Clinical Epidemiology of Stenotrophomonas maltophilia Colonization and Infection
2002; Wolters Kluwer; Volume: 81; Issue: 3 Linguagem: Inglês
10.1097/00005792-200205000-00006
ISSN1536-5964
AutoresMaría Dolores del Toro, Jesús Rodríguez‐Baño, Marta Herrero, Antonio Rivero, Miguel Ángel García-Ordóñez, Juan E. Corzo, ROGELIO PÉREZ-CANO,
Tópico(s)Antimicrobial Resistance in Staphylococcus
ResumoIntroduction There is general concern regarding the widespread resistance to antibiotics and the increasing prevalence of nosocomial infections caused by multiresistant pathogens (22), such as methicillin-resistant Staphylococcus aureus, glycopeptide-resistant enterococci, extended-spectrum beta-lactamase-producing Enterobacteriaceae, and multiresistant nonfermenting Gram-negative bacilli (8). While therapeutic options for managing these infections are limited, deeper knowledge of their epidemiology may provide valuable information for the establishment of preventive and control strategies. Stenotrophomonas maltophilia is a nonfermentative Gram-negative bacillus that may cause nosocomial infections, mainly in debilitated, immunocompromised patients (11,42,54). Although considered a low-virulence pathogen, infections caused by this organism are difficult to treat due to its intrinsic resistance to multiple antimicrobial agents, including carbapenems. During the last decade, it has emerged as a relevant nosocomial pathogen and it is being isolated with increased frequency from clinical samples (42,46,52). Several nosocomial outbreaks caused by this organism have been described (1,10,20,26,33,39,40,62,70,71,74). Potential risk factors for the acquisition of S. maltophilia have been suggested by several descriptive series. Some underlying conditions, such as malignancy or chronic respiratory diseases, long hospital stay, stay in an intensive care unit (ICU), previous antimicrobial treatment, and indwelling devices are frequent among patients infected or colonized with this organism (14,15,26,30,32,35,36,40,46,47,64,68,71). However, data from case-control or cohort studies are scarce and should be interpreted in the light of the epidemiologic setting in which they were performed. We conducted this study to describe the clinical epidemiology of S. maltophilia in the endemic setting and to analyze the risk factors associated with the nosocomial acquisition of this organism beyond a concrete epidemiologic situation, that is, in patients with diverse underlying diseases from different services and hospitals. Methods Location Six hospitals from 3 cities located in Andalucía, Spain, participated in the study. The hospitals range from 532 to 1,700 beds (Table 1). All the hospitals are public, have ICUs and oncology/ hematology services, and attend medical and surgical patients (adults and pediatrics). Five are teaching hospitals. None had apparent outbreaks caused by S. maltophilia during the year before the study period.TABLE 1: Features of participating hospitalsDesign All hospitalized patients from which S. maltophilia was isolated from clinical samples between 1 February 1998 and 30 June 1999 were included prospectively (cases). Cases were detected through daily revision of microbiology reports. For each case, 2 controls were included. Controls were randomly chosen among patients from whom a similar sample had been obtained that was negative for S. maltophilia. Frequency matching for hospital and unit of admittance was used. The following data were collected: demographic characteristics, type and severity of underlying diseases (classified as nonfatal, ultimately fatal, or rapidly fatal according to McCabe criteria) (44), antimicrobial use, immunosuppressive drugs including corticosteroids (prednisone >10 mg qod or equivalent during more than 3 weeks), neutropenia (less than 500 neutrophils per mm3), invasive procedures (surgical procedures, intravascular catheters, urinary catheters, mechanical ventilation), parenteral nutrition, previous ICU stay, length of hospital stay, and hospitalization within the previous 3 months. Differentiation between nosocomial and community-acquired isolates, and between colonization and infection were assessed according to Centers for Disease Control and Prevention (CDC) criteria (21,29) by the investigator in each hospital. Chronic underlying disease must have been evident before hospital admission; the diseases were defined as follows: Chronic liver disease: biopsy-proven cirrhosis or documented portal hypertension, episodes of past upper gastrointestinal bleeding attributed to portal hypertension, prior episodes of hepatic failure or encephalopathy. Cardiac insufficiency: class IV of New York Heart Association. Chronic respiratory disease: chronic restrictive, obstructive, or vascular disease resulting in severe exercise restriction (unable to perform household duties) or documented chronic hypoxia, hypercapnia, secondary polycythemia, or severe pulmonary hypertension (>40 mmHg). Renal insufficiency: renal disease requiring chronic dialysis. Immunocompromising disease: primary immunodeficiency, leukemia, lymphoma, or acquired immunodeficiency syndrome (AIDS). Microbiologic studies Samples were processed in each hospital using standard protocols. Laboratory identification of S. maltophilia was performed by the Vitek 2 System (bioMérieux-Vitek, Hazelwood, MO) or the AutoScan Walk-Away (Dade-Behring, Sacramento, CA) identification system. Antibiotic susceptibility testing of the first isolate from each patient was performed by microdilution. Organisms were classified as susceptible, moderately resistant, or resistant according to the National Committee for Clinical Laboratory Standards (NCCLS) criteria (48). Statistical analysis Univariate comparison between cases and controls was performed using the Student t test for continuous variables and the chi-squared test for categorical variables. Odds ratios and their 95% confidence intervals (CI) were calculated. Multivariate analysis of potential risk factors, including potential interactions, was performed by means of logistic regression analysis. Selection of variables was performed by a stepwise backward method, in which the less significantly associated variable was eliminated in each step. The variables "hospital" and "service" were kept in the models obtained as they were used for frequency matching. Results Incidence During the 17 months of the study, S. maltophilia was isolated from 129 hospitalized patients in the 6 participating hospitals (cases). The pooled-incidence was 5.73 per 10,000 admissions, ranging in the different centers from 3.4 to 12.1 per 10,000 admissions (see Table 1). There was no relation between incidence and the size or general features of the hospitals. Clusters of cases were not apparent throughout the study period in any hospital. Description of the cases Among the 129 cases, 7 were neonates (5%), 1 was 6 years old, and the rest were adults (94%). Neonates had a mean age of 33 days, and adults of 56 years (range, 19–90 yr). Eighty-six cases (67%) were male. When S. maltophilia was isolated, 41 patients (32%) were in an ICU, 24 (18%) in surgical services, 14 (11%) in oncology/hematology services, and 50 (39%) in other medical services. Seventeen patients (13%) had previously been in the ICU during the present admission. Overall, 102 patients (79%) had a chronic underlying disease; among them, chronic pulmonary disease was the most frequent (25% of cases), followed by neoplastic diseases (21%), diabetes (19%), and chronic renal insufficiency (11%). The underlying disease was considered nonfatal in 35% of the patients, ultimately fatal in 52%, and rapidly fatal in 13%. The median duration of hospitalization before the isolation of S. maltophilia was 17 days (range, 0–180 d). Thirty percent had been admitted to the hospital within the 3 months before the present admission. In 12 patients (9%), the sample was taken when the patient had been 2 or fewer days in the hospital (6 of them had been recently hospitalized). Forty-one percent of the patients had undergone surgery during the present admission, abdominal surgery being the most frequent (30%), followed by orthopaedic (17%), cardiac (11%), and cranial surgery (11%). Thirty percent had received immunosuppressive drugs, and 7% were neutropenic. Regarding devices, 48% had a urinary catheter (median days, 12.5), and 92% vascular catheters (43% of them being central venous catheters). The median duration of vascular catheterization was 14 days. Thirty-six percent of cases had been on mechanical ventilation during the preceding week for a median of 8 days, and 12% had received parenteral nutrition. Overall, 88% had received systemic antimicrobial therapy during the present admission. Among these patients, the mean number of antimicrobials received by each was 2.7 (range, 1–7), and the median duration of antimicrobial therapy was 11 days. The antimicrobials most frequently administered were third-generation cephalosporins (43%), aminoglycosides (29%), carbapenems (28%), glycopeptides (25%), and quinolones (23%). Clinical microbiology S. maltophilia was isolated from respiratory tract samples (52% of isolates), wounds (18%), urine (9%), blood (9%), catheter-tip (5%), intraabdominal fluid (4%), and other samples (3%). The distribution of samples was not homogeneous among the different services. Thus, respiratory samples were the most frequent in internal medicine (57%), pneumology (72%), ICU (67%) and neonatology units (85%); blood cultures predominated in hematology/oncology wards (35%); urine in nephrology (35%); and wounds in surgical services (58%). The organism was isolated from more than 1 sample in 21% of patients. In 26% of the samples, it was isolated together with 1 or more other microorganisms (the most frequent being Enterobacteriaceae, Enterococcus spp., other nonfermentative Gram-negative bacilli, and staphylococci). In 56% of cases, S. maltophilia was considered to be the cause of infection, while in the rest of the cases patients were considered colonized only. All patients with blood cultures and intraabdominal fluid yielding S. maltophilia were infected. The proportion of infected patients among those with urine, respiratory, and wound samples was 50%, 46%, and 43%, respectively. Respiratory tract infections were the most frequent, followed by surgical site infections, urinary tract infections, and intraabdominal infections (Table 2). Pneumonia occurred in 8 of 32 patients in other medical services and in 15 of 16 in ICUs. Twelve patients were bacteremic; sources of bacteremia were respiratory tract (3 patients), vascular catheter (3 patients), urinary tract (1 patient), and unknown (5 patients). For patients admitted to hematology/oncology services, primary bacteremia was the most frequent type of infection (4 of 9 infected patients). Among the 10 patients with surgical site infections, 3 had undergone orthopaedic procedures, 2 amputations, 2 intraabdominal surgery, 2 thoracostomy, and 1 drainage of fascitis. In 4 of these cases, the infection was polymicrobial. Eight of the 10 patients with surgical site infection had previously received at least 2 broad-spectrum antibiotics. Surgical site infections were the most common among surgical patients (6 of 12).TABLE 2: Type of infections due to Stenotrophomonas maltophiliaThere were no significant differences between patients with S. maltophilia infection and colonization with regard to baseline characteristics, underlying diseases, device use or antimicrobial use (data not shown), except for the following (multivariate analysis): infected patients were less frequently male (odds ratio [OR] = 0.4, 95% CI: 0.1–0.9, p = 0.04), had been less frequently on mechanical ventilation (OR = 0.3, 95% CI: 0.1–0.8, p = 0.02), and had received ceftazidime for a mean longer period of time (OR = 1.3, 95% CI: 1.01–1.75, p = 0.03). The antimicrobial susceptibility of S. maltophilia isolates is shown in Table 3. The most active agent in vitro was trimethoprim-sulfamethoxazole (TMP-SMX) (81% of isolates tested were susceptible or intermediately susceptible), followed by ciprofloxacin (54%), ceftazidime (50%), tetracycline (50%, but only 66 isolates were tested) and ticarcillin (43%). Ninety-eight percent of isolates were resistant to imipenem. Previous ceftazidime treatment was more frequent among patients with ceftazidime-resistant or intermediate isolates, and that difference almost reached statistical significance (16% versus 4%, OR = 4.1, 95% CI: 0.86–19.4, p = 0.05). Also, previous TMP-SMX use was more frequent among patients with TMP-SMX-resistant isolates (17% versus 2%, OR = 9.5, 95% CI: 1.6–55.4, p = 0.003). There was no association between susceptibility to other antimicrobial agents and previous antibiotic use, hospital, or unit of admission (data not shown).TABLE 3: Antimicrobial susceptibility of S. maltophilia isolatesCase-control study The 129 cases were compared with 250 controls with regard to risk factors. In 8 cases, only 1 suitable control was found. Bivariate analyses of the association of potential risk factors and the isolation of S. maltophilia from the clinical specimens are shown in Tables 4 and 5. Cases and controls were similar in age and gender distribution. A rapidly fatal chronic underlying disease and chronic renal insufficiency were significantly more frequent among the cases. There was no difference in any other underlying disease, including neoplasia, diabetes, liver or heart insufficiency, pulmonary disease, human immunodeficiency virus (HIV) infection, or other immunosuppressive illness, nor in previous hospitalization, ICU stay, service, or hospital. Hospitalization had been longer in cases than in controls. Cases had more frequently undergone surgery during present admission (the difference being in significance limits) and received immunosuppressive drugs, but there was no difference in the frequency of neutropenia. The percentage of patients with urinary catheter, vascular catheter, mechanical ventilation, or parenteral nutrition was similar between cases and controls; nevertheless, the duration of mechanical ventilation and urinary or vascular catheterization was significantly longer among cases.TABLE 4: Bivariate analysis of the association of categorical variables and the isolation of S. maltophilia in clinical samplesTABLE 5: Bivariate analysis of the association of continuous variables and the isolation of S. maltophilia in clinical samples*Previous antimicrobial treatment was more frequent among cases. Cases also received more antimicrobial agents and for a longer period of time. With regard to individual antibiotics, cases received significantly more ceftazidime, carbapenems, quinolones, aminoglycosides, and glycopeptides. The duration of use of these antimicrobials and of aminopenicillins was also significantly longer in cases. Multivariate analysis was performed to identify those variables independently associated with an increased risk of acquiring S. maltophilia. All variables were introduced into 2 different analyses. In the first (the "qualitative model"), antibiotics and invasive procedures were considered dichotomous variables (presence or absence), and the variable "duration of hospitalization" was introduced (Table 6). In the second model (the "quantitative model"), antibiotics and invasive procedures were considered continuous (number of days), and the variable "duration of hospitalization" was not introduced (Table 7). Interactions between procedures and underlying diseases with antimicrobials were tested but were not found to be significant. In the qualitative model, the variables associated with S. maltophilia colonization or infection were male gender, duration of hospitalization, mechanical ventilation, and previous use of ceftazidime, carbapenems, or quinolones. In the quantitative model, the significant variables were days of ceftazidime use, days of carbapenems use, days of quinolones use, and days of mechanical ventilation. Deviance was similar for both models (−2 log likelihood, 285 versus 286, p = 0.8).TABLE 6: Multivariate analysis of risk factors for the isolation of S. maltophilia in clinical samples: Qualitative modelTABLE 7: Multivariate analysis of risk factors for the isolation of S. maltophilia in clinical samples: Quantitative modelDiscussion The use of carbapenems, together with many other extended-spectrum antimicrobials, has increased in recent years as a consequence of the emergence of multidrug-resistant Gram-negative bacilli, such as Acinetobacter baumannii, Pseudomonas aeruginosa, extended-spectrum beta-lactamase producing Enterobacteriaceae, or derepressed mutants of Serratia, Enterobacter, or Citrobacter. Such a situation might be producing a favorable scenario for the emergence of carbapenem-resistant organisms (51). As a matter of fact, S. maltophilia (formerly Pseudomonas maltophilia or Xanthomonas maltophilia) has risen during the last decades as a relevant nosocomial pathogen (11,42,52). Reports from several centers have shown significant increases in the incidence of the isolation rates and bacteremia due to this organism during the 1980s and the 1990s (35,71). Incidence of S. maltophilia isolation reported from different hospitals (including both colonized and infected patients) ranged from 7.1 to 37.7 cases per 10,000 discharges (42,46) or 18.3 cases per 1,000 patient-days (71). Most of those reports were performed after perceived increase in the incidence. The incidence from the hospitals participating in our study is somewhat lower, ranging from 3.4 to 12.1 cases per 10,000 discharges, with no apparent clustering of cases. Whether differences in the incidence found among the participating hospitals are related to differences in antimicrobial consumption or other factors cannot be investigated with our data. These data reflect a baseline low-endemicity situation in our hospitals, which may be more similar to present incidence in most tertiary centers. Most research into the clinical epidemiology of S. maltophilia has been performed in the context of outbreaks or perceived increase in incidence. Also, many studies include only selected populations, mainly ICU patients (1,24,41,71), cancer patients (15,17,32,33,39,67), or cystic fibrosis patients (12,13,56). We may not be able to extrapolate results from those studies to other epidemiologic situations or other types of hospitalized patients. Our study includes the whole hospitalized population from 6 large hospitals, so a more global view of the epidemiology of this organism can be attained. Some authors have found S. maltophilia to be community acquired in 20%-30% of hospitalized cases, and have speculated that colonization might not be infrequent outside hospitals (26,40,52,64). In our study, only 9% of cases were considered community acquired, and half of these patients had been recently hospitalized, suggesting that S. maltophilia behaves primarily as a nosocomial pathogen, in agreement with the findings of other authors (46). Geographic differences in the community epidemiology of the organism have not been studied extensively and might partly explain the differences found among studies. S. maltophilia has been isolated from a wide variety of environments in hospitals, mainly from water sources (reviewed in reference 11). These environmental sources in particular seem to be the most important origin of nosocomial acquisition. In fact, several nosocomial outbreaks have been related to common environmental reservoirs (33,71,74). Cross-transmission of S. maltophilia has been demonstrated in neonatology units (20,62), probably related to work overload and noncompliance with hygiene measures, but it does not seem to be as important as with other multiresistant pathogens. ICU and neonatology units are the hospital areas where S. maltophilia is isolated most frequently (1,20,24,40,41,70,71), as happens with other multidrugresistant nosocomial organisms. In our study, 45% of patients were or had recently been in the ICU. The higher incidence of S. maltophilia isolation in these areas, in addition to the possibility of environmental reservoirs in any particular unit, probably reflects the higher consumption of antibiotics within ICUs. However, more than 50% of our cases were not ICUrelated, and occurred in internal medicine, pneumology, nephrology, oncology/hematology, traumatology, and general surgery services. Although infections due to S. maltophilia have been described in previously healthy patients (26,40,52), in most of the cases the organism affects debilitated patients with 1 or several underlying diseases, who have needed indwelling devices, invasive procedures, antimicrobials, and immunosuppressive drugs, thus behaving as a nosocomial opportunistic pathogen. In our study almost 80% of patients had a chronic underlying disease, which was considered ultimately or rapidly fatal in 65%. The underlying diseases most frequently found in different studies are summarized in Table 8. The design of our study does not allow us to study the association of those underlying diseases that are treated mostly in 1 specific unit (such as chronic pulmonary disease or malignancy) with the acquisition of S. maltophilia, as we used the unit of admission for frequency matching. Thus, we will comment only on the descriptive data obtained from our cases.TABLE 8: Chronic underlying diseases of patients colonized or infected with S. maltophilia, previous and present reportsThe most frequent underlying disease was chronic pulmonary disease (25%), most often chronic obstructive pulmonary disease. There are many other studies in which pulmonary disease is describe as the most frequent comorbidity in patients infected or colonized with S. maltophilia (15,24,31,40,64). It is not unusual for cystic fibrosis patients to be affected by this organism (12,13,56). However, only 1 case in our study suffered from cystic fibrosis, probably reflecting the fact that we only included hospitalized patients. Solid and hematologic neoplastic diseases also have been described frequently in patients with S. maltophilia (15,24,31,32,40), mainly in series studying bacteremia (6,14,27,36,43,45,47,59). In our study, 20% of patients had an underlying malignancy. Chronic renal insufficiency seems to be another frequent underlying disease in patients with S. maltophilia: 11% of our patients required chronic hemodialysis or peritoneal dialysis. This underlying disease was rather less frequent in previous studies of S. maltophilia: 5% of bacteremic patients in a multicenter study by Muder et al (47) were on hemodialysis, and 6% of colonized or infected patients had renal failure in a study by Laing et al (40). Peritoneal dialysis-associated infection (2,3,9,50,55,58) and catheter-related infection in patients on hemodialysis due to S. maltophilia (5,16,19,35,65) have been described. The acquisition of S. maltophilia in patients with chronic renal failure may be related to other predisposing factors: contamination of hemodialysis systems (5,16), other comorbidities (malnutrition, immunodepression), central venous catheterization and vascular accesses, and use of broad-spectrum antimicrobials. Diabetes mellitus has been considered a potential predisposing disease in some studies (15,24,31,36,40,59); 19% of our patients had diabetes. However, the frequency of diabetes was not significantly different among cases and controls. S. maltophilia was most frequently isolated from respiratory samples in our study, followed by wounds, urine, and blood cultures. The respiratory samples were also the most frequent source for S. maltophilia in many other studies, representing 40%-89% of samples (10,24,31,32,40,46,64). The distribution of samples in our study and others differs depending on the units where patients are treated and probably in relation to the underlying diseases. Thus, respiratory samples are more frequent among medical patients or mechanically ventilated individuals (10,24), blood cultures among cancer or severely immunosuppressed patients (15,31,32), and wound exudates in surgical patients. As happens with other low-virulence opportunis-tic microorganisms, differentiating colonization from infection is rather difficult. This is specially true for respiratory tract and wound exudate samples, or when mixed cultures are obtained. Holmes et al (28), in a retrospective study performed between 1966 and 1976, considered that only 6 of 128 (5%) S. maltophilia isolates were the cause of infection. More recent series found higher percentages of infection, ranging from 13% to 60% (24,30,31,32,40,52). Most of these series used CDC criteria for the diagnosis of infection. In our study, about half of the patients were considered to be infected. Villarino et al (71) considered 71% of S. maltophilia isolates to represent an infection in ICU patients. Laing et al (40) found that ICU patients were more frequently infected than patients in non-ICU settings. We found no difference in the rate of infection between ICU and non-ICU patients, probably due to the use of different criteria. Although it is difficult to compare the results from all these studies, it seems clear that S. maltophilia is able to cause nosocomial infections in a substantial proportion of colonized patients. However, clinicians must be aware of the need to consider strict clinical and microbiologic criteria for interpreting the isolation of S. maltophilia in clinical samples. A wide spectrum of clinical infectious syndromes has been attributed to S. maltophilia (11). Most reported series include a low number of patients (Table 9). Respiratory tract infections are the most commonly described (22%–88%). Infection and colonization are particularly difficult to differentiate in the case of respiratory samples. Only 33 of 67 (49%) patients with a positive respiratory sample were considered to have a respiratory tract infection in our study. Nosocomial pneumonia due to S. maltophilia has been associated frequently with mechanical ventilation (two-thirds of patients with pneumonia in our series), use of respiratory tract equipment, previous broad-spectrum antimicrobial use (100% in our series), and chronic respiratory disease (30% in our series) (15,32,40,46,71). Increased mortality has been found in patients with pneumonia due to this organism (46).TABLE 9: Type of infections caused by S. maltophilia, previous and present reportsBacteremia is particularly frequent in cancer patients (6,14,27,36,39,43,45,47,59). Most of the episodes are primary bacteremias; probably many of these bloodstream infections originate in vascular catheters (14,47). Thus, catheter-related infections should always be considered in bacteremic patients if no other source of infection is evident. In our study, 12 patients (17% of infected patients) were bacteremic, and 8 of them had primary bacteremia. It is not unusual for S. maltophilia to be isolated from wounds and ulcers, sometimes in mixed cultures, and on many occasions the organism seems to be only a colonizer (11). The way in which the sample was obtained as well as the clinical data should be considered carefully before attributing a wound infection to S. maltophilia. However, we feel it is worth emphasizing that, although this bacillus is not usually considered an important cause of surgicalrelated infections, we found 10 patients (14%) with a surgical site infection. Other authors have found similar percentages (see Table 9). Consequently, this organism should be considered a potential cause of surgical site infection in patients who had previously received several courses of broad-spectrum antimicrobial therapy. Antimicrobial susceptibility of S. maltophilia isolates in our study was similar to that previously reported (reviewed in reference 11). All isolates were resistant to many antimicrobial agents. As expected, TMP-SMX was the most active agent in vitro. Isolates from 24 patients (17%) were resistant to TMP-SMX in our study. This agent, although bacteriostatic against most isolates, is usually considered the drug of choice for the treatment of S. maltophilia infections (4,11,18,34,47,53). Gales et al (18) found that resistance to TMP-SMX was more frequent in Europe, Asia, and the United States (10%, 8%, and 5% of S. maltophilia isolates, respectively) than in Canada or Latin America (2%). The resistance to TMP-SMX decreased in the M. D. Anderson Cancer Center, Houston, Texas, over 12 years (66). The authors attributed this to the fact that TMP-SMX was no longer being used as a prophylactic agent in neutropenic patients. In Spain, Betriu et al (4) also found a decrease in the incidence of TMP-SMX resistance in 5 years. Among the beta-lactams tested, ceftazidime and ticarcillin were the most active in our study. Different reports have described a range of ceftazidime susceptibility from 15% to 75% (4,14,18,27,32,40,41,43,45,47,52,53,60,66,69). A trend toward an association between previous ceftazidime use and ceftazidime resistance was found in our study. Possible explanations are induction of beta-lactamase production in previously colonized patients or selection of previously resistant strains. However, these data are to be considered cautiously, as the number of patients previously treated with this antimicrobial was low. Piperacillin, cefotaxime, and cefepime have also shown some activity (11). Ticarcillin/ clavulanate have shown good activity in vitro against S. maltophilia in some studies (4,18,34,40,45,53,59). The use of a beta-lactam alone in the treatment of severe infections is not recommended as L1 and L2 (the main beta-lactamases produced by S. maltophilia, which confer resistance to most beta-lactam agents) are inducible. Results from an observational study (47) suggest that combination therapy with TMP-SMX and ticarcillin-clavulanate or ceftazidime might be superior to TMP-SMX alone in patients with bacteremia. Other antimicrobial agents that have shown variable activity in vitro against S. maltophilia in different studies are quinolones, tetracyclines, and aminoglycosides, although wide variation in susceptibility rates to these antimicrobials have been found (4,18,40,45,53,66,69,72,73), possibly due to the different methodology and criteria used to evaluate susceptibility and to the low number of strains included in some of them. Newer quinolones seem to be more active than ciprofloxacin (4,18,34,49,53,60,66,69,72,73), although reported clinical experience with these agents is lacking. Many risk factors for the acquisition of S. maltophilia have been suggested by descriptive series, such as previous antimicrobial therapy, central venous catheter, neutropenia, chemotherapy, corticosteroid therapy, prolonged hospitalization, admission to an ICU or neonatology unit, mechanical ventilation, tracheotomy, malignancy, and respiratory diseases (13–15,17,24,26,27,30–32,35–39,43,45–47,56,59,64,71). Among them, previous antibiotic use, and specifically those antibiotics that might select for this multiresistant organism, such as imipenem (7,30,40), is probably the most frequently observed. However, only 5 case-control or cohort studies specifically performed to investigate risk factors for S. maltophilia acquisition have been reported (Table 10). Four of those studies included only specific patient populations: cystic fibrosis patients (13,56), ICU patients (71), and cancer patients (15). Thus, to our knowledge, there is only 1 other hospital-based case-control study published to date (64).TABLE 10: Case-control and cohort studies on risk factors associated with S. maltophilia colonization and/or infection, previous and present reports*In cystic fibrosis patients, Denton et al (13) found that inpatient days, days of oral ciprofloxacin, days of intravenous antipseudomonal antibiotics, nebulized aminoglycosides, and chronic infection with other pathogens were associated with increased risk of S. maltophilia colonization or infection. Multivariate analysis was not performed in that study. Talmaciu et al (56) found that several factors related to antimicrobial therapy were the most predictive variables for S. maltophilia colonization/infection in a similar population using multivariate analysis: number of days on intravenous antibiotic therapy and chronic use of antibiotics. Elting et al (15) performed a case-control study in cancer patients with infection to investigate the factors associated with S. maltophilia etiology. Variables that independently increased the risk of S. maltophilia were previous therapy with imipenem or other antibiotics, and central venous catheter, while previous therapy with TMP-SMX was a protective factor. In a historical cohort study, Carmeli and Samore (7) concluded that patients treated with imipenem were not at higher risk for nosocomial acquisition of S. maltophilia than those treated with ceftazidime. However, multivariate analysis was not performed, and the study did not control for several variables, such as invasive procedures. In a respiratory ICU, Villarino et al (71) performed a historical cohort study during an outbreak. Mechanical ventilation, tracheostomy, transportation to the hospital by airplane, and receipt of a higher number of antimicrobials were significant independent predictors for S. maltophilia infection or colonization. No individual antimicrobial agent was identified as a risk factor. VanCouwenberghe et al (64) performed a case-control study to investigate factors associated with the isolation of S. maltophilia. Controls were patients whose cultures grew other Gram-negative bacilli, so that risk factors refer to the isolation of S. maltophilia instead of other Gram-negative bacilli. They performed 2 multivariate models. Variables found to be significantly associated with increased risk of S. maltophilia isolation in both models were previous therapy with ampicillin, gentamycin, metronidazole, and erythromycin (protective). Penicillin, cefotaxime, piperacillin, tobramycin, chronic respiratory disease, and female gender were significant in only 1 of the models. Imipenem was not a risk factor in that study, but the number of patients who had received this antimicrobial was very low. We were specifically interested in investigating the role of antimicrobial agents as risk factors for the acquisition of S. maltophilia. Different epidemiologic situations in participating hospitals and units were controlled in the design of the study by frequency matching. As a consequence, the implication of some underlying diseases (those usually treated in a particular unit) as risk factors was also controlled and could not be investigated. Confounding and interaction were evaluated by multivariate analysis. Our controls were patients whose culture did not grow S. maltophilia. Thus, the risk factors encountered refer to the risk of S. maltophilia isolation per se. The variables associated with increased risk in the 2 models we performed were previous use of carbapenems, ceftazidime, or quinolones; and mechanical ventilation, both as categorical and continuous variables. The implication of carbapenem, ceftazidime, and quinolones as risk factors may be explained by their broad-spectrum activity. It can be hypothesized that the patients might have acquired the organism before being admitted to the hospital, or more probably, during their hospital stay, mainly from environmental reservoirs. Treatment with those antimicrobials would select for S. maltophilia because of its intrinsic resistance to most antibiotics, thus making colonization easier to detect with clinical cultures and favoring the possibility of infection in debilitated patients in relation to invasive procedures. Our results might have several practical practical implications. First, S. maltophilia should be considered a potential cause of nosocomial infections in debilitated patients who previously received a prolonged course of a carbapenem, ceftazidime, or a quinolone. And second, prudent use of these antimicrobials might help to prevent and control the emergence of S. maltophilia in hospitals. Our study has some drawbacks. The first is that we did not use active surveillance to detect colonization. Patients detected as colonized by means of clinical samples probably represent only a proportion of the colonized population. However, the information provided by our data may be useful for practical purposes. A second limitation is that the study is a multicenter study. The identification of the organism and the study of antimicrobial susceptibility were performed in the laboratories in each of the participating centers, but in all of them standard methodology recommended by the NCCLS was used. Finally, we could not perform molecular typing of the isolates. Hence, although clusters of cases were not apparent, transmission of some common strains might have occurred. However, several studies have shown that, in the endemic setting, acquired strains of S. maltophilia are usually unrelated (12,40,57,62,63). Summary To study the incidence and risk factors for colonization and infection by Stenotrophomonas maltophilia, we performed a case-control study in 6 tertiary hospitals during a 17-month period. All hospitalized patients who had S. maltophilia isolated from clinical samples were included (cases). Controls were chosen among patients from whom a similar sample was negative for this organism. During the study period, 129 cases were included (121 adults, 7 neonates, and 1 child). The pooled incidence of S. maltophilia colonization or infection was 5.7 cases per 10,000 admissions. One-third of the patients were in the intensive care unit. In 91% of cases, the organism was considered nosocomially acquired. S. maltophilia was isolated more frequently from respiratory samples (52%). As expected, trimethoprim-sulfamethoxazole was the most active antimicrobial agent in vitro, followed by ciprofloxacin, ceftazidime, and ticarcillin, while 98% of isolates were resistant to imipenem. About half the patients were considered to be infected. Pneumonia was the most frequent type of infection (32%, two-thirds of them were ventilator-associated), followed by other respiratory tract infections (14%), surgical site infections (14%) and primary bacteremia (11%). Using multivariate analysis, the following risk factors for colonization or infection with S. maltophilia were found in the 2 models performed: previous use of carbapenems, ceftazidime, or quinolones; and mechanical ventilation. Acknowledgments We thank the microbiologists from our hospitals for their contribution in locating cases and controls and for providing the susceptibility data.
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