Changing Resistance Patterns in Enteric Pathogens
Ivan Guerrero, M.D., Senior Fellow, Infectious and Communicable Diseases Division, University of Florida and Duval County Health Department,
Jacksonville, Florida |
| The progressive increase in antimicrobial
resistance among enteric pathogens particularly Shigella,
Vibrio cholerae, Enterotoxigenic Escherichia Coli (ETEC),
Salmonella typhi and enteriditis species, and
Campylobacter jejuni is becoming a critical concern for both the people
of the developing world, where there are high rates of
diarrheal diseases and associated mortality; and for travelers
to these regions in selecting effective treatment for
traveler's diarrhea. Antimicrobial resistance in the developing
world is most likely related to the frequent unrestricted use
of over-the-counter drugs without medical supervision.
1
Most cases of bacterial gastroenteritis are self-limiting and in otherwise healthy patients, administration of antiobiotics is not necessary. However in infants, elderly people, granulcytopenic or immunodepressed patients with enteritis, and for patients with extraintestinal infections, particularly when bacteremia is suspected, antibiotic therapy is fundamental for illness control. 2 Shigella species are entero-invasive organisms that present the most pressing challenge for providing effective antimicrobial therapy. Over the past several decades they have progressively become resistant to most of the widely used and inexpensive antimicrobials as sulfonamides, tetracyclines, ampicillin, trimethoprin-sulfamethoxazole, nalidixic acid and pivmecillinam have all in succesion been used as first line antimicrobial drugs in many parts of the world. Shigella dysenteriae type 1 has become resistant to nearly all of the above-mentioned drugs and is now uniformly susceptible only to the fluoroquinolones. 3 Nalidixic acid-resistance is found in1%-2% of isolates of ETEC and Shigella other than S dysenteriae type 1 in Thailand. Nalidixic acid-resistant S. dysenteriae type 1 was first reported from Thailand in 1992. 1 In a Barcelona study of 56 Shigella isolates from patients with enteritis between 1995 and 1998, no resistance to fluoroquinolones or broad-spectrum cephalosporins was found. 2 Although rehydration therapy is the most important part of therapy for cholera, antimicrobials are important adjuvants for therapy and their use results in a marked decrease in overall stool volume and decreased length of illness. Tetracycline has been the drug of choice for treatments of cholera for the past 30 years. Resistance patterns for V. cholerae fluctuate, since the resistance is largely plasmid-mediated and since vibrios do not stably carry plasmids. Antimicrobial resistance in V. cholerae developed during a Latin American outbreak and in Zaire. On the other hand the newly emerged cholera vibrio, 0139 Bengal strain, is uniformly susceptible to tetracycline. 3 Variations in antibiotic resistance patterns of V. Cholerae within countries in the Eastern Africa region between 1994 and 1996 showed 80-100% of isolates from Kenya and South Sudan and 65-90% from Somalia to be sensitive to tetracycline. All isolates of V. Cholerae from Tanzania and Rwanda were 100% resistant to tetracycline. In the same study for chloramphenicol and cotrimoxazole 100% of the isolates of V. cholerae from Tanzania were resistant to these antibiotics, while in South Sudan more than 70% were sensitive. 4 Enterotoxigenic Escherichia coli (ETEC) is the most common cause of traveler's diarrhea. Antimicrobial resitance in the normal fecal flora in travelers to the developing world frequently develops. Initially, doxycycline was the drug of choice for treatment of traveler's diarrhea. However with the increased rates of resistance in ETEC and Shigella, trimethoprim-sulfamethoxazole and now the fluoroquinolones have become the drugs of choice. The quinolone resistance in E.coli has mainly been associated with mutations in the gyr A and parC genes. The level of resistance to nalidixic acid is generally low, but it is a matter of concern in some geographical areas such as India. Strains for which the MICs of nalidixic acid are high are likely to have at least one mutation of the gyr A gene. The induction of further mutations e.g., by exposing such strains to fluoroquinolones, is likely to result in a significantly reduced susceptibility to fluoroquinolones. Therefore it is important to continue the surveillance of enteric bacterial pathogens for quinolone resistance. 5 For most enteric Salmonella infections, antimicrobial therapy is not necessary, however it may be lifesaving in persons with invasive disease. A number of antimicrobials have been effective for therapy of Salmonella typhi, the agent causing typhoid fever. In the developing world, chloramphenicol is still widely used as therapy for typhoid fever as are the alternate drugs ampicillin and trimethoprim-sulfamethoxazole. In places where multidrug-resistant Salmonella typhi strains have been found and in cases of diarrheal disease due to these strains, use of fluoroquinolones is required. In the United States patients found to have multidrug-resistant Salmonella typhi or nalidixic-acid-resistant Salmonella typhi (NARST) infections acquired their infections outside the USA, specially in the Indian Subcontinent (Bangladesh, India and Pakistan). Some investigators have suggested that patients with a history of traveling to India in the 6 weeks before the onset of suspected typhoid fever should receive ciprofloxacin as first-line empiric therapy. They further recommend that ampicillin, chloramphenicol or trimethoprim-sulfamethoxazole not be used for empirical treatment of typhoid fever in people with a history of recent travel outside the United States. 6,7 For children with multidrug-resistant Salmonella typhi, or NARST infections, therapeutic options may be more limited, because fluoroquinolones are not approved for use in children at this time. 8 Although nalidixic acid is not a treatment for typhoid fever, this resistance may be clinically important, because of the decreased efficacy of ciprofloxacin in treating patients with NARST infections. 9 Epidemiologic investigations have demonstrated that in the United States, the use of antimicrobial agents in livestock is the principal cause of the emergence and dissemination of antibiotic resistant strains of nontyphoidal Salmonellae. This risk is exemplified by the widespread occurrence of cases and outbreaks of multidrug resistant Salmonella typhimurium DT104. 10 Campylobacter jejuni is a common cause of entero-invasive diarrhea in man. The disease is often milder than that caused by Shigellae. In Europe domestic infections occur in young children, whereas travel aquired infections occur in young adults. 9 This reflects the specific exposures of the age group and eating habits. The majority of infections are sporadic, although ocasionally outbreak associated, particularly with hygiene breaches in the preparing or serving poultry. Outbreaks of campylobacters enteritis have been associated with contaminated water and raw milk. Ususally diarrhea due to campylobacters is self-limiting and does not require therapy unless the individual is immunosuppressed or the infection is extra-intestinal. Campylobacter species resistant to ciprofloxacin as well as azythromycin have emerged as a threat to the effective treatment of travelers' diarrhea in Thailand. 11 Recent testing of isolates in Spain has shown most strains resistant to tetracyclines, nalidixic acid and fluoroquinolones. Erythromycin, as well as gentamicin, which has been recommended in bacteremic patients, remain active. 2 The high frequency of fluoroquinolone resistance in some countries has led to the recommendation that when antimicrobial therapy for campylobacteriosis is required, the drug of choice remains erythromycin; however there have been varying reports of resistance to this agent in addition to fluoroquinolones. Some risk factors associated with acquiring fluoroquinolone resistant Campylobacters are recent travel overseas (India,Thailand), and extensive use of quinolones in veterinary medicine,eg. the use of enrofloxacin in Europe for chicken farming in the first week of life to reduce vaccination problems, or in the third week to combat respiratory problems due to E.coli. Detection and reporting of resistant isolates rests upon the microbiology laboratory testing for susceptibility to fluoroquinolones in addition to nalidixic acid. 9 ConclusionsThe problem of changing resistance patterns in enteric pathogens will remain an ongoing threat for both developed and developing countries. Systematic surveillance and timely reporting of antibiotic resistance patterns among enteric pathogens from different regions of the world should become a high priority. It is important to bear in mind that the principal purpose of monitoring antibiotic resistance trends among enteric pathogens is to provide clinicians with data that can be used to select appropriate treatment regimens. Antimicrobial testing should include antibiotics that are currently being used for the treatment of bacterial diarrheas i.e. fluoroquinolones and azithromycin. The World Health Organizations recommends the use of antibiotics only for treatment of the severe diarrheal episodes (bloody diarrhea and cholera like illness) for indigenous children in developing countries. Among travelers the benefits of antibiotic therapy have been well established for non-bloody diarrhea of a variety of etiologies. A priority in new antibiotic development is to identify agents active against Salmonella, Shigella species and highly resistant campylobacters concurrent with the search for effective enteric vaccines. References
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