Figure 1

Figure 1. . Participating countries in the survey of multidrug-resistant Salmonella enterica serotype Typhimurium, 1992–2001, internationally (A) and in Europe (B).

The questionnaire was sent to 52 countries, and a completed questionnaire was received from 29, a response rate of 56% (Figure 1). Of the 52 invited countries, 23 were members of or affiliated with Enter-Net; from these a positive feedback was received from 20 (87%). These countries were Australia, Austria, Belgium, Canada, Denmark, England and Wales, Finland, Germany, Greece, Ireland, Japan, Luxembourg, the Netherlands, New Zealand, Norway, Scotland, South Africa, Spain, Sweden, and Switzerland. The 8 countries and 1 regional center (31% response rate) that participated in the survey that were not associated with Enter-Net when data were collected were Brazil, the Czech Republic, Hungary, Israel, Latvia, Malta, Republic of South Korea, United States, and the Caribbean Epidemiology Centre (CAREC), a regional center that represents 21 countries in the Caribbean (Anguilla, Antigua and Barbuda, Aruba, Bahamas, Barbados, Belize, Bermuda, British Virgin Islands, Cayman Islands, Dominica, Grenada, Guyana, Jamaica, Montserrat, Netherlands Antilles, St. Kitts and Nevis, St. Lucia, St. Vincent and the Grenadines, Suriname, Trinidad and Tobago, and Turks and Caicos). For the purpose of this study, CAREC was treated as 1 unit. The 29 participating countries had a total population of 1.028 billion in 2001.

Phage Typing

In 1992, phage typing was carried out in 6 of the participating countries; by 2001, this number had risen to 22. Five countries (Brazil, Japan, Norway, Switzerland, and the United States) only performed phage typing when an MDR strain was found or in outbreak situations. Although not all countries performed phage typing in accordance with the Colindale Scheme (28), the countries using different standards provided information that allowed for comparison with results obtained using the Colindale Scheme (29–31).

Figure 2

Figure 2. . Salmonella enterica serovar Typhimurium DT104 as percentage of all S. Typhimurium in 8 world regions, 1992–2001. Only countries that had data available for 2 or more 2-year periods are included:...

The proportion of S. Typhimurium strains that were DT104 and the proportion thereof that were found to be MDR are shown for each country in Table 2. In general, the incidence and proportion of DT104 increased throughout the period. In 1992, 8.7% of S. Typhimurium isolates were DT104, but in 2001 this proportion had increased to 33%. Again, large regional differences occurred. In the United Kingdom, the incidence peaked in 1996 and then decreased. In most other European countries and North America, the relative numbers of DT104 strains had increased throughout the period. In Australia and New Zealand, few DT104 isolates (0.7%) were seen among S. Typhimurium in 2001. The proportion of S. Typhimurium strains that were DT104 is depicted in Figure 2 (the countries are aggregated into 8 regions).

Antimicrobial Drug Resistance

Antimicrobial susceptibility testing became an increasingly common constituent of the surveillance during the study period. In 1992, susceptibility testing was performed in 14 of the 29 participating countries and in all but one in 2000. All countries routinely tested a minimum of 6 antimicrobial drugs, all belonging to different drug classes. The majority of countries (73%) used disc diffusion testing according to NCCLS standards. Listed by frequency, the most common antimicrobial drug classes included in the test panel were (fluoro)quinolones, broad-spectrum penicillins, phenicols, aminoglycosides, tetracyclines, cephalosporins, sulfonamides, and trimethoprim. In 21 countries, antimicrobial susceptibility testing was performed independently of phage typing results, but in 2 countries (Finland until 1999 and New Zealand), testing was only performed on strains found to be DT104.

Figure 3

Figure 3. . Multidrug-resistant Salmonella enterica serovar Typhimurium as a percentage of all S. Typhimurium in 9 world regions, 1992–2001. Only countries that had data available for 2 or more 2-year periods are...

Table 2 shows the distribution of MDR S. Typhimurium presented as 2-year time-bands. Figure 3 depicts the general trend, with countries divided into 9 different regions. In 1992 15% of all S. Typhimurium isolates were MDR; by 2001, this percentage had increased 3-fold to 42%. Once again, large variations occurred between countries and within countries from year to year. In most European countries and North America, MDR S. Typhimurium was common and, with the exception of the United Kingdom and Ireland, multidrug resistance increased from the mid-1990s to the end of the study period. For example, in 2001 multidrug resistance ranged from 22% (Greece) to 72% (Ireland). Only limited data were available from Brazil, the Caribbean region, South Africa, and the Republic of Korea. However, in these regions multidrug resistance was far less common, ranging from zero in the Caribbean region to 19% in the Republic of Korea. In Australia, multidrug resistance remained low throughout the period, with 1.0% of strains in 1997 and 3.6% in 2001.

MDR DT104 was a frequent subtype of MDR S. Typhimurium in most of the countries. In 1992, between 11% (Germany) and 77% (Scotland) of the MDR strains were DT104; in 2001 this ranged from 22% (Australia) to 94% (the Netherlands). Overall, the proportion of MDR DT104 of all DT104 has remained fairly stable; 84% of DT104 were classified as MDR in 2001, compared with 72% in 1992. Among MDR DT104, the classical penta-resistant phenotype, R-type ACSSuT, was by far the most common phenotype throughout the period. It was found in 99% of MDR DT104 strains in 1992 and in 94% of such strains in 2001 (data not shown).

Figure 4

Figure 4. . Proportion of multidrug-resistant Salmonella enterica serovar Typhimurium with additional resistance to quinolones, cephalosporin, or trimethoprim, 1992–2001.

Finally, we looked at trends in development of additional resistance in the classical penta-resistant phenotype (R-type ACSSuT), with focus on 3 clinically important antimicrobial drug classes: quinolones, cephalosporins, and trimethoprim. Both quinolone and trimethoprim resistance increased in MDR DT104 throughout the study period. In 1992, nalidixic acid susceptibility testing was performed on a total of 194 MDR DT104 isolates in 4 different countries; no resistant isolates were found. In 2001, nalidixic acid susceptibility testing of 1,812 MDR DT104 strains in 11 countries identified 109 (6.0%) resistant strains. Similarly, trimethoprim resistance was found in 1.2% of the 180 MDR DT104 strains tested in 1992, but in 6.6% of 1,855 MDR DT104 strains tested in 2001. Cephalosporin-resistant MDR DT104 remained rare, with only 0.5% resistant strains in 2001, and no clear trend observable. Figure 4 shows the overall trend of resistance to quinolone, trimethoprim, and cephalosporins from 1992 to 2001. The increase in quinolone resistance seen in 1996 and in 1998 was caused by a general increase in quinolone-resistant MDR DT104 in Scotland and an outbreak of quinolone-resistant MDR DT104 in Denmark (14), respectively. The increase in trimethoprim resistance from 1995 to 1996 was also caused by a general increase in trimethoprim-resistant MDR DT104 in Scotland.

The present survey was conducted to gain a better understanding of the global impact of DT104 and MDR S. Typhimurium, given the severity of illness than can result from infection with S. Typhimurium and MDR strains in particular. The survey's primary findings are that during the period 1992–2001, the total number of MDR S. Typhimurium and S. Typhimurium DT104 cases increased, while that of other types of S. Typhimurium decreased. The total number of nontyphoidal Salmonella and S. Typhimurium cases also decreased. However, these general findings mask large differences in regional trends. The collected data also may not always accurately describe the real national incidence or be directly comparable between countries.

The total number of isolates of nontyphoidal salmonellae registered at the national level decreased from 1992 to 2001. This result may be biased because of changes in surveillance practices. Since the survey indicated that surveillance systems generally improved throughout the study period, this trend is most likely correct, however. Concurrent with this decrease, an overall decrease in the number of S. Typhimurium isolates was observed, thus keeping the proportion of S. Typhimurium cases among total Salmonella cases constant. The decrease was primarily seen in Europe and North America, whereas Australia and New Zealand saw an increase in both the number of cases of S. Typhimurium and of the total number of nontyphoidal Salmonella cases. In Germany the total number of nontyphoidal Salmonella cases is available for the whole country, but for administrative reasons data on serotypes, antimicrobial susceptibility, and phage types are based only on results from the new federal states of Germany (formerly East Germany) and the city of Berlin. However, German studies have shown that serotype distribution and drug resistance are comparable between former West and East Germany (32) (W. Rabsch, pers. comm.).

MDR S. Typhimurium has increased in the past decades in almost all the regions covered in this study. Most of this increase is due to the concurrent upsurge of DT104, whereas other phage types, such as U302, DT120, DT12, and DT193, were reported to play a smaller role in this development. A high proportion of MDR S. Typhimurium was primarily observed in Europe and North America. Because of the low coverage of participating countries in Asia, South America, and Africa, the situation in these areas was difficult to assess. Both Australia and New Zealand, however, reported high incidence of S. Typhimurium, but MDR strains of S. Typhimurium and DT104 were largely absent. The isolated increase in MDR S. Typhimurium in Australia in 2001 can be explained by a large outbreak of MDR DT104 associated with consumption of halva (dessert made of sesame seeds) (33). That DT104 has not spread markedly in Australia and New Zealand may be explained both by geography and the very strict food and livestock import restrictions in force in these countries, which prevent any large-scale introduction and spread of foreign Salmonella types in the food animal production chain (34).

Although high and generally increasing levels of MDR S. Typhimurium were observed in Europe, the United Kingdom presents a special case. It and Germany had an increase in DT104 in the beginning of the 1990s, before most other countries (5,35). In fact, DT104 was first isolated in the United Kingdom in the early 1980s, years before it was isolated in other countries (5). In the United Kingdom, the incidence of DT104 peaked in 1996 and has since declined ([5] and this study). Possible explanations for this finding include the management of bovine spongiform encephalitis in the United Kingdom, associated general improvements in farm hygiene, and an overall decline in cattle production (36).

Although multidrug-resistance and DT104 were closely linked, large country-specific differences were seen, even between neighboring countries. Most pronounced was the difference between Germany and the Netherlands in 2001, where 64% and 94%, respectively, of MDR isolates were DT104. Such differences probably reflect both real differences and biases resulting from, for instance, different laboratory reporting practices. For example, some of the countries in this survey (New Zealand, Norway, and the United States) performed antimicrobial susceptibility tests on all their DT104 isolates but only on a subset of non-DT104 strains.

In Australia and in Scandinavia, where the incidence of domestically acquired salmonellosis is generally low, many cases appeared to be imported. In a recent study of Australian DT104 isolates, 37% were associated with travel abroad, particularly to Southeast Asia (D. Lightfoot, pers. comm.). Complete data on travel association of MDR S. Typhimurium cases were available for Norway and Finland and showed that most MDR S. Typhimurium patients were infected abroad. In Sweden, where information on DT104 but not MDR was available, most DT104 patients were infected abroad.

A special issue concerns the possibility of acquisition, with time, of resistance traits additional to the classical penta-resistant pattern. Of particular concern is the additional acquisition of quinolone resistance by MDR DT104, since fluoroquinolones are often the drugs of first choice when treating severe salmonellosis. Our data indicate that the prevalence of quinolone resistance has increased. As mentioned, several studies have now shown that multidrug resistance and quinolone resistance may be associated with particular adverse health effects. When seen in the light of the ability of DT104 to spread and establish itself in a large variety of food animal lines (cattle, pigs, poultry), the increase in the number of MDR S. Typhimurium strains that include quinolone resistance becomes particularly problematic. Quinolone, and in particular the fluoroquinolones, have been part of human medicine since the 1980s, resulting in no or very limited resistance in salmonellae. It was not until the license of fluoroquinolones for food animal production in the early 1990s that resistant Salmonella strains emerged (37). The use of fluoroquinolones for food production animals should therefore be discontinued or at least severely restricted as quickly as possible.

This survey has several important limitations. First, it was limited to countries with relatively sophisticated surveillance systems in place, since only countries performing phage typing or resistance testing in addition to serotyping were eligible. This meant that Asia, Africa, and South America were barely covered. Therefore, the survey contains no representative data on the situation in these regions. WHO Global Salm-Surv seeks to enhance the capacity of countries to provide such data. Second, the collection of isolates at the national level is likely to vary from country to country, depending on a number of factors such as sampling frequency at the local level, availability of laboratory reagents, and the degree to which isolates and results are forwarded to the national level. Local practice, the priority given to foodborne illnesses, and financial factors will influence on how often a physician will request a fecal sample. Furthermore, many countries stated that strains and information were not always routinely collected centrally, while in some of the countries strains were never forwarded from certain local laboratories. For these reasons, care should be taken in the interpretation of results of this survey; in particular when comparing incidence rates between countries. However, these limitations are inherent to surveillance in general and do not apply only to this survey. Cross-checking these survey data with available published surveillance data showed them to be in line with each other in the United States (38), the Netherlands (39), and Denmark (40).

In summary, on a global scale, only a small number of countries perform antimicrobial susceptibility testing or phage typing, although the number of countries doing so more than doubled throughout the study period. Despite its limitations, the survey showed that the incidence of both MDR S. Typhimurium and MDR S. Typhimurium DT104 increased markedly worldwide during the 1990s, although the problem has primarily affected Europe and North America. Of special concern is the increasing incidence of quinolone-resistant S. Typhimurium. The survey implies that MDR S. Typhimurium poses a serious and increasing public health problem in large parts of the world. Surveillance and control programs such as the Global Salm-Surv international network recently launched by WHO should therefore be reinforced.