- Email: [email protected]
Drug-resistant bacteria: responding to the infectious disease crisis
Persp e tires
r ..r. e
lrl" f e c t i ° ..
....... s
e cr'lsms
The 1990s have been a period of growing anxiety about the emergence of antibiotic-resistantbacteria. Public health, society and the research communitymus~ respond quickByto safeguard existing drugs and develop new ones to prevent resistance ove~hemming heaRhcaresystems wormdwide. The medical and pharmaceutical sciences have been very successful at developing and introducing powerful and effective antibiotics. However, the inevitable result of the widespread use of any antibacterial agent is that resistant bacteria will emerge, a direct consequence of rapidly replicating, fas|-mutating organisms. Antibiotic resistance in the 1990s According to |he World Health Report (Wor!d Health Assembly, May 1996L infectious diseases are the major cause of prema|ure death, killing 17 million people last year (9 million of |hem children). The reasons why these diseases arc rising up the public heahh agenda are complex: some increases arise from changes in public heahi! policy, and some from demographic and social ct!angcs (such as poverty, migration, war or civil unrest), but part of this resurgence result.,; from a breakdown in the effective control of infections by existing drugs, This is not a new problem; although no figures are available to quantify ils extent, antibiotic Ivsistance has been reported |br at least 20 years. Antibiotic resistance is mo~,.t often first recognized in vulnerable gr,:~ps such as the very young, the very old, the immunosuppressed (particularly cancer patients and post-transplant patients) and those with AIDS. The total number of individuals in these vulnerable groups is rising worldwide ar,d this partly explains the current 'crisis'. The list of most disquieting drug-resistant bacteria does change, but those identified so far include: Mycobacterium tuberculosis (see Box l), Neisseria gonorrhoeae, Sltwtot'oct'us pyogenes, Streptococcus pneumoniae and Escherichia coli. These all are commonly mul',drug resistant (see Box 2). Antibiotic misuse Almost all antibiotics were, and in many cases still at., overprescribed, available without medical supervision or ,.sod by the consumer in such a way that the selection and outgro, ah of resistant organisms is encouraged. In addition to their medical use, antibiotic drugs are widely used in food production and ar.: given to animals Copyright ©1996 Elsevier Science Ltd. All rights reserved 1357 - 4310/96/$15.00
as growth promoters as well as to prevent and cure diseases of animals. The quinolone antibiotics, such as ciprofloxacin, are verb p ,,verful drugs active against a wide range of Gram-positive at., Groansnegative organisms, and are frequently used to treat infe,,~ons ot the respiratory tract, urinary tract, bone and skin involv:,~g E. colt, N. ,~tmorrhoeae, H. it!ihwnzae and Legionella tmetv, phila. The, ~e~e welcomed when imroduced taboul ten years 4o1 because ~t was claimed that their use did not lead to antibi,'*+c resistance, ltowevct, resistance has recently appeared ili Mra; ~S Ol Campyh~bacwr m 'a number of European countries, and ,,m contributirlg iactor is the widespread use of quinohmes ill pw ary rearing and fish tanmng. ............. {an amibiolic relal, a t~ vancomycin) ix widely used in Europe and elsewhere as a gr ,wlh promoter tbr cattle and other animals. Its use has been imrhcated in the emergence of vancomycie° resistant enterococci. Lpramychl is an aminoglycoside antibiotic {licensed ot~iy lbr ao:,nal use) but some apramyci,>rcsistant bacteria have also been D.,nd to be resistant to other aminog!ycosides, such as gentamycin and tobramycin, which are widely used in clinical practice. Thee is also evidence for the spread of the plasmids enc~}ding resistance ,o apramycin between strains and even between species. M o k c u l a r mechanisms of antibiotic resistance Experts at a recent conference* rejected the term widely used in ,no media - 'superbug' - to describe multi-drug resistance bacteria because, in their opinion, all of these microorganisms are super: they have an amazing capacity to mutate their own housekeeping genes. take on a drug,resistant phenotype or alternatively zcquire genes from other related or unrelated bacterial species (via transposon,~,
* Wellcome Centre tot Medical Science and Ciba Foundation meeting on Antibiotic Resistance: Origins, Evolution, Selection and Spread, 19 July 1996, Proceedings, of the preceding Ciba Symposium will be published by the Ciba Foundation lale in 1996.
Pn: si357-4310t96)20032-2
499
NIt:)LI~CtlI.AR KIFA)iCINIE TOI)A'V. 131:.C,I~:.MI:H.~I~ I~O~
Ma~ people considered TB a 'disease of the past'; by the late 1970s it sectrLedto be effectively under control, at least in the developed world. Contacts of patients with TB were quickly traced and treatment was effective if a combination of powerful antibiotics was used for a sufficiently long ~ o d , usually 6-12 months. In the UK, the number of annually reccmiedcases had fallen steadily since the start of this century. However, in the late 1980s the incidence of TB began to increase dramatically, particularly in the developing world and especially in areas w ~ HIV infection was rife. People who become HIV positive dramatically lose the function of the cellular arm of their immune system. becoming less able to combat a wide variety of diseases. The World Health Organization ~)w predicts that TB will be the main cause of death in HIV-positivepatients in the world by the end of this century. An additional factor is the spread of resistance to isoniazid, one of the cornerstones of TB therapy, and this is particularly important in the USA in subgroups of the population such as Hispanics, In 1994, TB :tiled 29 000 people in the Confederacy of Independent States (CIS), and deaths from ~ in Moscow have doubled in the past two years.
• My¢obacteriumtuberculosis (see Box 1), Q Stophyltwoccu,~ aureus infections canse ba~teraemia, endocarditis. pneumonia and other disca~s, !n the past, such infections could be effectively ~ated by a v~t~ty of antibiotics such as nafcillin and oxacillin; this is no longer the case and in developed countries vancomycin remains the only antibiotic that can now be used to treat systemic infection resulting t~m this mlemorgttnism, Most ~xpert opinion now thinks that it is only a mittter of time bofo~ we see v~u~comy¢in,resistant smdns of st~phyl~occi, • The incidence of Clostridium d~cile infection increased sixfold in ~ l a n d and Waks over the period 1 ~ 1 9 9 3 , Although there are a numMr of ~ l b l e reaso~ to expMn this, intrepid environmental con, tamination by C, d~cite spores and increased antibiotic use arc almost c~ainty con~betin8 factors, • Recently,penicillin-resistantStreptococcus pneumoniae has emerged; it has been found that standard doses of third-generation cephalospodns such as ce~a,xone and ¢efotaxim¢ have been ineffective, making the treatment of this form of pneumococcal meningitis more complicated, particularly in children (who ~ more susoeptibleL However, high doses of these agents have been found to be effective in this form of meningitis w ~ used in combination with vancomycin, How long this will continue remains m be seen.
• Enterococci resistant to vancomycin were first reported only nine y ~ ago, bet in the interveningperiod they have become established in many highdcperflcncy hospital areas (such as renal ~d intensive care units) throughout Europe, the USA and elsewhere, The source of infection is normally by transmission of faecal flora from one patient to ~other, vi~ toilets and inadequate sterile. ~ u ~ s , Although e.nteroco¢¢ai inf~tions ate rarely life threatening, they signal another weakness in our armmentadum because glycopeptides such as vancomycin and teic®lanin are our last defenc'e in many cases,
$OO
plasmids, bacteriophages, DNA uptake, transduction, transportation or conjugation). Many individual bacteria show multiple mechanisms for resistance to diverse drugs (including antiseptics and disinfectants). The individual mechanisms by which this occurs are increasingly being discovered (for example, much work is currently being done on mobile genetic elements such as integrons and mobile gene cassettes) and in the future we can expect new classes of drugs that will target these mechanisms rather than the resistance genes themselves. A novel source of resistance genes was discussed at the same conference by Julian Davies (University of British Columbia, Canada). Antibiotics are often commercially produced by fermentation using microorganisms that, to survive, must have resistance genes. Studies have shown that clinical-grade antibiotic preparations themselves have contaminating DNA present from these producer organisms. DNA has been cloned out of these contaminants and resistance has been transferred to bacteria in vinw. Whether this is a true, important source of resistance genes is not yet known, but is well worth studying because it should be relatively easy to monitor and remove this source of contamination. Response by the pharmaceutical industry In the 1960s, widespread use of ampicillin and related [3dactamcontaining agents led to the evolution and spread of plasmidmediated [3dactamase TEM (named after 'Temovera', the first patient from whom a bacterium carrying the gene was recovered) and its close relative SHV. Both SHV and TEM confer resistance to ampicillin, penicillin and related antibiotics. In response, drug companies developed new antibiotics, ~uch as methicillin and cefotaxime (extended-spectrum ~-!actams), which were very resistant to such enzymatic breakdown. However, heavy use of these new drugs has now led to the appearance of extended-sl~ctrum ~-hctamases (ESBLs; Professor P.M, Hawkey at the Department of Microbiology, Leeds General Infirmary, prefers to define ESBLs as 'ever stranger hurtling lactamases'), initially, ESBLs appeared in Europe, but |hey are now found everywhere and, according to Hawkey, the spread of ESBLs is undermining the clinical effectiveness of extended-spectrum ~dactams. Many bacteria, particularly Gram-negative strains such as Escherichia colt and Haemophilus b~fluenzae, have genes that encode ~-Iactamases and, under normal circumstances, these would only be expressed at very low levels and would not be capable of transfer between strains; however, some bacterial mutations result in large quantities of such enzymes being produced with the consequent emergence of [~-Iactam resistance. These drugs wer~ the result of enormous research effort and experience by the pharmaceutical industry and it is startling that the substitution of just one or two amino acids can have such a fundamental effect oa 13-1actamasc function. Recycling established drugs Some drugs developed for appl',caiions other than as anti-infecfives are effective antibiotics. Exploiting these compounds obviously makes good economic sense and the Intematiunal Society for Antimicrobial Activity of Non-Antibiotics was formed a few years ago, holding its first meeting in Copenhagen in 1990. A typical example of this approach is the phenothiazines, developed initially as psychotropic agents. These drugs also have antibacterial, antiplasmid and imnmnomodulatory effects. For a variety of reasons, the incidence of TB is high in some groups of people with severe
fv
mental illnesses. When the phcnoflfiazines we~v fh's~ ~sed m some of these patients, an improvemem in ~heir TB slams was noted. There is a structural shuilarity between ch~orproma~:ine, one of ~he i"ks~ phenothiazines, and the dye methylene bh~e used extensive!y m his~olog>~ to siain bacteria. Local anaesthetics and even ~-Nocke~s are now ~so being evaluated for their effects on Gram-positive and Gram-negative bacteria. It shoutd be quicker and cheaper to test existing drugs for antibacterial use and their toxicity will be better understood. New targets and new technology The search for new drugs, or more powerful combinations, continues following several different strategies. A number of companies have taken up the challenge of antibiotic resistance. In response to the re-emergence of TB, |br example, Glaxo=Welicome have set up a major international mtdtidisciplina~/TB programme aimed at studying the pathology of TB and using this infom~adon to develop ratio° na! strategies for new drugs, vaccines or immunotherapy. Detailed analyses of the population genetics of a number of bacteria have been carried out over the past ten years and it is now cleat" that distinct bacterial clones are responsible for many disease outbre'~ks and the incleasing incidence of some infections (see Box 3). Among the new targets for novel anti-infective agents identified so far are the effiux pumps on bacterial membranes, and the processes of bacterial DNA replication and cell division, because these play important roles in bacterial development. In addition, the twocomponent signalling systems in bacteria that regulate their responses to ex|emal stimuli are also being studied and a number of inhibitors have been identified. Rh6ne@oulenc Rorer are developing a new oral streptogramin. RP 59500, which is a combination of quinupristin and dalfopristin with a synergistic effect against Gram-positive bacteria, including those resistant to vancomycin. Semi-synthettc glycopeptide antibiotics are also being developed, such as the Lilly compound LY264826; these iue effective against current glycopeptideq'esistant entemcocci as well as methicillin-resistant Staphylo,:'o,','us amwus and penicillinresistant pneumococci. These drugs ate cur|e!ll!y t!ndergoillg clinical trials. We can, however, expect resistance to these drugs to develop with use.
Priorities for R&D bmlgets Huge numbers of novel compounds are available to the phannaceutical industry |br testing, and advances in combinatorial chemistry, rapid synthesis and automated testing should accelerate the discovery of drag leads~ According to Dr Barry Ross (Glaxo-Wellcome, Uxbridge, UK), for all therapeutic applications, 'recent advances now allow Glaxo to screen 1130million sample compounds a year.' Cynics have claimed that antibiotic resistance keeps R&D departments in full employment. However, even the largest companies have severe restrictions on their budgets and most concentrate on a selected number of therapeutic areas. All this research is expensive, and a recent estimate suggests that it now costs about US $250 million and takes 10--12 years to get a new chemical entity onto the clinical market. Only the largest pharmaceutical companies have the resources and experience to achieve this. Development of a constant stream of antibiotics is not as attractive as it used to be, particularly if resistance develops after a relatively short period, perhaps before R&D costs can be recouped. This is reflected in the fact that in 1995 only two new antibacterial agents - meropenem (a carbapenem
....
The complete genomes of two bacterial pathogens, eqaemoph3us infiue
produced by Zeneca)and cefph'ome /a ceplmlosp~rm produced by Roussel) -- wei=e launched in the UK. Also, a decade or more ago, when it w,ts thought that we had developed efi~ctive therapies or vac~, cines for most of the infectious diseases, a number of pharmaceutical companies switched the major part of their research eflbrls to olher areas of hwestigation (particularly chronic diseases). Consequently, the challenges of stroke, obesity, cancer, inflammation and AiDS have taken a large portion of the available linancial and human resources. Changes in the delivery and economics of healthcare systems across the world, including the introduction of 'managed care', have also put additional pressure on industry to make difficult R&D decisions using pharmaco-economic data to prioritize target illnesses.
Reversal of resistance? Studies have shown that if antibiotics are taken for a period of time the sampled E. colt in the gut becomes resistant to the antibiotic mixtures. For a period of time alter cessation of use, the E. colt remain resistant. In some cases, the sensitive bacteria eventually overgrow, but some degree of resistance is never lost. It is thought that in a mixed flora the sensitive bacteria could have a marginal advantage over the resistant ones, although the resistant bacteria soon compensate for the slight 'cost' of being resistant. Once antibiotic resistance has occurred, its spread is selected for by the clinical and environmental use of antibiotics. The experts at the Ciba conference 501
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• $~ c~ of antibiotics • Cyclical use of antibiotics • ~ n t use of antibiotics • Education of the public, healthcare professionals and pharmaceuticrd c~es (to m~et antibiotics in a different way to consumers: 'use and sty') • ~ e l o ~ e n t of 'resistance-resistant' drugs, or drugs to novel targets • ~elopment of drugs for new applications • R~on o [ ~ i n i t i a l florato a 'susceptible'phenotype
proposed that one achievable goal is to encourage drug.sensitive bacteria to 'reassert themselves'; one chemical approach is to use drug combinations such as clavulanic acid (a suicide inhibitor of t~-Iac° tanaases) and amoxicillin, However, such 'poisoning' of the resistance mechanism will not be easy to achieve, Prev~,ntion of re,~i~tance We cannot eXl~Ct the ph~tnnaceutical industry alone to bear the strain of antibiotic resistance, There are several ways in which healthca~ workers, consumers and policy makers can help (Box 4), Antibiotic resistance only becomes a problem when socioeconomic factors encourage the rate of emergence to increase to the extent where human health is compromised, We need to understand these factors further and act on them in order to safeguard our existing and future armamentarium of drugs. According to Professor D'~vid Greenwood tQueen's Medical Centre, Nottingham, UK), 'We have enough anttbacterial agents, but we must learn to use them more circumspectly,' Certainly, dt~tors are now [~ing encouraged to restrict the prescribing of antibiotics for trivial complaints, and there is now much greater awareness of the problem among the medical profession, In an ideal world, antibiotic sensitivity testing would be carried out belbre drugs are prescribed and the most appropriate agent (or combin~tion) would be used, followed by more testing to ensure that the infection had been eliminated. Obviously, this is not practicable and our best approach is to use more carefully those drugs for which there is least evidence of resistance (for example vancomycin) while concentrating efforts on developing new agents to replace them. The general public also needs to be educated not to e:~pect antibiotics and not to misuse them. Much of this current crisis is a direct result of human action and it is unrealistic to expect professionals to eliminate antibiotic resistance entirely.
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Public health must continue to monitor the incidence of antibiotic resistance worldwide, and molecular epidemiological techniques need to be further applied to follow the migratior~ of particular mutations/genes and predict their spread. It is also imperative that there is effective dialogue between the food industry and public health authorities to protect humans from the additional risk arising from antibiotic use in animals. Indeed, in August there was a plea in The Lancet from Dutch microbiologists to ban the use of all antibiotics as animal growth-promoting agents [van den Boga,'u'd, A.E. ,and Stobberingh, E.E. (1996)Lancet 348, 619].
Optimism for the next century? As far as the broader picture is concerned, Dr Davies is cautious: 'No matter what agent is used, sooner or later the bugs will develop resistance, so in one sense we will never win the battle. Whal is needed is to change the prescribing practices and to guarantee a constant pipeline of new antibiotics which should be used prudently.' Dr Stuart Levy (Tufts University School of Medicine, Boston, MA, USA) regards antibiotics as societal drugs: 'Each time one is used it contributes to the sum total of societ3~'s antibiotic exposure.' However, Dr Levy remains optimistic: 'Here at Tufts, and with the Alliance for the Prudent Use of Antibiotics ~, we are educating the public and doctors not to prescribe antibiotics unless absolutely necessary. Economics will also play a role. In the USA, managed healthcare organizations are reluctant to allow doctors to prescribe expensive antibiotics and so education and economics are both important factors.' Meanwhile, the new "molecular approaches' to drug discovery and development should be expected to reduce the impact of antibiotic resistance in the early part of the next century.
TheAllianceforthe PrudentUseofAntibiotics(APUA)is an internationatorganization in 93 countriesdedicatedto promotingthe effectiveuse of antibioticsworklwidethrough educationand research,
r ..r. e
lrl" f e c t i ° ..
....... s
e cr'lsms
The 1990s have been a period of growing anxiety about the emergence of antibiotic-resistantbacteria. Public health, society and the research communitymus~ respond quickByto safeguard existing drugs and develop new ones to prevent resistance ove~hemming heaRhcaresystems wormdwide. The medical and pharmaceutical sciences have been very successful at developing and introducing powerful and effective antibiotics. However, the inevitable result of the widespread use of any antibacterial agent is that resistant bacteria will emerge, a direct consequence of rapidly replicating, fas|-mutating organisms. Antibiotic resistance in the 1990s According to |he World Health Report (Wor!d Health Assembly, May 1996L infectious diseases are the major cause of prema|ure death, killing 17 million people last year (9 million of |hem children). The reasons why these diseases arc rising up the public heahh agenda are complex: some increases arise from changes in public heahi! policy, and some from demographic and social ct!angcs (such as poverty, migration, war or civil unrest), but part of this resurgence result.,; from a breakdown in the effective control of infections by existing drugs, This is not a new problem; although no figures are available to quantify ils extent, antibiotic Ivsistance has been reported |br at least 20 years. Antibiotic resistance is mo~,.t often first recognized in vulnerable gr,:~ps such as the very young, the very old, the immunosuppressed (particularly cancer patients and post-transplant patients) and those with AIDS. The total number of individuals in these vulnerable groups is rising worldwide ar,d this partly explains the current 'crisis'. The list of most disquieting drug-resistant bacteria does change, but those identified so far include: Mycobacterium tuberculosis (see Box l), Neisseria gonorrhoeae, Sltwtot'oct'us pyogenes, Streptococcus pneumoniae and Escherichia coli. These all are commonly mul',drug resistant (see Box 2). Antibiotic misuse Almost all antibiotics were, and in many cases still at., overprescribed, available without medical supervision or ,.sod by the consumer in such a way that the selection and outgro, ah of resistant organisms is encouraged. In addition to their medical use, antibiotic drugs are widely used in food production and ar.: given to animals Copyright ©1996 Elsevier Science Ltd. All rights reserved 1357 - 4310/96/$15.00
as growth promoters as well as to prevent and cure diseases of animals. The quinolone antibiotics, such as ciprofloxacin, are verb p ,,verful drugs active against a wide range of Gram-positive at., Groansnegative organisms, and are frequently used to treat infe,,~ons ot the respiratory tract, urinary tract, bone and skin involv:,~g E. colt, N. ,~tmorrhoeae, H. it!ihwnzae and Legionella tmetv, phila. The, ~e~e welcomed when imroduced taboul ten years 4o1 because ~t was claimed that their use did not lead to antibi,'*+c resistance, ltowevct, resistance has recently appeared ili Mra; ~S Ol Campyh~bacwr m 'a number of European countries, and ,,m contributirlg iactor is the widespread use of quinohmes ill pw ary rearing and fish tanmng. ............. {an amibiolic relal, a t~ vancomycin) ix widely used in Europe and elsewhere as a gr ,wlh promoter tbr cattle and other animals. Its use has been imrhcated in the emergence of vancomycie° resistant enterococci. Lpramychl is an aminoglycoside antibiotic {licensed ot~iy lbr ao:,nal use) but some apramyci,>rcsistant bacteria have also been D.,nd to be resistant to other aminog!ycosides, such as gentamycin and tobramycin, which are widely used in clinical practice. Thee is also evidence for the spread of the plasmids enc~}ding resistance ,o apramycin between strains and even between species. M o k c u l a r mechanisms of antibiotic resistance Experts at a recent conference* rejected the term widely used in ,no media - 'superbug' - to describe multi-drug resistance bacteria because, in their opinion, all of these microorganisms are super: they have an amazing capacity to mutate their own housekeeping genes. take on a drug,resistant phenotype or alternatively zcquire genes from other related or unrelated bacterial species (via transposon,~,
* Wellcome Centre tot Medical Science and Ciba Foundation meeting on Antibiotic Resistance: Origins, Evolution, Selection and Spread, 19 July 1996, Proceedings, of the preceding Ciba Symposium will be published by the Ciba Foundation lale in 1996.
Pn: si357-4310t96)20032-2
499
NIt:)LI~CtlI.AR KIFA)iCINIE TOI)A'V. 131:.C,I~:.MI:H.~I~ I~O~
Ma~ people considered TB a 'disease of the past'; by the late 1970s it sectrLedto be effectively under control, at least in the developed world. Contacts of patients with TB were quickly traced and treatment was effective if a combination of powerful antibiotics was used for a sufficiently long ~ o d , usually 6-12 months. In the UK, the number of annually reccmiedcases had fallen steadily since the start of this century. However, in the late 1980s the incidence of TB began to increase dramatically, particularly in the developing world and especially in areas w ~ HIV infection was rife. People who become HIV positive dramatically lose the function of the cellular arm of their immune system. becoming less able to combat a wide variety of diseases. The World Health Organization ~)w predicts that TB will be the main cause of death in HIV-positivepatients in the world by the end of this century. An additional factor is the spread of resistance to isoniazid, one of the cornerstones of TB therapy, and this is particularly important in the USA in subgroups of the population such as Hispanics, In 1994, TB :tiled 29 000 people in the Confederacy of Independent States (CIS), and deaths from ~ in Moscow have doubled in the past two years.
• My¢obacteriumtuberculosis (see Box 1), Q Stophyltwoccu,~ aureus infections canse ba~teraemia, endocarditis. pneumonia and other disca~s, !n the past, such infections could be effectively ~ated by a v~t~ty of antibiotics such as nafcillin and oxacillin; this is no longer the case and in developed countries vancomycin remains the only antibiotic that can now be used to treat systemic infection resulting t~m this mlemorgttnism, Most ~xpert opinion now thinks that it is only a mittter of time bofo~ we see v~u~comy¢in,resistant smdns of st~phyl~occi, • The incidence of Clostridium d~cile infection increased sixfold in ~ l a n d and Waks over the period 1 ~ 1 9 9 3 , Although there are a numMr of ~ l b l e reaso~ to expMn this, intrepid environmental con, tamination by C, d~cite spores and increased antibiotic use arc almost c~ainty con~betin8 factors, • Recently,penicillin-resistantStreptococcus pneumoniae has emerged; it has been found that standard doses of third-generation cephalospodns such as ce~a,xone and ¢efotaxim¢ have been ineffective, making the treatment of this form of pneumococcal meningitis more complicated, particularly in children (who ~ more susoeptibleL However, high doses of these agents have been found to be effective in this form of meningitis w ~ used in combination with vancomycin, How long this will continue remains m be seen.
• Enterococci resistant to vancomycin were first reported only nine y ~ ago, bet in the interveningperiod they have become established in many highdcperflcncy hospital areas (such as renal ~d intensive care units) throughout Europe, the USA and elsewhere, The source of infection is normally by transmission of faecal flora from one patient to ~other, vi~ toilets and inadequate sterile. ~ u ~ s , Although e.nteroco¢¢ai inf~tions ate rarely life threatening, they signal another weakness in our armmentadum because glycopeptides such as vancomycin and teic®lanin are our last defenc'e in many cases,
$OO
plasmids, bacteriophages, DNA uptake, transduction, transportation or conjugation). Many individual bacteria show multiple mechanisms for resistance to diverse drugs (including antiseptics and disinfectants). The individual mechanisms by which this occurs are increasingly being discovered (for example, much work is currently being done on mobile genetic elements such as integrons and mobile gene cassettes) and in the future we can expect new classes of drugs that will target these mechanisms rather than the resistance genes themselves. A novel source of resistance genes was discussed at the same conference by Julian Davies (University of British Columbia, Canada). Antibiotics are often commercially produced by fermentation using microorganisms that, to survive, must have resistance genes. Studies have shown that clinical-grade antibiotic preparations themselves have contaminating DNA present from these producer organisms. DNA has been cloned out of these contaminants and resistance has been transferred to bacteria in vinw. Whether this is a true, important source of resistance genes is not yet known, but is well worth studying because it should be relatively easy to monitor and remove this source of contamination. Response by the pharmaceutical industry In the 1960s, widespread use of ampicillin and related [3dactamcontaining agents led to the evolution and spread of plasmidmediated [3dactamase TEM (named after 'Temovera', the first patient from whom a bacterium carrying the gene was recovered) and its close relative SHV. Both SHV and TEM confer resistance to ampicillin, penicillin and related antibiotics. In response, drug companies developed new antibiotics, ~uch as methicillin and cefotaxime (extended-spectrum ~-!actams), which were very resistant to such enzymatic breakdown. However, heavy use of these new drugs has now led to the appearance of extended-sl~ctrum ~-hctamases (ESBLs; Professor P.M, Hawkey at the Department of Microbiology, Leeds General Infirmary, prefers to define ESBLs as 'ever stranger hurtling lactamases'), initially, ESBLs appeared in Europe, but |hey are now found everywhere and, according to Hawkey, the spread of ESBLs is undermining the clinical effectiveness of extended-spectrum ~dactams. Many bacteria, particularly Gram-negative strains such as Escherichia colt and Haemophilus b~fluenzae, have genes that encode ~-Iactamases and, under normal circumstances, these would only be expressed at very low levels and would not be capable of transfer between strains; however, some bacterial mutations result in large quantities of such enzymes being produced with the consequent emergence of [~-Iactam resistance. These drugs wer~ the result of enormous research effort and experience by the pharmaceutical industry and it is startling that the substitution of just one or two amino acids can have such a fundamental effect oa 13-1actamasc function. Recycling established drugs Some drugs developed for appl',caiions other than as anti-infecfives are effective antibiotics. Exploiting these compounds obviously makes good economic sense and the Intematiunal Society for Antimicrobial Activity of Non-Antibiotics was formed a few years ago, holding its first meeting in Copenhagen in 1990. A typical example of this approach is the phenothiazines, developed initially as psychotropic agents. These drugs also have antibacterial, antiplasmid and imnmnomodulatory effects. For a variety of reasons, the incidence of TB is high in some groups of people with severe
fv
mental illnesses. When the phcnoflfiazines we~v fh's~ ~sed m some of these patients, an improvemem in ~heir TB slams was noted. There is a structural shuilarity between ch~orproma~:ine, one of ~he i"ks~ phenothiazines, and the dye methylene bh~e used extensive!y m his~olog>~ to siain bacteria. Local anaesthetics and even ~-Nocke~s are now ~so being evaluated for their effects on Gram-positive and Gram-negative bacteria. It shoutd be quicker and cheaper to test existing drugs for antibacterial use and their toxicity will be better understood. New targets and new technology The search for new drugs, or more powerful combinations, continues following several different strategies. A number of companies have taken up the challenge of antibiotic resistance. In response to the re-emergence of TB, |br example, Glaxo=Welicome have set up a major international mtdtidisciplina~/TB programme aimed at studying the pathology of TB and using this infom~adon to develop ratio° na! strategies for new drugs, vaccines or immunotherapy. Detailed analyses of the population genetics of a number of bacteria have been carried out over the past ten years and it is now cleat" that distinct bacterial clones are responsible for many disease outbre'~ks and the incleasing incidence of some infections (see Box 3). Among the new targets for novel anti-infective agents identified so far are the effiux pumps on bacterial membranes, and the processes of bacterial DNA replication and cell division, because these play important roles in bacterial development. In addition, the twocomponent signalling systems in bacteria that regulate their responses to ex|emal stimuli are also being studied and a number of inhibitors have been identified. Rh6ne@oulenc Rorer are developing a new oral streptogramin. RP 59500, which is a combination of quinupristin and dalfopristin with a synergistic effect against Gram-positive bacteria, including those resistant to vancomycin. Semi-synthettc glycopeptide antibiotics are also being developed, such as the Lilly compound LY264826; these iue effective against current glycopeptideq'esistant entemcocci as well as methicillin-resistant Staphylo,:'o,','us amwus and penicillinresistant pneumococci. These drugs ate cur|e!ll!y t!ndergoillg clinical trials. We can, however, expect resistance to these drugs to develop with use.
Priorities for R&D bmlgets Huge numbers of novel compounds are available to the phannaceutical industry |br testing, and advances in combinatorial chemistry, rapid synthesis and automated testing should accelerate the discovery of drag leads~ According to Dr Barry Ross (Glaxo-Wellcome, Uxbridge, UK), for all therapeutic applications, 'recent advances now allow Glaxo to screen 1130million sample compounds a year.' Cynics have claimed that antibiotic resistance keeps R&D departments in full employment. However, even the largest companies have severe restrictions on their budgets and most concentrate on a selected number of therapeutic areas. All this research is expensive, and a recent estimate suggests that it now costs about US $250 million and takes 10--12 years to get a new chemical entity onto the clinical market. Only the largest pharmaceutical companies have the resources and experience to achieve this. Development of a constant stream of antibiotics is not as attractive as it used to be, particularly if resistance develops after a relatively short period, perhaps before R&D costs can be recouped. This is reflected in the fact that in 1995 only two new antibacterial agents - meropenem (a carbapenem
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The complete genomes of two bacterial pathogens, eqaemoph3us infiue
produced by Zeneca)and cefph'ome /a ceplmlosp~rm produced by Roussel) -- wei=e launched in the UK. Also, a decade or more ago, when it w,ts thought that we had developed efi~ctive therapies or vac~, cines for most of the infectious diseases, a number of pharmaceutical companies switched the major part of their research eflbrls to olher areas of hwestigation (particularly chronic diseases). Consequently, the challenges of stroke, obesity, cancer, inflammation and AiDS have taken a large portion of the available linancial and human resources. Changes in the delivery and economics of healthcare systems across the world, including the introduction of 'managed care', have also put additional pressure on industry to make difficult R&D decisions using pharmaco-economic data to prioritize target illnesses.
Reversal of resistance? Studies have shown that if antibiotics are taken for a period of time the sampled E. colt in the gut becomes resistant to the antibiotic mixtures. For a period of time alter cessation of use, the E. colt remain resistant. In some cases, the sensitive bacteria eventually overgrow, but some degree of resistance is never lost. It is thought that in a mixed flora the sensitive bacteria could have a marginal advantage over the resistant ones, although the resistant bacteria soon compensate for the slight 'cost' of being resistant. Once antibiotic resistance has occurred, its spread is selected for by the clinical and environmental use of antibiotics. The experts at the Ciba conference 501
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• $~ c~ of antibiotics • Cyclical use of antibiotics • ~ n t use of antibiotics • Education of the public, healthcare professionals and pharmaceuticrd c~es (to m~et antibiotics in a different way to consumers: 'use and sty') • ~ e l o ~ e n t of 'resistance-resistant' drugs, or drugs to novel targets • ~elopment of drugs for new applications • R~on o [ ~ i n i t i a l florato a 'susceptible'phenotype
proposed that one achievable goal is to encourage drug.sensitive bacteria to 'reassert themselves'; one chemical approach is to use drug combinations such as clavulanic acid (a suicide inhibitor of t~-Iac° tanaases) and amoxicillin, However, such 'poisoning' of the resistance mechanism will not be easy to achieve, Prev~,ntion of re,~i~tance We cannot eXl~Ct the ph~tnnaceutical industry alone to bear the strain of antibiotic resistance, There are several ways in which healthca~ workers, consumers and policy makers can help (Box 4), Antibiotic resistance only becomes a problem when socioeconomic factors encourage the rate of emergence to increase to the extent where human health is compromised, We need to understand these factors further and act on them in order to safeguard our existing and future armamentarium of drugs. According to Professor D'~vid Greenwood tQueen's Medical Centre, Nottingham, UK), 'We have enough anttbacterial agents, but we must learn to use them more circumspectly,' Certainly, dt~tors are now [~ing encouraged to restrict the prescribing of antibiotics for trivial complaints, and there is now much greater awareness of the problem among the medical profession, In an ideal world, antibiotic sensitivity testing would be carried out belbre drugs are prescribed and the most appropriate agent (or combin~tion) would be used, followed by more testing to ensure that the infection had been eliminated. Obviously, this is not practicable and our best approach is to use more carefully those drugs for which there is least evidence of resistance (for example vancomycin) while concentrating efforts on developing new agents to replace them. The general public also needs to be educated not to e:~pect antibiotics and not to misuse them. Much of this current crisis is a direct result of human action and it is unrealistic to expect professionals to eliminate antibiotic resistance entirely.
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Public health must continue to monitor the incidence of antibiotic resistance worldwide, and molecular epidemiological techniques need to be further applied to follow the migratior~ of particular mutations/genes and predict their spread. It is also imperative that there is effective dialogue between the food industry and public health authorities to protect humans from the additional risk arising from antibiotic use in animals. Indeed, in August there was a plea in The Lancet from Dutch microbiologists to ban the use of all antibiotics as animal growth-promoting agents [van den Boga,'u'd, A.E. ,and Stobberingh, E.E. (1996)Lancet 348, 619].
Optimism for the next century? As far as the broader picture is concerned, Dr Davies is cautious: 'No matter what agent is used, sooner or later the bugs will develop resistance, so in one sense we will never win the battle. Whal is needed is to change the prescribing practices and to guarantee a constant pipeline of new antibiotics which should be used prudently.' Dr Stuart Levy (Tufts University School of Medicine, Boston, MA, USA) regards antibiotics as societal drugs: 'Each time one is used it contributes to the sum total of societ3~'s antibiotic exposure.' However, Dr Levy remains optimistic: 'Here at Tufts, and with the Alliance for the Prudent Use of Antibiotics ~, we are educating the public and doctors not to prescribe antibiotics unless absolutely necessary. Economics will also play a role. In the USA, managed healthcare organizations are reluctant to allow doctors to prescribe expensive antibiotics and so education and economics are both important factors.' Meanwhile, the new "molecular approaches' to drug discovery and development should be expected to reduce the impact of antibiotic resistance in the early part of the next century.
TheAllianceforthe PrudentUseofAntibiotics(APUA)is an internationatorganization in 93 countriesdedicatedto promotingthe effectiveuse of antibioticsworklwidethrough educationand research,