Emerging antibiotic resistance in enteric bacterial pathogens

Emerging Antibiotic Resistance in Enteric Bacterial Pathogens Larry K. Pickering

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ntimicrobial resistance, a problem of increasing proportion, occurs in many classes of bacteria in all areas of the world. 13 Resistance is promoted in settings in which antibiotic use is frequent and inappropriate, allowing for selection of resistant strains, 3 and in which the potential for transmission among people is high, such as tertiary care hospitals, child care centers, animal feedlots, and developing countries. Other conditions that affect the transmission of resistant organisms are international travel and societal changes that have resulted in emergence and spread of various infectious diseases. The mechanisms of bacterial resistance to antimicrobial agents have been reviewed in the medical literature. 4'5 Resistance of enteric pathogens to antimicrobial agents is a problem of increasing proportion that reflects the general increase in resistance patterns of many classes of bacteria, including Enterobacteriaceae. In the gastrointestinal tract, resistance genes often are transferred from enteric flora to enteric pathogens or from enteric pathogens to gut flora, 6-1~ amplifying the difficulty of treating not only enteric infections II but also a broad spectrum of infections caused by bacteria that reside in the gastrointestinal tract. 6 This article reviews antimicrobial resistance patterns among enteric bacterial pathogens, factors that influence development of resistance, therapy for these enteric pathogens, and concerns that are specific to children. Ent erohemorrhagic Escherichia coli and Helicobacterpylori are covered elsewhere in this issue and have not been included in this discussion.

General Considerations Most children with acute infectious diarrhea will not benefit from therapy with an antimicrobial agent. The potential benefits of antimicrobial therapy for persons infected with bacterial enteropathogens or who have diseases produced by bacterial enteropathogens are shown in Table 1. Antimicrobial therapy is administered to relieve clinical signs and symptoms of disease, to reduce shedding of the organism to decrease potential for transmission, and potentially to decrease the incidence of extraintestinal manifestations of gastrointestinal tract infections. ~2 There are many reasons that make it difficult to determine the exact magnitude of antimicrobial resistance for most

From the Centerfor PediatricResearch,Departmentof Pediatrics, Children's Hospital of The King's Daughters,Eastern VirginiaMedical School,NooColk,VA. Supportedin part byNIH-NICHHD GrantNo. 13021. Address correspondenceto Larry K. Pickering, MD, Centerfor Pediatric Research,855 W BrambletonAve., Norfolk, VA 2351O-1001. Copyright9 1996by W.B. SaundersCompany 1045-1870/96/0704-0010505.00/0 272

enteric pathogens. Many studies of resistance patterns are regional and of limited duration, making extrapolation of results to other geographic areas inappropriate. Without welldesigned, ongoing surveillance systems, data about trends in antimicrobial resistance may not represent results of sporadic publications of resistance patterns from individual medical centers. These studies may overestimate resistance patterns in the community. A lack of a surveillance system also may result in an underestimate of the prevalence of resistance, such as occurrences in underdeveloped countries, where antibiotic use is high, crowding is common, and outbreaks due to resistant enteric organisms may persist for prolonged periods before being detected. Another problem in this area deals with the timely dissemination of information about resistance patterns of enteric organisms. Many reports in the literature dealing with resistant strains were published several years ago, and although they highlight the problem, they may not reflect current patterns. The delay between identification of a resistance pattern of an enteric pathogen and dissemination of data may be more than 1 year if we rely on the medical literature. Several publications, such as Morbidity and Mortality Week~ Report from the Centers for Disease Control and Prevention (CDC), newspapers published by the American Academy of Pediatrics (AAPNews) and Philip A. Brunell (Infectious Diseases in Children), and The Pediatric Infectious Diseases Journal, which has a short 3- to 4-month publication time, can be used to help disseminate data in a timely manner.

Antimicrobial Resistance of Enteric Pathogens Campylobacter Campylobacterjejuni strains generally are susceptible to a wide variety of antimicrobial agents, including erythromycin, furazolidone, quinolones, aminoglycosides, tetracycline, chloramphenicol, imipenem, and clindamycin, whereas penicillin, ampicillin, and the cephalosporins are relatively inactive. 1322 In patients with Campylobacter enteritis, erythromycin, ciprofloxacin, or ofloxacin represents the agent of choice. 23 Ciprofloxacin and ofloxacin have been approved by the Food and Drug Administration (FDA) for the treatment of Cjguni enteritis in persons older than 17 years of age. In double-blind, placebo-controlled trials of the treatment of patients with Campylobacter enteritis, erythromycin eradicated Campylobacter from feces but did not alter the natural course of enteritis when administered 4 days or longer after the onset of symptoms. Studies in which therapy was initiated early in the course of illness gave conflicting results with regard to clinical resolution, although Cjejuni was eliminated from stools significantly faster in the treatment groups of

Seminars in Pediatric Infectious Diseases, Vol 7, No 4 (October),1996.'pp 272-280

Enteric Bacterial Pathogens T a b l e 1. Potential Benefit of Antimicrobial Therapy for Bacterial Enteropathogens or Diseases Produced by Bacterial Enteropathogens

Potential Benefit Established

Enteropathogen or Disease Antimicrobial-associated colitis (Clostridium Cholera Enterotoxigenic Escherichia coli Invasive E coli

ShigeUa Any bacterium that produces bacteremia (eg, Salmonella typhi) Questionable or unknown

Campylobacterjquni Intestinal salmonellosis Enterohemorrhagic E coli

Yersinia enterocolitica both studies. ~a,25 Azithromycin therapy is an effective alternative to ciprofloxacin in areas where ciprofloxacin-resistant Campylobacter species are prevalent, as shown in travelers to Thailand. 26 Clindamycin and amoxicillin plus clavulanate are alternative choices in children, t),27 but studies supporting their effectiveness are limited. The frequentT of isolation of erythromycin-resistant Campylobacter strains ranges from less than 1% in Canada and the United Kingdom 16,19,28,29 to 8% in Belgium and 10% in Sweden. 3~ Some countries report a high level of resistance to erythromycin, including a 53% resistance rate to erythromycin reported in orphanages in Bangladesh ta and a 51% resistance rate reported in Singapore. 32 In one stud)" from the United States published in 1984, 3% of Carnpylobacter strains from human sources were resistant to erythromycin? 3 In the same study, a higher frequency of erythromycin resistance was noted in hog isolates, most of which were Campylobacter coll. 33 Other studies have reported that the frequency of resistance in Ccoli is higher than it is in Cjejuni. 14.18,21,22,33,34This resistance may be due to production of an RNA methylase or a mutational change of a ribosomal protein gene. 28 Strains of Cjquni and C coli that show high-level resistance to erythromycin also appear to be resistant to clarithromycin and azithromycin. 1a,35In a report of three persons with acquired immunodeficiency syndrome, sequential development of multidrug resistance in Cjquni, including erythromycin, was described and correlated with clinical relapse. 36 Initial studies showed that the newer quinolones had excellent in-vitro activity against Campylobacter.37 However, rapid emergence of resistance in Campylobacter species has been reported in several studies T M after widespread use of these compounds. Resistance by Cj~uni to ciprofloxacin developed in two individuals during therapy with ciprofloxacin. 44 Treatment failed microbiologically in these individuals and in one failed clinically. Resistance has occurred because of alteration in the drug target, bacterial deoxyribonucleic acid ~Tase, 4446 and perhaps because of decreased accumulation of the drug within bacteria.

Nontyphoidal Sa/mone//a The syndrome produced by Salmonella dictates the selection and duration of antimicrobial therapy. Antibiotics have been shotaa

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to prolong symptoms or increase the risk of complications among persons t'ho are nontyphoid Salmonella carriers or in patients who have mild gastroenteritis. Randomized studies, including studies of newer antimicrobial agents, have found no difference bett'een treated and untreated patients. 47Antimicrobial therapy may convert intestinal carriage to systemic disease with bacteremia, produce a bacteriologic and symptomatic relapse, encourage development or selection of resistant strains, or prolong fecal excretion, m'm Antibiotic treatment of patients with Salmonella infection is recommended for persons with (1) typhoid fever, including patients with clinical illness and carriers, (2) bacteremia from nontyphoidal strains, and (3) dissemination with localized suppuration. Antimicrobial therapy also should be considered in newborn infants and in patients with enterocolitis who have an underlying condition or disease that impairs host resistance. Recommended antimicrobial agents include ampicillin, chloramphenicol administered intravenously or orally, and trimethoprim/sulfamethoxazole (TMP/SMX). 23j~ However, high rates of resistance to ampicillin and/or T M P / S M X have been reported from medical facilities and from studies of outbreaks in many parts of the t,orld. 5257 Resistance patterns differ markedly among institutions in the same country, as in Thailand. 58,59 Resistance patterns of nontyphoidal Salmonella strains are largely unknotTa because of their lack of identification and underreporting to public health authorities. It does not appear that there is a species-specific resistance because multiple resistant strains of many of the hundreds of different species of Salmonella have been reported. In the United States and Canada, surveillance of nontyphoidal Salmonella isolates generally has shown resistance rates of 10% to 15% of all isolates 6~ to ampicillin or TMP/SMX. Higher rates of resistance have been reported from hospitalbased studies 61.64and outbreaks. 56,65,66Hospital-based reports in the United States s h o t higher rates of resistance than found in the national surveillance s)~tem of the CDC for ampicillin (20% v 9%) and "IAIP/SMX (3% v 1%). 61"64 In the United States, attention has focused on resistance of nontyphoidal Salmonella strains, which have their major reservoir in animals. Several outbreaks of muhidrug-resistant Salmonella infection have been traced to animal sources in the United States and are a major problem in various parts of the world. 65,66 The magnitude of disease associated with outbreaks was shown in an outbreak originating from a dairy in Illinois that was caused by a strain of Salmonella typhimurium resistant to both ampicillin and tetracycline. This outbreak resulted in more than 16,000 culture-confirmed cases of salmonellosis. 66 Outbreaks caused by resistant strains enhance the difficulty in managing infected persons. The August 1995 approval by the FDA of sarafloxacin, a fluoroquinolone antibiotic, for use in drinking water of poultry to control illness caused bv E coli raises concern about emergence of resistance among CarnD'lobacterand Salmonella strains. 67 The FDA, CDC, a sample of state public health laboratories, and the United States Department of Agriculture are implementing a national surveillance program for Salmonella isolates obtained from clinical specimens from humans and animals (farm and companion), health) farm animals, carcasses at

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slaughter plants, and vegetables to monitor changes in antimicrobial susceptibilities. Persons infected with Salmonella strains resistant to ampicillin and T M P / S M X have been treated with third-generation cephalosporins and fluoroquinolones. Strains of Salmonella that are resistant or that have decreased susceptibility to these agents have been detected. 687~ S typhimurium gyrA mutations associated with fluoroquinolone resistance have been reported. 71

Salmonella typhi Since the 1950s, chloramphenicol has been the agent of choice for treating persons with typhoid fever. 72 In the early 1970s, large outbreaks of chloramphenicol-resistant Salmonella typhi occurred in Mexico 73and Vietnam. 74,75In Mexico, the incidence of infections with chloramphenicol-resistant S typhi declined after this outbreak. In the 1980s, an epidemic of antibioticresistant S typhi occurred in Asia, 76 and unlike the outbreak in Mexico, this epidemic resistant strain became endemic. The strain is resistant to ampicillin, chloramphenicol, and T M P / SMX. In the Indian subcontinent, more than 50% of S typhi infections in hospital-based reports are caused by antibioticresistant strains. 77-m In the United States, antimicrobial resistance of S typhi has been less of a problem; only 2% to 3% of S typhi strains are resistant to ampicillin and chloramphenicol. 8~ However, because of international travel, the potential exists for importation of resistant strains. 82,83From 1975 to 1984, 62% of the cases of acute typhoid fever in the United States were acquired in other countries, with Mexico (39%) and India (14%) being the major sources. 82 California, Texas, and New York reported the greatest number of cases. In general, S typhi has remained susceptible in comparison with the nontyphoidal Salmonella strains. Drugs that have been used successfully to treat typhoid fever include chloramphenicol, ampicillin, and TMP/SMX. Cefotaxime, ceftriaxone, and cefoperazone are effective against S typhi and nontyphoidal Salmonella strains that are resistant to ampicillin, chloramphenicol, and TMP/SMX. e4"86 In prospective, randomized studies of children and adults with confirmed typhoid fever,8e'88ceftriaxone administered for 3 to 5 days was as effective and safe as a 2- to 3~ course ofchloramphenicol. Ciprofloxacin is active in vitro against Salmonella, including S typhi, and has been used clinically with success. 89,9~A 3-day course of ofloxacin given to adults was safe and effective in the treatment of uncomplicated, multidrug-resistant typhoid fever. 91 A 5-day course of treatment with oral ofloxacin was significantly better (P < .01) with regard to cure than was a 3-day course of ceftriaxone. 92 A 14-day course of cefixime and a 5-day course of ceftriaxone were effective in the treatment of multidrug-resistant S typhi septicemia in children in Egypt. 93 In another study from Egypt, 14 adults with typhoid fever showed clinical and bacteriologic response to therapy with azithromycin. 94 Many other antibiotics are active in vitro against Salmonella strains, including S typhi, but susceptibility correlates poorly with in vivo response. 95 The presence of cholefithiasis may affect significantly the efficacy of therapy for the chronic carrier state. When gallbladder disease was present, the failure rate of ampicillin was 75%. 98 In patients without gallbladder disease, ampicillin with proben-

ecid or amoxicillin administered for 6 weeks is the treatment of choice for chronic enteric carriers. 97,9~Norfloxacin99 and ciprofloxacin 1~176 also have been reported to be successful in eradicating S lyphi in adults who are chronic carriers.

Sh~ In the United States, 60% of reported cases of diarrhea associated with Shigella are caused by Shigella sonnei; Shigella flexneri serotypes account for the majority of the remaining cases. Shigella dysenteriae is an uncommon cause of diarrhea in the United States. The treatment of choice for shigellosis is T M P / S M X for susceptible strains. 11,101"1~ ShigeUa strains became progressively resistant to multiple antimicrobial agents, shortly after they became commercially available, initially to sulfonamides, then to tetracycline, chloramphenicol, and streptomycin less than 10 years after each was introduced, and subsequently to ampicillin, kanamycin, and T M P / S M X because of rapid dissemination of resistance plasmids. 1~ Transmissible antimicrobial resistance by plasmids first was described in Shigella strains, w8 In most countries in Asia and Africa, in certain Latin American countries, and in Israel, more than 50% of all Shigella isolates are resistant to ampicillin and T M P / SMX. 1~ Resistance appears to be more common among strains o f S dysenteBae.111,114,115 In the United States, approximately 20% of Sflexneri strains are resistant to ampicillin, whereas more than 50% of the S sonnei strains are resistant. 11'122Less than 10% of tested strains are resistant to TMP/SMX. 1~2Outbreaks of Ssonnei resistant to both agents have been reported in the United States] 23 and multidrug-resistant S sonnei and Sflexneri now are endemic on Native American reservations in the American Southwest. H In children with ampicillin-susceptible strains, ampicillin is an accepted treatment and can be given orally or intravenously. Amoxicillin is not as effective as ampicillin and should not be u s e d . 124 Single-dose tetracycline therapy is effective in the treatment of Shigella infection in adults regardless of clinical expression of illness and may be useful in the treatment of disease from tetracycline-resistant strains. 1~ Furazolidone has been shown to be effective in children infected with susceptible strains.t25,126 Parenterally and orally administered third-generation cephalosporins have been used successfully in the treatment of children with shigellosis. 127"129Two-day and 5 - d a y 129 c o u r s e s of ceftriaxone were effective in eradication of Shigella from stool and reduction of the duration of diarrhea. In one study, a single parenteral dose of ceftriaxone produced a moderate reduction in diarrhea but failed to eradicate Shigella strains from stools. 13~ Cefotaxime was reported to have failed clinically and bacteriologically in a child infected with a susceptible strainJ 31 Previous studies of first- and second-generation cephalosporins for treatment of shigellosis have found them to be ineffective. 132,133 Cefixime administered orally has been shown to be therapeutic for children and adolescents whose isolates were resistant to T M P / S M X ] ~7 although it is not approved by the FDA for this condition. In addition, cefixime was ineffective clinically in seven (47%) adults treated for shigellosis due to susceptible strains.134 Ceftibuten, an orally administered, third-generation cephalosporin, has shown good in vitro activity against various enteric

Enteric Bacterial Pathogens pathogens and promising clinical effica%, in patients with shigellosis.t35 Ciprofloxacin, norfloxacin, and enoxacin have been used successfully to treat adults with shigellosis, even those infected with resistant strains. 1~ In a study evaluating dosing of ciprofloxacin in adults, 10 l-g doses (5 days) was effective therapy for patients infected with S dysenteriae type 1. For other ShigeUa species, a single, 1-g dose was sufficient, m~Ciprofloxacin is FDA-approved for the treatment of gastrointestinal tract infections caused by S sonnei and Sflexnen. The fluoroquinolones, including ofloxacin and ciprofloxacin, have greater activity against gram-negative bacteria than do the older DNA ~Tase inhibitors, such as nalidixic acid. However, reduced susceptibility to ciprofloxacin and ofloxacin, probably caused by mutation in the DNA gyrase subunit A gene, has been noted in S sonnei and S dysenteriae strains isolated from patients with d}senteu'. 14~ Resistance to nalidixic acid has been described in a r e a s w h e r e it h a s been used as the drug of choice, especially among S dysenteriae strains. 107,109,117,142,143Although resistance to the fluoroquinolones is not yet common among Shigella strains, the emergence of resistant strains o r E coli indicates that this problem may become more widespread.144

Vibrio cholerae Diarrhea caused by infection with Vibrio cholerae 01 is uncommon in the United States, although the organism is endemic along the Gulf Coast. In addition, since appearing in Peru in 1991, V cholerae has spread to most countries in South and North America. Antimicrobial therapy for gastroenteritis from cholera will shorten the duration of diarrhea and reduce fluid losses. For most patients, either tetracycline or doxycycline is the drug of choice. 145149 Other effective antimicrobial agents are "IMP/ SMX, furazolidone, and ewthromycin. Ciprofloxacin and ofloxacin are effective therapy for persons with cholera 1~,15~ but are not approved for use in individuals younger than 17 }ears of age. V cholerae has remained relatively susceptible to antibiotics; however, resistance to tetracycline, streptomycin, chloramphenicol, sulfonamides, ampicillin, kanamycin, and TMP/SMX h a s been reported from Bangladesh, Africa, Thailand, and South America.4,152-157

Vcholerae 0139 has been associated with a large outbreak of cholera-like disease in Bangladesh. This organism has been shou~ to be susceptible to tetracycline, ampicillin, chloramphenicol, ewthromycin , and ciprofloxacin but not to T M P / S M X and furazolidone, two agents often used to treat cholera in children. 158-160

Other Bacteria Other bacteria that infrequently produce diarrhea in children in the United States areEcoli (other thanEcoli O157:H7), Yersinia enterocolitica, and Vibrio parahaemolyticus. Yersinia enterocolitica occurs infrequently in the United States. 161It usually is susceptible in vitro to aminoglycosides, chloramphenicol, tetracycline, T M P / SMX, third-generation cephalosporins, and quinolonesJ 61.m2 Strains often are resistant to penicillin, ampicillin, and firstgeneration cephalosporins. T h e r e are no data to support the use of antimicrobial agents in diarrhea caused bv this organism.

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Patients with Yenterocolitica-induced septicemia should be treated with gentamicin, chloramphenicol, or third-generation cephalosporin antibiotics. C a W responses have been reported in the treatment of Y enterocolitica septicemia with third-generation cephalosporins and ciprofloxacin, m3 Despite treatment, the mortality rate for this condition approaches 50%. Vparahaemolyticus gastrointestinal tract infection is self-limited, and antimicrobial therapy shortens neither the clinical course nor the duration of fecal excretion of the organism. Diarrhea caused by enterotoxigenic E coli usually is selflimited, but studies have sho~aa that antimicrobial agents such as TMP/SMX and ciprofloxacin are effective. 1~ Ciprofloxacin is FDA-approved for the treatment of persons with diarrhea caused by enterotoxigenic E coll. Little is known about the treatment of enteroinvasive E coli infection because it usually is not diagnosed. Antimicrobial therapy of enteroinvasire Ecoli should be similar to that administered to patients with shigellosis. Resistance has been noted in developing countries.t64 In ~itro studies have shown that more than 90% of 131 strains of Aer0monas species were susceptible to aminoglycosides, ureidopenicillins, third-generation cephalosporins, aztreonam, quinolones, tetraQcline, and chloramphenicol; more than 75% w e r e susceptible to TMP/SMX; and all strains were resistant to ampicillin, m5 Differences in susceptibility patterns may exist among geographic areas and within species ofAer0monas. Invasire strains generally are treated with aminoglycosides, thirdgeneration cephalosporins, or imipenem, m6 Infections of the gastrointestinal tract may respond to T M P / S M X or ciprofloxacin, which is approved only for patients older than 17 years of age. Plesiomonas shigelloides has been identified as a cause of endemic and travelers' diarrhea. This organism is susceptible to TMP/SMX, ciprofloxacin, cephalosporins, and imipenem. 167 Many strains are resistant to aminoglycosides. Antimicrobial-Associated

Colitis

In patients with antimicrobial-associated colitis, the most important aspects of therapy are discontinuation of the antimicrobial or antineoplastic agent and replacement of fuid and electroktes. If symptoms persist or worsen or if the disease is severe, specific therapy with vancomycin, 1~17~ metronidazole, mS,m or bacitracin 172"17~is recommended. All strains ofClostridium d i ~ l e are susceptible to vancomycin, 175 and resistance to metronidazole and bacitracin has been reported.17~ To decrease the emergence of vancomycin-resistant enterococci in hospitals, man}" experts recommend the use of metronidazole as the first treatment of most persons with C difficile colitis, with oral vancomycin being reserved for use only for persons with severe antimicrobial-associated colitis or for those who do not respond to metronidazole. 23 The oral preparation of metronidazole is less expensive than vancomycin, lf~ but it is not approved bv the FDA for the treatment of patients with this condition. Bacitracin, although a useful alternative to metronidazole and vancomycin, has a slower and less certain response rate than vancomycin j73,jTt and is not approved by the FDA for this condition. Bacitracin can be toxic if absorbed from an inflamed intestine. Relapses occur in 10% to 20% of patients treated with vancomycin, metronidazole, or bacitracin, 16~,17~ generally 1 to 4 weeks after treatment is stopped. Recurrences

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are caused by either g e r m i n a t i o n o f C d i ~ l e spores that persist despite t r e a t m e n t or reinfection with C di~cile acquired from h u m a n or environmental exposure and not to e m e r g e n c e o f resistant strains. Relapses generally respond to metronidazole or vancomycin. T h e combination o f s t a n d a r d antibiotics and Saccharomyces boulardi was shown to result in a lower recurrence rate o f patients with recurrent antimicrobial-associated colitis t h a n was the combination o f standard antibiotics and placebo. 176 Teicoplanin, a glycopeptide antibiotic, has b e e n used successfully to treat patients with antimicrobial-associated colitis] 77 but additional studies are needed.

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