Original Article
The Carriage of Escherichia coli Resistant to Antimicrobial Agents by Healthy Children in Boston, in Caracas, Venezuela, and in Qin Pu, China
N Engl J Med 1990; 323:285-289August 2, 1990
- Abstract
- Abstract
Background and Methods.
The healthy members of a community represent its largest reservoir of bacteria resistant to antimicrobial agents. We compared the resistance to eight agents of Escherichia coli in stool samples from untreated, healthy children in cities on three continents.
Results.
When screened by a selective method that detected 1 resistant colony in 10,000 colonies, nearly half the children in Boston (18 of 39) had no resistant colonies — a finding consistent with the findings of other surveys performed in developed countries. However, all but 1 of 41 children screened in Caracas, Venezuela, and all but 2 of 53 in Qin Pu, China, carried resistant strains. Only 1 child in Boston but 25 in Caracas and 34 in Qin Pu carried strains resistant to trimethoprim. None of the children in Boston or Caracas but 17 in Qin Pu carried strains resistant to gentamicin.
Among 10 colonies selected randomly from each stool sample, the average frequency of resistance in Caracas was 3.6 times greater than in Boston, and that in Qin Pu was 5.3 times greater. There was resistance to five or more antimicrobial agents in 20 percent of the Qin Pu strains and in 6 percent of the Caracas strains but in none of the Boston strains
Conclusions.
In addition to clinical isolates, as reported previously, the bacteria that colonize healthy children in the community may be resistant far more often in some regions than in others. A low rate of carriage of antimicrobial resistance in the community should become a public health goal. (N Engl J Med 1990; 323:285–9.)
Media in This Article
Figure 1
Proportion of E. coli Strains Resistant to Antimicrobial Agents, According to Study Center.Table 1
Distribution of Children with Antimicrobial-Resistant Strains of E. coli, According to Study City and Method of Testing Colonies.Article Activity
- Article
Bacteria from patients in some countries are more likely to be resistant to antimicrobial agents than comparable isolates from patients in other countries.1 2 3 Comparative surveys, however, have included strains that were epidemic in some regions or endemic in hospitals. Such surveys have thus not established whether the bacteria of healthy people are also more often resistant in some countries than in others. Resistant bacteria in the community are important because they may represent the largest reservoir of resistance genes and because most infections arise in the community. In addition, the causes of resistance and remedies for it may differ with the flora in the hospital and community.4 , 5
Investigators in several countries have used various methods to study the resistance to antimicrobial agents of bacteria isolated from healthy volunteers or untreated patients,5 6 7 8 9 10 11 12 13 but there has been no systematic comparison between countries. Moreover, none of these studies have been conducted in developing countries, where resistance was found to be most prevalent by the surveys of patients' isolates cited above.2 , 3 For these reasons, we used the same methods to survey the resistance to antimicrobial agents of fecal Escherichia coli from healthy children in each of three cities on different continents.
Methods
Subjects
The study populations consisted of healthy urban children between the ages of five months and six years. Children were excluded if within the previous four months they had taken antimicrobials, been hospitalized, had gastrointestinal symptoms, or traveled outside the country, Parents were contacted directly, through well-child visits to health care clinics (Caracas and Boston) or through workers at nursery schools (Qin Pu). Medical histories were obtained from the parents, who were interviewed by an investigator fluent in their language. The households selected were located in different areas of each city, and only one child in each household was studied.
Approval of the survey was obtained from the human-studies committee of the Harvard Community Health Plan (Boston) and from the participating institutions in China and Venezuela.
Sample Collection and Processing
Sampling was performed during 1986 and 1987. Stool samples were obtained either by rectal swab or from freshly passed feces and were transferred to the laboratory within two to six hours in Amies transport medium (Difco, Detroit) in aliquots in sterile glass tubes (Caracas), or by means of the Culturette Collection and Transport System (Marion Scientific, Kansas City, Mo.) (Boston and Qin Pu). Levine EMB (eosin-methylene blue) agar and MacConkey agar (Difco) were used in the initial isolation of E. coli colonies and were found to give equivalent results with duplicate samples. Antimicrobial-susceptibility testing was performed with a standard disk-diffusion method14 using Mueller-Hinton medium (Difco). The disks (BBL Laboratories, Cockeysville, Md.) had the following potencies: ampicillin, 10 μg; chloramphenicol, 30 μg; gentamicin, 10 μg; kanamycin, 30 μg; streptomycin, 10 μg; sulfamethoxazole, 300 μg; tetracycline, 30 μg; trimethoprim, 5 μg; and ofloxacin, 5 μg (used only in China). Bacteria for which zone diameters indicated intermediate resistance were classified as susceptible.
Two procedures were used to detect resistant colonies. According to the first method, MacConkey or Levine EMB plates that had been inoculated with a stool sample and sequentially streaked to yield isolated colonies were examined for colonies with the morphologic appearance of E. coli; 10 of these colonies were selected at random, purified, and tested for susceptibility.
In the second procedure, colonies were selected by means of disks containing antimicrobials (screening
10,000 bacteria). This method was similar to one employed in earlier studies of community resistance.6 , 7 , 11 , 12 In Qin Pu and Boston, the swabs were dispersed before plating in 1 ml of sterile 0.9 percent saline, approximately the same volume in which the swabs were transported in Caracas. The sample swabs were used to inoculate MacConkey or Levine EMB plates. Disks were applied to the plates, and colonies falling within the zones of inhibition were purified and tested for susceptibility. An inoculum of 107 bacteria per plate (8.8 cm in diameter) was required to yield the growth of confluent colonies after 18 to 24 hours of incubation at 37°C. Samples yielding nonconfluent colonies (less than 10 percent of samples from each region) were not included in the study.The inoculum plated more than 104 bacteria between the circumference of each disk and that of its zone of inhibition for susceptible bacteria, which exceeded 10 mm in diameter around all but the gentamicin disk. More than 103 bacteria were plated in the inhibition zone for gentamicin, which was more than 9 mm in diameter. Reconstruction experiments using mixtures of susceptible and resistant strains confirmed the sensitivity of this method in detecting infrequent strains (strains resistant to gentamicin, 10-4 to 10-3; strains resistant to all other antimicrobials, 10-5 to 10-4 [data not shown]).
In Boston, 0.1 ml of each stool sample was also inoculated with a fresh swab onto plates containing antimicrobial agents (ampicillin, 10 μg per milliliter; chloramphenicol, 20 μg per milliliter; gentamicin, 10 μg per milliliter; streptomycin, 20 μg per milliliter; kanamycin, 25 μg per milliliter; tetracycline, 20 μg per milliliter; and trimethoprim, 100 μg per milliliter). Plates thus inoculated were shown by dilution studies to have 105 to 106 bacteria on their surface.
Bacteria were excluded from the study if they were not identified as E. coli according to the Analytical Profile system (API, Analytab Products, Plainview, N.Y.), since the inclusion of other lactose-positive colonies might have resulted in higher carriage rates for resistance.13 Overall, 9.9 E. coli isolates were analyzed per child in Boston, 9.6 in Caracas, and 9.9 in Qin Pu. The samples were analyzed by the same investigator in all three cities.
Hospital Data
The clinical microbiology laboratories of Brigham and Women's Hospital (Boston), Hospital Centro Medico (Caracas), and Hua Shan Hospital (Shanghai, 20 km from Qin Pu) provided data on antimicrobial-susceptibility testing for clinical E. coli isolates. The data were for the same years as the community survey, 1986 and 1987, with the exception of data from Hospital Centro Medico on resistance to tetracycline and kanamycin, of which the most recent were for 1984. The laboratories also tested susceptibility with the disk-diffusion method, using Mueller-Hinton agar and BBL susceptibility-testing disks.14 Resistance to trimethoprim was detected by a combination trimethoprim–sulfamethoxazole disk.
Statistical Analysis
The carriage rates of resistant E. coli in stool for the three cities were compared by calculating P values with an exact test for two-by-three tables.15 To adjust for the multiple comparisons made, the Bonferroni correction16 was used to calculate an appropriate level of significance for each test in order to preserve a global 5 percent level of significance (i.e., 0.05/18 = 0.0028).
Results
Characteristics of the Study Populations
The three populations were composed of healthy boys and girls between the ages of five months and six years who lived in the urban areas of Boston (n = 39), Caracas, Venezuela (n = 41), and Qin Pu, China (n = 53). Only children who had not received antimicrobial agents within the previous four months were enrolled in the study. Less than 10 percent of the total number of children examined in each location met the inclusion criteria of the study. Of this group, 12 children in Boston (31 percent), 9 in Caracas (22 percent), and 15 in Qin Pu (28 percent) had never received antimicrobial agents. Comparison of children above and below the median age of 17 months in Boston (range, 7 to 36 months), 16 months in Caracas (range, 5 to 60), and 53 months in Qin Pu (range, 6 to 72) or above and below the age of three years in each city showed no effect of age on the prevalence of resistance to any of the antimicrobial agents.
Resistant E. coli
The carriage rates of resistant E. coli in stool were higher among the children in Caracas and Qin Pu than among the children in Boston (Table 1Table 1
Distribution of Children with Antimicrobial-Resistant Strains of E. coli, According to Study City and Method of Testing Colonies.), whether testing by random selection of colonies or testing by disk selection was used to detect resistant bacteria.The 1000-fold greater sensitivity of the disk-selection method in detecting resistant colonies roughly doubled the rates of carriage observed on testing of 10 colonies chosen randomly from each specimen, but the rank orders of carriage rates of strains resistant to each antimicrobial agent for each city and the ratios between cities remained similar.
The disk-screening method detected a resistant strain in all but one of the children in Caracas and in all but two of those in Qin Pu; it detected no resistant strains in nearly half the children in Boston. Plating of the specimens from children in Boston on agar containing antimicrobials, which increased the number of bacteria screened an additional 10-fold, did not identify additional carriers of resistant strains. The children who had never received antimicrobial agents did not carry significantly fewer resistant strains of E. coli than did those who had received antimicrobials more than four months before sampling. Only 1 child in Boston but 25 children in Caracas and 34 in Qin Pu carried strains resistant to trimethoprim. None in Boston or Caracas but 17 in Qin Pu carried strains resistant to gentamicin.
The frequency of resistance to each of the eight antimicrobial agents among the 10 colonies of E. coli selected randomly from each child's stool sample averaged, overall, 0.05 in Boston, 0.19 in Caracas, and 0.29 in Qin Pu (the frequency was calculated by dividing the total number of colonies resistant to a single antimicrobial agent by the total number of colonies tested, then averaging over the number of antimicrobials [eight]). Resistance to three or more of the antimicrobials was found in 42 percent of the colonies from Qin Pu and 30 percent of the colonies from Caracas, but in only 6 percent of the colonies from Boston (Table 2Table 2
Distribution of Antimicrobial-Resistant Strains of E. coli, According to Study City and Number of Agents Resisted.). Resistance to five or more antimicrobial agents was found in none of the colonies from Boston, but in 20 percent of those from Qin Pu (from 15 children) and 6 percent of those from Caracas (from 7 children) (Table 2).Figure 1Figure 1
Proportion of E. coli Strains Resistant to Antimicrobial Agents, According to Study Center. shows that the percentage of E. coli strains from the children in each city that were resistant to each antimicrobial agent was always less than but related to the corresponding percentage of the clinical isolates of E. coli routinely tested in a nearby hospital. Consequently, the rank order of the three cities according to the percentage of strains resistant to each of the antimicrobial agents was the same when the cities were ranked according to the colonies from the children or according to the hospitals' laboratory isolates.Discussion
During the past half century, the wide use of each new antimicrobial agent has led eventually to the emergence of genes encoding resistance to it, the spread of resistance genes on plasmids through the world's bacterial populations, and the selective overgrowth of strains with the resistance genes.2 , 3 This process is known to have distributed resistance unevenly. Resistant strains of enteric pathogens have been epidemic in certain regions of the world.2 Other resistant pathogens, such as penicillinase-producing Neisseria gonorrhoeae,17 methicillin-resistant Staphylococcus aureus,18 and penicillin-resistant Streptococcus pneumoniae,19 have been more prevalent in some areas. Gram-negative bacilli of patients in medical centers in some countries have been resistant an average of 3 times as often, and to some antimicrobial agents, more than 10 times as often, as have comparable isolates elsewhere.1 , 2
Excess resistance observed in routine isolates from patients in a region predicts the related excess costs of treatment failure and the need for expensive new antimicrobial agents. Such isolates may misrepresent the resistance of a region's bacterial populations, however, in that resistant strains that are epidemic or nosocomially endemic there may have been oversampled or other populations of bacteria that may be reservoirs of resistance genes may have been undersampled.20 , 21
The healthy members of a community provide its largest reservoir of E. coli strains.22 We chose to study the E. coli of children not recently treated with antimicrobial agents, as a means of sampling this reservoir. Earlier surveys had found fecal carriage of resistant E. coli in one third to two thirds of residents of developed countries5 6 7 8 9 10 11 12 — an observation consistent with our finding fecal carriage of resistant E. coli in half the children in Boston, but not with our finding it in nearly all the children we tested in Caracas and Qin Pu.
Excess resistance in the bacteria that colonize people in a region may be an indicator of excess resistance in the bacteria that infect them, since the latter arise largely from the former.23 Even if the infecting strains were distinct subpopulations of the colonizing strains, they would still have shared the environment that produced the excess resistance of the colonizing strains and would also have had an excess probability of acquiring mobile resistance genes from them.24
Such a correlation between the resistance of colonizing bacteria in a region and the resistance of infecting bacteria is supported by the similarity in the ratios of the percentage of resistant colonies from children to the percentage of resistant isolates from patients in each city (Fig. 1). These findings suggest that the patients' isolates are a mixture of strains as resistant as local colonizing strains, plus nosocomial and treatment-selected strains that are proportionally more resistant.5 , 25 This suggestion could be confirmed by comparing the resistance of fecal E. coli in different regions, as we did, with the resistance of E. coli from (for example) initial urinary tract infections acquired in communities of those regions.
Carrying no bacteria resistant to an antimicrobial agent is different from carrying a few. Persons with a few resistant bacteria will have more of them after taking an antimicrobial agent and thus will have more chance of a resistant infection in the future. Persons with no resistant strains, however, will continue to have none after treatment unless they acquire some, which is less likely in places where few people have any. Almost no U.S. patients had trimethoprim-resistant E. coli before or after taking trimethoprim in the United States, for example,26 , 27 whereas a third of traveling U.S. students had them before taking trimethoprim in Mexico and nearly all had them afterward.28
The tendency of the excess resistance genes to cluster in multiresistant strains, as shown in Table 2 and as noted elsewhere,1 , 29 reflects their carriage on plasmids and predicts both frequent treatment failure, particularly where susceptibility testing is unavailable, and consequent further overgrowth of resistant strains.30
These considerations argue for ongoing surveillance in every country of the resistance in clinical isolates, which are the immediate focus of antimicrobial therapy, and also of the resistance in the bacteria of untreated healthy citizens, which reflects the potential for resistance in future infections. Excess resistance in a community could be due to environmental conditions, such as crowding, poor sanitation, or contamination of food, that tend to disseminate resistant strains or to practices in using antimicrobial agents that select for the overgrowth of resistant strains.4 In the present study, environmental effects are suggested by the observation that children who had never received antimicrobial agents had no less resistance than those who had received them four or more months earlier. On the other hand, an effect of the use of antimicrobial agents is suggested by the observation that resistance to gentamicin was widespread in one city but undetectable in the other two. An investigation of the causes in these three cities would need to consider the differences in their systems of sanitation, food supply, child care, and health care.
Although all but one child in Caracas and all but two children in Qin Pu carried strains resistant to some of the antimicrobial agents, resistance to others remained low in these regions. In Caracas, none of the children were found to be carriers of gentamicin resistance. In China, an additional screening for ofloxacin resistance failed to identify any children colonized by resistant strains. These observations demonstrate that high levels of resistance to an antimicrobial agent are not inevitable in a community.
Although it might prove difficult to evaluate and remedy the causes of excess resistance in a region, identifying such resistance could be an important beginning. Both sanitary practices and the use of antimicrobial agents are the subjects of countless decisions at all levels, from the household through health care workers to government departments of health. Surveillance for resistance might increase awareness of the nature of this health care problem. A low level of carriage of resistant strains should become a public health goal, as have normal blood pressure and lower serum cholesterol levels.
Supported by a grant (AI-23474) from the National Institutes of Health and by funds from Hoechst Pharmaceuticals (for the survey in China). Dr. Lester was a recipient of a one-year fellowship from Harvard Medical School.
We are indebted to the children and parents of Caracas, Qin Pu, and Boston who generously donated their time and help to this study; to the health care workers of Harvard Community Health Plan (Boston), Vargas Hospital (Caracas), Hua Shan Hospital (Shanghai), and Qin Pit Regional Hospital (Qin Pu), without whose support this study could not have been done; to Dr. Manuel Guzman, Dr. Raoul Isturiz, and Dr. Jorge Murillo for providing clinical data from Hospital Centro Medico; and to Dr. Roger Davis for statistical consultations.
Source Information
From the Department of Medicine and the World Health Organization Collaborating Center for Surveillance of Antimicrobial Resistance, Brigham and Women's Hospital, and Harvard Medical School, Boston (S.C.L., T.F.O.); the Institute of Biomedicine, Vargas Hospital, Caracas, Venezuela (M.P.P., I.P.S.); and the Hua Shan Hospital, Institute of Antibiotics, Shanghai Medical University, Shanghai, China (F.W., H.J.). Address reprint requests to Dr. O'Brien at Brigham and Women's Hospital, Laboratory of Microbiology, 75 Francis St., Boston, MA 02115.
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