Erythromycin-Resistant Campylobacter Infections in Thailand

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Mar. 1987, 0066-4804/87/030438-05$02.00/0 Copyright © 1987, American Society for Microbiology

p.

Vol. 31, No. 3

438442

Erythromycin-Resistant Campylobacter Infections

in

Thailand

TAYLOR,'*

MARTIN J. BLASER,2 PETER ECHEVERRIA,' CHITTIMA PITARANGSI,' LADAPORN BODHIDATTA,' AND WEN-LAN L. WANG2 Department of Bacteriology, Armed Forces Research Institute of Medical Sciences, Bangkok 10400, Thailand,' and DAVID N.

Medical and Laboratory Services, Veterans Administration Medical Center, Denver, Colorado 802202 Received 22 September 1986/Accepted 18 December 1986

Erythromycin therapy was compared with no treatment in a prospective trial of acute diarrheal disease 100 infants in an orphanage in Bangkok. Within 24 h of the onset of diarrhea, 50 children received erythromycin ethylsuccinate (40 mg/kg per day) in four divided doses for 5 days. Campylobacterjejuni isolated from 31, Campylobacter coli isolated from 21, and ShigeUa spp. isolated from 21 of 100 children were the most commonly recognized pathogens; use of a sensitive, nonselective method substantially increased Campylobacter isolation. Treatment with erythromycin had no effect on the duration of diarrhea caused by Campylobacter spp., Shigella spp., or other agents; 37% of the treatment group and 35% of the control group had diarrhea for 1 week. Of 23 Campylobacter strains isolated from the treatment group before treatment, 15 (65%) were resistant (MIC, .8 9Lg/ml) to erythromycin. Among orphanage-acquired strains, 53% of 43 C. jejuni strains and 91% of 23 C. coli strains were resistant to erythromycin compared with 11% of 114 C. jejuni strains and 46% of 35 C. coli strains that were community acquired. Erythromycin resistance is common among Campylobacter strains in Bangkok, especially in an institutional setting, which may account for the lack of efficacy of erythromycin for treatment of acute diarrheal illnesses.

among

Antimicrobial therapy is given to patients with bacterial of diarrhea to reduce the severity and duration of illness and to shorten the duration of excretion to diminish secondary transmission (7). Campylobacter enteritis is usually self-limited and of short duration, and in the majority of cases fluid replacement without antibiotics is sufficient treatment (5). When antibiotic treatment is indicated because of febrile, bloody, or prolonged diarrhea, erythromycin is the recommended therapy because most Campylobacter strains are susceptible to it and it shows little propensity to select for plasmid-mediated antibiotic resistance (19). In a number of clinical trials performed in adults and children, erythromycin has not been shown to significantly alter the clinical course of Campylobacter infection (1, 12, 13, 15, 16, 20). Results of one study, however, found that when Peruvian children with bloody diarrhea due to Campylobacter isolates were treated early in the course of illness with erythromycin, they improved earlier than children given placebo (21). In all of these studies erythromycin treatment of Campylobacter enteritis shortened the duration of convalescent excretion. Campylobacter enteritis is common among children in developing countries (18), and the organism may be excreted by up to 40% of children under 5 years of age (4, 6, 17, 18). Thus, in developing countries where the pool of asymptomatic excreters may be sufficiently large to contribute to the transmission of disease, treatment could play a role in decreasing transmission. Erythromycin also may be effective against other enteropathogens. After oral dosing intraluminal erythromycin concentrations can inhibit the majority of Shigella strains in vitro (11). An oral dose of 1 g of erythromycin daily prevented traveler's diarrhea among tourists in Mexico (2), suggesting that it has broad antibacterial effects. Based on these observations, we studied the effect of erythromycin on diarrheal illnesses in a clinical trial among children at an orphanage in Bangkok, Thailand.

MATERIALS AND METHODS

causes

*

Subjects. Phayathai Orphanage (Bangkok, Thailand) has a population of 250 to 300 children ranging in age from a few months to 5 years. Consent for the study was given by the Ministry of Education, Thailand. From November 1984 to January 1985 children who had diarrhea (defined as three or more loose stools combined with fever, vomiting, or colic) for less than 24 h were alternately selected to receive erythromycin ethylsuccinate oral suspension (40 mg/kg per day) in four divided doses for 5 days or to receive no erythromycin (control group). Supportive treatment such as oral or intravenous rehydration was provided to all patients, as required by the attending physician. If the illness appeared clinically severe and antibiotics were judged necessary, patients in the control group could receive trimethoprim-sulfamethoxazole at a dose of 8 mg of trimethoprim and 40 mg of sulfamethoxazole per kg per day in two divided doses for 5 days. The diarrheal symptoms and stool consistency of each child were monitored for 1 week. The diarrheal episode was completed when the stools resumed normal consistency. Fecal samples, which were obtained from each child on the first day of illness (day 0), daily for the next 3 days (days 1, 2, and 3), and at the end of 1 week (day 7), were cultured for bacterial pathogens as described below. Microbiology. Stool specimens or rectal swabs transported in Cary-Blair medium were plated onto MacConkey and Hektoen agars and inoculated into Selenite-F Enrichment (BBL Microbiology Systems, Cockeysville, Md.) broth. After overnight incubation at 37°C, Selenite-F was subcultured to MacConkey, Hektoen, and Desoxycholate agars for the isolation of Shigella spp., Salmonella spp., and Escherichia coli. Ten E. coli colonies from initial cultures were tested for enterotoxin production by Y-1 adrenal cell and suckling mouse assays (9). To isolate Campylobacter spp., Campy-BAP selective agar medium (3), which was prepared without cephalothin, and an enrichment medium described by Doyle and Roman

Corresponding author. 438

ERYTHROMYCIN-RESISTANT CAMPYLOBACTER SPP.

VOL. 31, 1987 TABLE 1. Comparison of four methods to isolate Campylobacter spp. in 331 specimens obtained from 100 childrena Isolation method

No. (%) of isolates

Before enrichment Filter onto nonselective media ........................ Direct onto selective media ........................

101 (74) 52 (38)

After enrichment Filter onto nonselective media ........................ Direct onto selective media ........................

92 (67) 39 (29)

aA total of 137 strains were positive by one or both methods.

(8) were inoculated with one swab. A small amount of fecal material also was mixed with 1 ml of sterile saline, and 0.1 ml of this solution was spotted onto a sterile filter (pore size, 0.45 Lm; Millipore Corp., Bedford, Mass.) placed onto Mueller-Hinton agar with 5% sheep blood without antibiotics (22). The filter was removed from the plate after 30 min and discarded. The plates and enrichment broth were incubated at 42°C in a microaerobic atmosphere by using a GasPak (BBL) without catalyst. After overnight incubation, the broth was inoculated onto Campy-BAP medium and onto the nonselective Mueller-Hinton medium by the filter method described above. Antimicrobial susceptibility testing. Presumptive Campylobacter isolates were confirmed by standard procedures (3) and tested for susceptibility to antimicrobial agents by a standard agar dilution method (26). Campylobacter species isolated at the orphanage from the same patient at different times were considered different strains if the antimicrobial susceptibility of the strains differed by more than 2 dilutions. For comparison, 35 Campylobacter strains previously isolated from domestic animals were tested against five antimicrobial agents; 149 Campylobacter isolates from children with diarrhea seen at the outpatient department of Children's Hospital, Bangkok, were tested for susceptibility to erythromycin and tetracycline. Resistance was defined as an MIC of erythromycin and tetracycline of -8 ,ug/ml and an MIC of clindamycin, rosaramicin, and Schering 32063 of -2 p.g/ml (26). Shigella flexneri strains that were obtained just before the drug trial from 76 patients at the orphanage were also tested for erythromycin MIC (11). Statistical methods. Significant differences among erythromycin-treated and nontreated groups were determined by the x2 test. RESULTS Isolation methods for Campylobacter spp. During the study Campylobacter spp. were isolated from 168 (44%) of 331 specimens: C. jejuni from 104 and C. coli from 64. Campylobacter spp. were isolated from 137 (41%) of 331 specimens in which all four isolation methods were performed. There was nearly a twofold increase in the Campylobacter isolation rate when the filter was used compared with standard plating on selective media (Table 1). The two methods with the filter (direct and after enrichment) detected all but two of the positive specimens. Both filter methods were positive in 58 (42%) isolates, the direct filter method alone was positive in 43 (31%) isolates, and the enrichment culture alone was positive in 34 (25%) isolates. Treatment trial. A total of 50 children with diarrhea were treated with erythromycin, and 50 other children with diarrhea who were not treated with erythromycin served as the

439

control group. The mean age of the patients was under 1 year (range, 2 to 28 months) in both groups (Table 2). The mean duration of diarrhea before therapy was longer for the erythromycin group than the control group, but it was less than 24 h in both groups. Most children had watery or mucoid diarrhea; only one child had visibly bloody diarrhea. On the first day of diarrhea, Campylobacter spp. were isolated from over 50% of the children in each group. Shigella spp. were isolated from 28% of children in the erythromycin group and 14% in the control group (Table 3). Multiple pathogens were isolated from the initial culture from 28% in the erythromycin group and 16% in the control group. Nine (18%) of the control patients received trimethoprim-sulfamethoxazole during the course of their illness. Overall there was no difference in the duration of diarrhea between the two groups. On day 7, 15 (37%) of 41 children in the erythromycin group and 16 (35%) of 46 in the control group still had diarrhea. A total of 8 (16%) children in the erythromycin group compared with 2 (4%) children in the control group required hospitalization (P = not significant). On day 7 Campylobacter spp. were isolated from 18 (44%) of 41 children in the erythromycin group and 17 (37%) of 46 children in the control group. For children initially infected with Campylobacter spp., by day 7, 5 (26%) of 19 in the erythromycin group and 9 (36%) of 25 in the control group still had diarrhea; 63% of children in the erythromycin group and 64% of children in the control group remained infected with Campylobacter spp. Among isolates obtained before treatment was begun, 15 (65%) of 23 Campylobacter isolates from children in the erythromycin group and 7 (54%) of 13 strains in the control group were resistant to erythromycin. Among isolates obtained after treatment was begun, 44 (96%) of 46 from children in the erythromycin group were resistant and 18 (56%) of 32 from children in the control group were resistant (P < 0.001). In all eight children in the treatment group who were infected with erythromycin-susceptible Campylobacter strains, erythromycin-susceptible strains were cleared from the stools within 24 h. Treatment had no effect in this group, however, for the following reasons. Two children were coinfected with Shigella sonnei and continued to have diarrhea and excrete S. sonnei to day 7; one of these patients and two others also acquired erythromycin-resistant C. jejuni infections while under therapy; two other children also acquired Salmonella infections that caused diarrhea to recur, and two others, one coinfected with S. flexneri, were hospitalized and lost to follow-up. Of 12 children enrolled in the erythromycin group who had negative initial cultures, 5 (41%) acquired a new pathogen TABLE 2. Characteristics of diarrheal illness and children who received erythromycin ethylsuccinate or no treatment (control) Treatment group Control (n =50) (n= 50)

Characteristic

Erythromycin

Mean age (mo + SE) Sex (no. of males [%]) Mean duration of diarrhea before

7.3 ± 0.71 26 (52) 17.0 + 1.3

9.2 ± 0.61 31 (62) 10.4 + 1.3

15 (30) 31 (62) 3 (6) 1 (2)

22 (44) 19 (38) 9 (18) 0

therapy (h + SE) Type of diarrhea (no. [%]) Watery Mucoid Loose Visible blood

440

ANTIMICROB. AGENTS CHEMOTHER.

TAYLOR ET AL.

TABLE 3. Nurnber of enteropathogens recovered from 100 children with diarrhea during a week-long period of surveillancea Treatment group and day of illness

Erythromycin 0 1 2 3 7 Control 0 1 2 3 7

No. of the following pathogensb:

No. of

isolatesShglaamoea C. jejuni C. coli Salmonella Shigella cultured 50 48 44 42 41

11 5 9 11 11

50 50 48 47 46

20 20 13 11 10

15 9 7 7 7 6 6 6c 6c 7c

ETEC

Other

None

14 8 8 5 5

1 3 1 2 3

8 ND ND ND ND

3 1 0

2 0

12 26 23 19 18

7 4 2 5 6

2 1 2 2 4

5 ND ND ND ND

0 1 1 1 0

18 21 28 25 20

aHalf (50) of the children received erythromycin ethylsuccinate (40 mg/kg per day) for 5 days. b Abbreviations and explanations: ETEC, enterotoxigenic E. coli; ND, not done; Other, Plesiomonas spp. (seven isolates), Aeromonas spp. (two isolates); None, no pathogen isolated. c Includes Campylobacter isolates that were not identified to the species level.

the next 7 days, as did 8 (44%) of 18 comparable children in the control group. Among the children who were initially infected with Shigella spp., the duration of diarrhea or excretion was not significantly different between the two groups. By day 7, three (38%) of eight children in the erythromycin group and one (14%) of seven in the control group still had diarrhea. Antimicrobial susceptibility. High-level erythromycin and tetracycline resistahce was prevalent in the orphanage (Table 4). For Campylobacter isolates in the orphanage, 23 (53%) of 43 C. jejuni strains and 21 (93%) of 23 C. coli strains were erythromycin resistant (MIC, .8 ,ug/ml). Among the community-acquired strains isolated from outpatients at Children's Hospital, 12 (11%) of 114 C. jejuni strains and 16 (46%) of 35 C. coli strains were erythromycin resistant, and 74 (65%) of 114 C. jejuni strains and 28 (80%) of 35 C. coli strains were resistant to tetracycline. In the community 27 of 28 C. jejuni and C. coli strains that were resistant to erythromycin also were resistant to tetracycline. In contrast, among the isolates from domestic animals, none of 19 C. jejuni strains and 4 (25%) of 16 C. coli strains were resistant to erythromycin. Resistance to clindamycin, rosaramicin, and Schering 32063 was significantly greater in C. coli than in C. jejuni isolates from both humans and animals (Table 4). With an inoculum of 105 CFU/ml, 5 (7%) of 76 S. flexneri strains were resistant to greater than 50 p.g/ml, and with an inoculum of 107 CFU/ml, 9 (12%) of 76 strains were resistant to 50 ,ug of erythromycin per ml. over

DISCUSSION In the orphanage Campylobacter spp. were isolated from more than half of the children with diarrhea. The isolation rate was high in part because multiple isolation methods were used, including placing a filter directly onto a nonselective agat. This method was advantageous because the filter eliminated other enteric bacteria, a relatively large specimen could be inoculated onto the plate, and the plates did not contain antibiotics that may have inhibited some Campylobacter spp. The use of enrichment broth with the filter further increased the isolation rate and complemented the direct filter method. Erythromycin treatment had no effect on the duration of diarrhea. Other treatment studies have not demonstrated a

decrease in symptoms, in part because the symptoms were too short-lived to measure a significant difference between treatment and control groups (1, 12, 13, 15, 16, 20). In our study in the orphanage, however, 37% of the treatment group and 35% of the control group still had diarrhea 7 days after therapy was begun. As illustrated by the eight children infected with erythromycin-susceptible Campylobacter strains, some children did not improve because they were infected with multiple pathogens, most commonly Shigella TABLE 4. Antimicrobial susceptibility of Campylobacter spp. isolated from children in an orphanage and domestic animnals in Thailand to five antimicrobial agents Isolate source, organism, and antimicrobial agent

No. of isolatesMIC obtained (,u.g/lnil):at the following

MIC_(jig/nil):_

0.25 0.50 1.0 2.0 4.0 8.0 16.0 32.0 -64.0

Human isolates

C. jejuni (n = 43) Erythromycin Tetracycline Schering 32063 Rosaramicin Clindamycin C. coli (n = 23) Erythromycin Tetracycline Schering 32063 Rosaramicin Clindamycin

6 7 3

6 4 8 7 4

1 1

1 1

2 1 1 1

10 2 7 1

4 14

1 11 5 7 11

1

21

5

7 2

5 2 3

1 2

1

2

5

8

1

4

13

4 4 1

2 3

23 5 19 19 6 16 21 16 16 3

Animal isolates

C. jejuni (n = 19) Erythromycin Tetracycline Schering 32063 Rosaramicin

Clindamycin C. coli (n = 16)

Erythromycin Tetracycline Schering 32063 Rosaramicin Clindamycin

9 11 1

1 2 3 1

2 2 2

5 3 3 3 6

9

4 6 4 3 5

7 2 7 5 6

5 2

1 3

1 7

1 3 2

VOL. 31, 1987

and Salmonella spp. Of 12 other children who were initially culture negative, 5 children failed to improve because they acquired a new pathogen during treatment, including erythromycin-resistant Campylobacter spp. Patients infected with Shigella or Salmonella spp. failed to improve with erythromycin therapy. Shigella isolates from Thailand are as susceptible to erythromycin as strains isolated in other areas (11), yet erythromycin has no clinical or bacteriological effect on shigellosis. The effect of stool pH on bactericidal activity with erythromycin is a possible factor. Erythromycin is inhibitory to most gram-negative bacteria in the urine if the pH is greater than 7; however, diarrheal stools, particularly of infants, are often acidic (23). Erythromycin treatment also had no effect on the duration of excretion of Campylobacter spp. In the orphanage 15 (65%) of 23 Campylobacter strains isolated on initial culture were resistant to erythromycin; most of these strains showed high-level resistance (MIC, .64 ,ugIml). While erythromycin-susceptible Campylobacter strains were eliminated from the stool within 24 h, erythromycin-resistant Campylobacter spp. were isolated from three of eight of these children within a few days after therapy began. Resistant Campylobacter isolates may have been present before therapy was begun and were selected for by the erythromycin treatment. In the orphanage 53% of C. jejuni isolates and 91% of C. coli isolates were resistant to erythromycin. Other investigators have found that C. coli strains are more resistant than C. jejuni strains, but resistance in more than 10% of isolates has not been reported previously (10, 26). The emergence of a single resistant clone may be a possible explanation for the high prevalence of erythromycin-resistant Campylobacter spp. in an institutional setting. However, both C. jejuni and C. coli biotypes were resistant in the orphanage, and erythromycin-resistant Campylobacter strains isolated in the community belonged to multiple serotypes. The pattern of antimicrobial resistance differed among community-acquired and orphanage-acquired Campylobacter isolates. Most erythromycin-resistant C. jejuni isolates in the orphanage were susceptible to tetracycline, while most erythromycin-resistant C. coli isolates were also resistant to tetracycline. Among community-acquired infections, all erythromycin-resistant strains also were resistant to tetracycline. Tetracycline, but not erythromycin, resistance is plasmid mediated in Campylobacter spp. (24). Our data indicate that erythromycin resistance can occur independently of tetracycline resistance. In the United States and Europe, animal Campylobacter isolates are more resistant to antibiotics than are human Campylobacter isolates (10, 26). The genus Campylobacter has a large animal reservoir that is believed to be a major source of infection in developed countries. In Thailand campylobacters isolated from animals were generally susceptible to the antibiotics tested, which may be related to the less intensive use of antibiotics in Thai animal husbandry. Antibiotic resistance of Shigella spp. and other pathogens that do not have animal reservoirs is also a major problem in Bangkok (14, 25). In Thailand erythromycin is not often recommended for the treatment of diarrhea, but the use of oral erythromycin for other indications has increased dramatically in the last 5 years. At Children's Hospital, Bangkok, the use of erythromycin estolate has increased 30-fold since 1981 (Usa Thisyakorn, personal communication). The large reservoir of asymptomatic carriers of enteric pathogens and the frequent and often indiscriminant use of antibiotics probably

ERYTHROMYCIN-RESISTANT CAMPYLOBACTER SPP.

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plays an important role in the induction of antimicrobial resistance. ACKNOWLEDGMENTS This study was supported in part by an interagency agreement between the United States Army Research and Development Command and the Medical Research Service of the Veterans Administration. We thank Ovath Thonglee, Chuanchom Pravichpram, Duangratana Plianbangchang, and Penelope Powers for technical assistance and Udom Leksomboon for support. LITERATURE CITED 1. Anders, B. J., B. A. Lauer, J. W. Paisley, and L. B. Reller. 1982. Double-blind placebo controlled trial of erythromycin for treat-

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