WHO/CDS/CSR/DRS/2001.8 ORIGINAL: ENGLISH DISTRIBUTION: GENERAL Antimicrobial resistance in shigellosis, cholera and campylobacteriosis David A. Sack, Christine Lyke, Carol McLaughlin and Voravit Suwanvanichkij Copies can be obtained from the CDS Information Resource Centre World Health Organization World Health Organization, 1211 Geneva 27, Switzerland fax: +41 22 791 42 85 • email: [email protected] WHO/CDS/CSR/DRS/2001.8 ORIGINAL: ENGLISH DISTRIBUTION: GENERAL Antimicrobial resistance in shigellosis, cholera and campylobacteriosis David A. Sack, Christine Lyke, Carol McLaughlin and Voravit Suwanvanichkij Johns Hopkins University School of Hygiene and Public Health Baltimore, MD, United States of America World Health Organization A BACKGROUND DOCUMENT FOR THE WHOFOR GLOBAL CONTAINMENT STRATEGY OF ANTIMICROBIALRESISTANCE Acknowledgement The World Health Organization wishes to acknowledge the support of the United States Agency for Inter- national Development (USAID) in the production of this document. © World Health Organization 2001 This document is not a formal publication of the World Health Organization (WHO), and all rights are reserved by the Organiza- tion. The document may, however, be freely reviewed, abstracted, reproduced and translated, in part or in whole, but not for sale or for use in conjunction with commercial purposes. The views expressed in documents by named authors are solely the responsibility of those authors. 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Designed by minimum graphics Printed in Switzerland WHO/CDS/CSR/DRS/2001.4 DRUG RESISTANC IN MALARIA Contents Summary of antimicrobial resistance in bacterial enteric pathogens 1 Interventions 2 Research 5 Review of Vibrio cholerae 8 Introduction 8 Microbiology 8 Transmission 9 Spectrum of illness 9 Disease incidence and trends 10 Regional resistance trends 11 Causes of resistance 14 The question of prophylaxis 17 Potential vaccines 17 Recommendations 18 Research priorities 19 Conclusion 20 Review of Shigella spp. 21 Introduction 21 Organisms and syndrome 21 Geographical distribution 22 Diagnosis and resistance detection 22 Pathogenesis 23 Therapy 23 Drug resistance and trends 25 Mechanisms of resistance 26 Intervention strategies and research needs 29 Conclusion 30 Review of Campylobacter jejuni 31 Introduction 31 Microbiology 31 Transmission 31 Spectrum of illness 32 Pathogenicity 33 Diagnosis and identification 34 Therapy 34 Antimicrobial resistance 35 Mechanisms of resistance development 38 Prevention 39 Intervention strategies 40 Conclusion 40 Conclusion 42 Bibliography 43 iii WHO/CDS/CSR/DRS/2001.8 ANTIMICROBIAL RESISTANCE IN SHIGELLOSIS, CHOLERA AND CAMPYLOBACTERIOSIS Summary of antimicrobial resistance in bacterial enteric pathogens Important enteric pathogens are becoming in- view was clearly incorrect, as resistant strains caused creasingly resistant to the major antibiotics that large epidemics in the United Republic of Tanza- are needed for optimal treatment of patients. The nia and Bangladesh in the late 1970s. Since then, three bacterial pathogens chosen for this review antibiotic resistance patterns have varied widely at (Vibrio cholerae, Shigella spp. and Campylo- different times and in different places, with multi- bacter jejuni) are very different from one another. ply antibiotic-resistant strains commonly found They cause quite different clinical syndromes; during epidemics. Unlike Shigella spp., however, their ecology, epidemiology and modes of trans- strains of V. cholerae frequently revert to antibiotic mission are distinct; and they are widely sepa- sensitivity. An example of reversion to resistance rated genetically. The fact that three such occurred with the new serotype, O139. Initially all different organisms are becoming increasingly strains of this new pathogen were resistant to antibiotic-resistant underlines the pervasiveness trimethoprim, but now most strains are sensitive. of the pressures that lead to the emergence and The reversion to sensitivity is probably best ex- spread of resistance. plained by the ecology of the vibrio. Being prima- rily an environmental water organism and only Shigella spp. show a pattern of steadily increasing secondarily a human pathogen, it must adapt to resistance to antibiotics. Among the four species, the conditions of its primary ecological niche, in S. dysenteriae 1 (Shiga’s bacillus) is generally the first which antibiotic resistance does not provide a to develop resistance to a new antibiotic, but then major benefit to the bacteria. the other Shigella species follow. Rarely does sus- Campylobacter jejuni has yet another ecological ceptibility reappear once resistant strains have niche, being primarily adapted to animals, in par- become endemic in a region. In order to ensure ticular to birds. The industrialization of poultry appropriate treatment, continual surveillance is production has provided an environment in which required to determine which antibiotics are still resistant bacteria flourish, and these strains are then active. This strategy of “trying to keep one step easily spread to humans. Especially worrisome is ahead” implicates the continual development and the routine use of fluoroquinolones for growth pro- testing of new antibiotics, which inevitably are more motion in poultry. Generally, antibiotics used in expensive. After extensive use of these new antibi- animals should be different from those used for otics, their prices do fall, but not to the level of the humans, but in this instance an antibiotic class with older, previously effective antibiotics. In this race unique benefits for humans is, for economic rea- between the development of new antibiotics by the sons, being used in animals, with resulting loss of pharmaceutical industry and the development of its effectiveness for treating human disease. This resistance in Shigella, it seems that the bacteria are would seem to be a matter for government regula- winning, and we face the prospect of having no tion. However, the difficulties are illustrated by the effective antibiotics for future epidemics of shigel- example of the United States of America, where losis. Expecting the pharmaceutical industry to different agencies regulate drugs for human and develop a novel and cost-effective antibiotic every animal use. The loss of the fluoroquinolones as few years is unrealistic over the long term. effective therapy for C. jejuni infections means that Vibrio cholerae, the agent that causes cholera, has ciprofloxacin will no longer be efficacious in the a much different history of antibiotic resistance. syndromic treatment of dysentery. A question that For many years it was thought that cholera epi- is not yet answered is the extent to which the demics caused by antibiotic-resistant strains were genetic determinants of fluoroquinolone resistance unlikely to occur because the bacteria seemed to can be transferred from C. jejuni to other enteric lack the ability to retain resistance plasmids. This and nonenteric bacteria. If this were to occur, the 1 ANTIMICROBIAL RESISTANCE IN SHIGELLOSIS, CHOLERA AND CAMPYLOBACTERIOSIS WHO/CDS/CSR/DRS/2001.8 spread of resistance originating in antibiotic-treated Factors involved in the emergence animals would represent an even more serious threat. of antibiotic resistance Among the common bacterial infectious agents, With all three organisms, the primary factor is the Neisseria gonorrheae and C. jejuni, which were once overuse of antibiotics; i.e. antibiotic pressure selects generally sensitive to most antibiotics, are now for resistant strains. Antibiotic pressure may be ex- becoming increasingly resistant to ciprofloxacin. erted directly (e.g. use of an antibiotic for shigello- sis to which the bacteria are resistant, thus favouring Clinical consequences of resistance the very bacteria one is attempting to eliminate). However, antibiotic pressure on an organism may The clinical consequences of antibiotic resistance occur indirectly, i.e. from using the antibiotics for vary among the three bacterial diarrhoea agents. entirely different reasons. Examples of inappropri- For shigellosis, antibiotics are the primary treat- ate uses of antibiotics that exert selective pressure ment. Patients treated with an ineffective antibi- for resistance in various bacteria are: administering otic may have more complications than if they had them to patients who have viral upper respiratory not been treated, because the antibiotic is likely to tract infections; feeding them to farm animals to affect the normal intestinal flora, thus actually enhance their growth. favouring the growth of the resistant shigella. In treating cholera, antibiotics have been shown to reduce the duration of illness and the fluid loss, Relationship between duration of treatment and but they