats from which bacteria may gain entry to the blood stream. The movement of teeth loosened by periodontal disease may pump bacteria into inflamed tissues and then into the blood stream. Ingestion and aspiration of pathogens into the mouth may offer further oppportunities for bacterial entry. The aim of this conference was to explore the evidence for bacterial migration, to discuss the techniques that may be useful to study these processes and to examine ways in which such activities may be controlled. Pll: S0966 842X{96)30026 7
()(7I()t',l.~R
1996
Events
resistance: the new apocalypse?
A
nt bmtlC e'~
0
•
Caroline Ash
p
erhaps not yet. Nevertheless, in the 1990s the public perception of the threat from new infectious agents has been fuelled by fear of AIDS, Ebola virus, Salmonella and mad-cow disease. A problem that is more likely to affect us personally is infection by antibiotic-resistant bacteria. Yet, few countries have any policy about regulating the use of antibiotics for human or agricultural use, few data are collected in a systematic way on the incidence of antibiotic resistance and there is no global surveillance. What there is, however, is increasing recognition among the scientific community of the global nature of this growing problem. Alexander Fleming was aware of the potential for bacteria adapting to avoid antibiotics, and the past 50 years have seen an extraordinary evolutionary 'experiment' in progress. Stuart Levy (Tufts University, Boston, MA, USA) presented the notion that antibiotics are societal drugs and that antibiotic resistance is an ecological problem. Antibiotic resistance has occurred by two distinct genetic mechanisms: (1) endogenous mutation, for example multiple drug resistance in Mycobacterium tuberculosis, and (2) the acquisition of resistance genes, for example aminoglycosidemodifying enzymes (Julian Davies, University of British Columbia, Vancouver, Canada). The origin of mobile resistance genes could be the antibiotic-producing organisms themselves; DNA can be detected in antibiotics prepared by fermentation. An interesting possibility is that antibiotics act almost as aphrodisiacs to stimulate conjugative transposition and, thus, facilitate the spread of plasmids that may contain drug-resistance genes. Of major concern is the nearuniversal use of antibiotics as growth promoters for the livestock
Ciba Foundation Symposium No. 207, Antibiotic resistance: origins, evolution, selection and spread. Held at the WeUcome Centre for Medical Science, London, UK, 19 July 1996. [email protected]
industry and the potential this has for the selection and transmission of antibiotic resistance. What is disturbing is the apparent lack of recognition by the industries involved of the relatively small benefit (3-4% growth gains) and the potentially serious consequences of persistent use of glycoside antibiotics, like avoparcin, for this purpose. Avoparcin resistance confers cross-resistance to glycosides such as vancomycin, which is the last effective antibiotic in human use for multiply resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Avoparcin use has led to a reservoir of transferable vanA-mediated glycopeptide resistance in Enterococcus faecalis. This organism can be transferred to humans in meat products and has been found in
HI: S0966-842X(96)30028-0
Copyright © 1996 Elsevier Science Ltd. All rights reserved. 0966 842X/96/$15.00
TRENDS,N
MIC
ROBIOLO
Y
371
VOL. 4
NO.
human faecal samples (Wolfgang Witte, Robert Koch Institute, Wernigerode, Germany). Bill Noble and colleagues have experimentally transferred vanA from E. faecalis to S. aureus (Ref. 1). Although this was achieved with difficulty in vitro, it seems that it will only be a matter of time before it happpens in nature. It is puzzling that it appears such a difficult transposition to make. The mechanisms by which antibiotic-resistance genes move between organisms are complex, ancient and fascinating. One strategy used by strains of S. aureus is to place resistance genes onto the chromosome, thus producing more stable multiple drug resistance (Ron Skurray, University of Sydney, Australia). Ruth Hall (CSIRO, Sydney, Australia) described the intricacies of the nested sets of mobile elements that, under selection, can arrange and rearrange to adapt an organism to survive multiple antibiotics. At the first level are gene cassettes, consisting of a single gene and a 59-bp recombination site. Gene cassettes move by means of site-specific recombinases (integrases) that are encoded by an integron. Several gene cassettes can be taken into an integron site. There are three integron families and gene cassettes can move between them. Class 1 integrons can themselves be mobile and are also found on plasmids or within other transposons, as well as on chromosomes. Integron mobility dictates gene-cassette transfer between species. Although integration occurs at a very low frequency (10-7), this is obviously sufficient, and, once it has happened, it can spread very rapidly and is not lost when the selective pressure is removed. How stable is antibiotic resistance? It appears that there is little physiological cost to becoming drug resistant and what there is, is
10
OCTOBE
1996
C O M M E N T
compensated for by increased fitness (Bruce Levin, Emory University, Atlanta, GA, USA). By modelling resistance to two drugs, and together with the immune response, which of course acts on both sensitive and resistant organisms, it can be seen that selection favours some degree of resistance over sensitivity. Levin models antibiotic resistance arising from poor compliance or premature halting of drug treatment. Other important factors in selecting for resistance are variability in tissue and cellular distribution of an antibiotic in the context of the tendency for infections to compartmentalize. Classic examples are provided by M. tuberculosis and malaria, but all infections
compartmentalize to some extent. Some drugs act better in different compartments than others; the prodrug pyranizamide is used for M. tuberculosis living in the acid vacuoles of macrophages, but other tuberculosis drugs are ineffective against this stage. Therefore, it is important that a variety of antibiotics is used against this organism, otherwise it will be able to escape the effects of the drug and recolonize from a 'protected' compartment. As it is improbable that we will eliminate antibiotic resistance, it is vital that we buy time for the development of new antibiotics by the considered and responsible use of antibiotics. Penti Huovinen (University of Turku, Finland) demon-
strated just how effective community-based control of the use of erythromycin can be in reducing the incidence of resistant cases. This sort of programme needs to be accompanied by improved diagnostics and identification of the organisms causing an infection at the time of treatment, so that the most appropriate drug can be chosen. Additional measures include national and international policies for education, surveillance and use; there is currently no need to deny treatment to any patient. Reference
1 Noble,W.C.,Visari,Z. and Cree,R.G.A. (1992) FEMSMicrobiol. Lett. 93, 195-198
Oral pathogens as contributors systemic infections
to
Haroun N. Shah, Saheer E. Gharbia, David M.A. Andrews, Jonathan C. Williams, Nina Mehta and Kishor Gulabivala he mucosal surfaces of the oral cavity, gingival crevice and teeth provide selective habitats for a large and varied collection of specialized microbial communities. Constant changes in environmental influences dictate changes in the relative abundance between the species. The tooth provides a unique environment for bacteria in disease and health. The bulk of the tooth consists of dentine, a rigid structure that encapsulates the dental pulp, a soft connective tissue. The space occupied by the pulp usually follows the shape of the tooth but in the roots this space becomes very complex and convoluted and is known as the root canal system. The dentine is permeated by millions of tiny tubules that radiate outward from the pulp to its periphery and, in health, contain the cellular processes of specialized cells, the odontoblasts, which are bathed in a serum-derived fluid and
T
Overview of a conference held at the Eastman Dental Institute and Hospital for Oral Health Care Sciences and the Royal College of Surgeons of England, London, UK, 7-8 March 1996. H.N. Shah*, S.E. Gharbia, D.M.A. Andrews, J.C. Williams and N. Mehta are in the Dept of Microbiology,, and K. Gulahivala is in the Dept of Conservative Dentistry, Eastman Dental Institute, UniversiB, of London, 256 Gray's Inn Road, London, UK W C I X 8LD. *tel: +44 171 915 1052, fax: +44 171 915 1127, e-maih [email protected]
secrete the dentine. The dentine is covered on the outer surface by hard and less permeable tissues, constituting enamel in the crown region and cementum in the root region. The cementum attaches one end of the collagenous fibres that are also embedded in the investing bone and coronally in the gingival tissue,
Copyright © 1996 Elscvier Science Ltd. All rights reserved. 0966 842X/96/$15.00
,N
372
Vo,
4
iN{). 1 0
forming the periodontal ligament. This suspends the tooth and has viscoelastic properties. In health, the mucosal, gingival, dental and pulpal tissues provide effective barriers to bacterial invasion. However, during disease, ulceration of the mucosa, loss of attachment of periodontal tissues, loss of enamel or cementum and the necrosis of the dental pulp provide selective habitats from which bacteria may gain entry to the blood stream. The movement of teeth loosened by periodontal disease may pump bacteria into inflamed tissues and then into the blood stream. Ingestion and aspiration of pathogens into the mouth may offer further oppportunities for bacterial entry. The aim of this conference was to explore the evidence for bacterial migration, to discuss the techniques that may be useful to study these processes and to examine ways in which such activities may be controlled. Pll: S0966 842X{96)30026 7
()(7I()t',l.~R
1996