The Oregon Health Authority conducts active, laboratory-based surveillance for all cases of NTS infection. Physicians and laboratories are required by law to report laboratory-confirmed and clinically suspected cases of salmonellosis to the patient’s local health department; reports should contain the patient’s date of birth, sex, diagnosis, date of symptom onset, date of specimen collection, and laboratory test results. All Salmonella isolates are forwarded to the Oregon State Public Health Laboratory (OSPHL), where they are serotyped. Local health department officials interview patients about hospitalization, clinical outcomes, additional demographic information, and exposure history for the 7 days before illness onset. Risk-factor questions ask about specific travel, human, animal, and high-risk food exposures. International travel was considered a risk factor only if it had taken place in the 30 days before illness onset. Patients with recurrent infection or multiple Salmonella isolates (of same serotype within a plausible time frame for the original infection) are interviewed only once, at the time of initial illness onset.

During 2004–2009, the population of Oregon was 3.6–3.8 million persons, which is ≈1.2% of the US population (21,22). The surveillance system in Oregon is estimated to capture >99% of laboratory-confirmed cases of salmonellosis; however, for every 1 case confirmed, an estimated 25 additional cases are not detected (2).

For 2004 and 2005, all confirmed isolates were forwarded to the Oregon State University Veterinary Diagnostic Laboratory for susceptibility testing. From 2006 through 2009, susceptibility testing was performed by OSPHL. All isolates were tested by using broth microdilution to determine MICs for the following 10 antimicrobial agents: ampicillin, ceftriaxone, chloramphenicol, ciprofloxacin, gentamicin, nalidixic acid, nitrofurantoin, sulfamethoxazole, tetracycline, and trimethoprim/sulfamethoxazole. Susceptibilities were determined according to Clinical and Laboratory Standards Institute interpretative criteria (23). To ascertain cephalosporin resistance, OSPHL tested isolates for ceftriaxone susceptibility; and the Oregon State University Veterinary Diagnostic Laboratory tested for susceptibility to cefuroxime and cephalothin by using analogous broth microdilution methods. MIC results were dichotomized as susceptible or resistant.

Isolates were included in analyses only if they were cultured from specific specimens, such as feces, urine, or blood or other normally sterile tissues (i.e., cerebrospinal fluid). CIR was defined as resistance to at least 1 of the following: ampicillin, ceftriaxone, ciprofloxacin, gentamicin, or trimethoprim/sulfamethoxazole (13). We used the Cochran-Armitage test for trend to analyze NTS case data for 2004–2009 to determine whether the proportion of Salmonella isolates with CIR increased significantly. Demographic and exposure risk factors, specifically international travel, were evaluated as risk factors for acquisition of a resistant isolate. The 9 most common Salmonella serotypes were fixed (included in all models regardless whether they met the p<0.05 level of significance) in all analyses, and remaining serotypes were grouped as “all other.” Serotype Enterditis is the most frequently isolated serotype in Oregon and was therefore used as the referent for all comparisons.

We sought to evaluate whether resistance was associated with increased disease severity, including hospitalization and invasive infection. Invasive infection was defined as isolation of Salmonella from a normally sterile body site or tissue, such as blood (13). Multiple logistic regression models were constructed with variables that were significant at the p<0.25 level in unadjusted analyses. Salmonella serotype and patient race, age, and year of illness onset were fixed in all models. Other variables were given further consideration according to disease severity or relevance for external validity. Predictor variables significant at p<0.05 were retained in the final model, and adjusted log odds ratios (aORs) were calculated. Model fit was assessed by using the Hosmer–Lemeshow goodness-of-fit test.

All analyses were performed by using SAS version 9.2 (SAS Institute Inc., Cary, NC, USA). Because this study involved more extensive analysis only of data collected routinely as part of public health surveillance, it was not considered human subjects research.

From 2004 through 2009, a total of 2,255 laboratory-confirmed cases of nontyphoidal salmonellosis were reported in Oregon. In accordance with Oregon law, 2,153 isolates were forwarded to OSPHL, and 2,127 (98.8% of all NTS isolates) were cultured from a specific source and had antimicrobial drug susceptibility testing information (Figure). Of these isolates, 26 (1.2%) were obtained through a nonspecific source, such as lesions or sputum, and were excluded from analysis.

The most common Salmonella serotypes detected were Enteritidis (18.4%), Typhimurium (14.3%), Heidelberg (8.2%), Typhimurium var. Copenhagen (5.1%), and Newport (4.5%). Cases that were part of identified outbreaks represented 24.1% of the cohort; the remaining 75.9% were considered sporadic cases. The median age of patients was 29 years (interquartile range 9–51 years), and 53.1% of patients were female. Information about race was not available for 9%; of patients for whom race was known, 91.8% were white and 9.2% were not white. Similarly, information about ethnicity was not available for 10.5% of patients. Among patients for whom ethnicity was known, 87.4% were not Hispanic and 12.6% were Hispanic. Isolates from 1,213 (57%) patients were susceptible to all antimicrobial drugs screened (pansusceptible), and isolates from 347 (16.3%) had CIR (Table 1). Of the 2,127 patients, 412 (19.4%) were hospitalized and 110 (5.2%) had invasive disease.

The proportion of isolates that were pansusceptible significantly decreased from 69.5% in 2004 to 53.6% in 2009 (p<0.01). CIR did not significantly increase during this study period (p = 0.27). Stratification by serotype revealed that CIR increased among the 3 most common serotypes: Enteritidis (3% to 8%, p = 0.02), Typhimurium (19% to 34%, p = 0.03), and Heidelberg (6% to 30%, p<0.01). Significant increases were identified for resistance to ciprofloxacin (p<0.05), nalidixic acid (p<0.01), sulfamethoxazole (p<0.01), tetracycline (p<0.01), and trimethoprim/sulfamethoxazole (p<0.01). Cephalosporin resistance increased, although not significantly (p = 0.06).

We suspected that these findings were confounded by serotype and therefore used logistic regression to model the odds of acquiring a resistant infection for each of the clinically important antimicrobial drugs (ampicillin, ceftriaxone, ciprofloxacin, gentamicin, or trimethoprim/sulfamethoxazole) as well as CIR. Serotype-adjusted log odds ratios were generated with year of infection entered as a discrete continuous variable. After adjusting for serotype, we found that with each subsequent year, patients were 30% more likely to acquire an infection that was resistant to quinolones (nalidixic acid or ciprofloxacin) and trimethoprim/sulfamethoxazole (Table 2). Resistance to ampicillin and cephalosporin also increased, although not significantly. We also found that with each year, odds of acquiring an infection with CIR increased by 13%.

CIR was associated with hospitalization (odds ratio [OR] 1.5, 95% CI 1.1–2.0). This association was preserved after adjustment for serotype, patient age, patient race, and year (aOR 1.7, 95% CI 1.2–2.1). For patients with CIR infections, odds of invasive infection were increased, although not significantly, according to unadjusted or adjusted analyses (OR 1.4, 95% CI 0.9–2.2 and aOR 1.5, 95% CI 0.9–2.5, respectively).

Of the 2,127 patients included in the previous analyses, 1,813 (84.2% of all Oregon patients with NTS) were interviewed. For 305 (16.8%) of these patients, isolates had CIR, and for the remaining 1,508 (83.2%), isolates were susceptible to all clinically important antimicrobial drugs (Figure). Of the 1,508 isolates susceptible to clinically important drugs, 1,002 (55.3%) were susceptible to all drugs screened and 506 (27.9%) were resistant to at least 1 non-CIR drug.

According to the unadjusted analysis, several serotypes were more likely than the referent serotype, Enteritidis, to be resistant to >1 clinically important antimicrobial drug (Table 3). Patient sex, race, age, and ethnicity were not significantly associated with resistance.

CIR was not associated with any other demographic risk factors or high-risk food or animal exposures. However when international travel was examined by individual countries or applicable United Nations region, CIR was significantly associated with travel to Southeast Asia (24). Associations of resistance with travel to Mexico and eastern Asia also approached significance (Table 4). The most common travel destinations in Asia where resistant infections were acquired were Thailand, China, and Malaysia/Indonesia. On the basis of these findings, we analyzed international travel by 3 destinations: Central America, including Mexico (135 patients), eastern and Southeast Asia (46 patients), and all other international travel destinations (77 patients).

Patients who were part of identified outbreak clusters were significantly less likely than patients with sporadic infections to have a resistant infection (OR 0.5, 95% CI 0.4–0.8). During our study period, 131 outbreaks (406 cases) occurred, and for 25 of these outbreaks a causative vehicle was successfully identified. To assess whether oversampling of cases from outbreak clusters could explain this association, we first restricted cases to 1 isolate per outbreak where a causative vehicle was implicated while retaining all cases from outbreaks for which a vehicle was not implicated (302 cases). Second, we further restricted cases to 1 isolate per outbreak, regardless whether a vehicle was identified (131 cases). In each of these analyses the magnitude, direction, and significance of the association was preserved (OR 0.6, 95% CI 0.4–0.8 and OR 0.5, 95% CI 0.3–0.9, respectively), suggesting that oversampling could not have explained this association. Furthermore, 53.6% of outbreaks had intra-outbreak cases for which the antimicrobial drug susceptibility profiles of the isolates differed.

The resultant main-effects model included the fixed variables of serotype, patient age, year of onset, and patient race, along with travel to eastern or Southeast Asia, and outbreak association (Table 3). We hypothesized that effect modification occurred between the variables of outbreak cases and travel to eastern or Southeast Asia, as well as between travel to eastern or Southeast Asia, serotypes, and outbreaks. However, no significant interactions at the p<0.25 level were identified. No other variables or exposures were significantly associated with CIR. This model had excellent goodness-of-fit (p = 0.87). The association between resistance and travel to eastern or Southeast Asia was preserved after exclusion of all outbreak-associated cases (aOR 4.6, 95% CI 2.3–9.4; Table 5). Similarly, the association between resistance and outbreak-associated cases was preserved after exclusion of patients with a history of international travel (aOR 0.5, 95% CI 0.4–0.8; Table 6). Therefore, these results suggest that inclusion of patients with a history of travel to Asia, as well as patients with outbreak-associated infections for the main analysis, was appropriate.

Patients with a history of recent travel to eastern or Southeast Asia were >5 times more likely to acquire a CIR infection than were patients with no history of recent international travel. The most common serotypes acquired among persons with a history of travel to Asia were Enteriditis (n = 13, 54% CIR), Typhimurium (n = 5, 60% CIR), Newport (n = 4, 25% CIR), I 4, 5, 12:i:- (n = 4, 50% CIR), Stanley (n = 3, 33% CIR), and Typhimurium var. Copenhagen (n = 2, 100% CIR). Patients with outbreak-associated infections were half as likely as those with sporadic infections to have CIR (Table 3).

To identify risk factors for resistance to individual antimicrobial drugs, we constructed models with each of the clinically important antimicrobial drugs. Travel to eastern or Southeast Asia was significantly associated with resistance to ampicillin, quinolones (nalidixic acid or ciprofloxacin), and trimethoprim/sulfamethoxazole (Table 7). Only individual serotypes were associated with resistance to cephalosporins or gentamicin, and no other risk factors were significantly associated with resistance to ampicillin, quinolones, or trimethoprim/sulfamethoxazole.