Abstract

TEXT

Stenotrophomonas maltophilia is an emerging nosocomial pathogen, mainly in immunocompromised patients, and is associated with high mortality (1,–4). Trimethoprim-sulfamethoxazole (TMP-SMX) is recommended as the treatment of choice for S. maltophilia infections (5,–7). However, because of concern regarding adverse events related to TMP-SMX, levofloxacin has also been used for treating these infections. The purpose of this study was to compare clinical outcomes between TMP-SMX and levofloxacin for the treatment of S. maltophilia bacteremia.

A retrospective cohort study that involved adult patients with S. maltophilia bacteremia at Samsung Medical Center, a 1,945-bed tertiary care facility in Seoul, South Korea, was undertaken from 2000 to 2012. Antimicrobial susceptibility testing was performed using a Vitek 2 system (bioMérieux, Inc., Hazelwood, MO, USA), and breakpoints were those defined by the Clinical and Laboratory Standards Institute (8). Patients were included in the study if they received either intravenous TMP-SMX or levofloxacin for more than 48 h and if the causative isolate was found to be susceptible to the prescribed drug. TMP-SMX was administered in a dose of 15 to 20 mg/kg of body weight/day (based on the trimethoprim component), and levofloxacin was administered in a dose of 750 mg once daily in patients with normal renal function. Dosage adjustments were made according to creatinine clearance in patients with renal impairment. Demographic characteristics, underlying diseases or conditions, severity of the underlying disease, severity of bacteremia, site of infection, and antibiogram results were recorded. Definite catheter-related infection (CRI) was defined according to the Infectious Diseases Society of America guidelines (9). Possible CRI was indicated by the finding of a positive blood culture with no apparent source of bacteremia other than the catheter. Recurrent bacteremia was defined as the reappearance of S. maltophilia bacteremia within the first 3 months. The main outcome measure used was the overall 30-day mortality. We also assessed length of hospital stay, adverse events, and recurrent bacteremia. Continuous variables were compared using Student's t test, and categorical variables were compared using χ² or Fisher's exact test. Multivariate logistic regression analysis was used to evaluate the effects of levofloxacin treatment. A P value of less than 0.05 was considered statistically significant. SPSS statistical software for Windows, PASW version 18.0, was used for the statistical analyses.

During the study period, we identified 203 adult patients with S. maltophilia bacteremia. Among all S. maltophilia isolates, the rates of susceptibility to TMP-SMX and levofloxacin were 96.1% and 87.1%, respectively. After the exclusion of patients according to our study criteria, 53 patients received TMP-SMX and 35 patients received levofloxacin. Of the 53 patients who received TMP-SMX, the causative isolates from 2 patients were resistant in vitro to TMP-SMX, and these patients were excluded from the study. However, in the levofloxacin treatment group, there were no patients excluded because of resistance to levofloxacin (Fig. 1).

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FIG 1

Study inclusion and exclusion criteria applied for patient identification.

The baseline characteristics between the groups were similar (Table 1). However, compared to patients in the TMP-SMX treatment group, patients in the levofloxacin group were predominantly male. In the levofloxacin treatment group, no resistance to TMP-SMX was detected, whereas 7 patients were nonsusceptible to levofloxacin in the TMP-SMX treatment group. Outcomes are presented in Table 2. The overall 30-day mortality rates did not show statistically significant differences between the TMP-SMX treatment group and the levofloxacin treatment group (14 of 51 patients [27.5%] versus 7 of 35 patients [20.0%], P = 0.429). After exclusion of patients who had combination therapy or polymicrobial bacteremia from the analysis, there was no difference in the 30-day mortality rates between the groups (9 of 31 patients [29.0%] versus 5 of 27 patients [18.5%], P = 0.351). In a univariate analysis, old age, septic shock, and pneumonia were significantly associated with increased mortality of S. maltophilia bacteremia, while definite CRI was found to be a protective factor for 30-day mortality (Table 3). In multivariate analyses, pneumonia and septic shock were significantly associated with 30-day mortality. However, levofloxacin treatment was not associated with 30-day mortality. In 10 patients treated with TMP-SMX, TMP-SMX was withdrawn due to adverse events. The most common adverse events related to TMP-SMX were cytopenia and hepatotoxicity. Treatment with levofloxacin was switched to TMP-SMX in eight patients. However, among these patients, treatment failure related to levofloxacin was not observed. Of these eight patients, three developed rash or cytopenia after changing to TMP-SMX. Additionally, in two patients, levofloxacin was changed to ceftazidime or tigecycline for broader coverage. Among eight patients with recurrent bacteremia, levofloxacin-resistant S. maltophilia was isolated from four patients (two patients from the levofloxacin group and two patients in whom TMP-SMX was switched to levofloxacin).

TABLE 1

Demographic and clinical characteristics of patients in the TMP-SMX and levofloxacin groups

Characteristica	No. of patients (%) with characteristicb			P value
	Total (n = 86)	TMP-SMX group (n = 51)	Levofloxacin group (n = 35)
Age, median (IQR)	58 (45–67)	56 (40–67)	61 (49–68)	0.153
Older age (≥65 yr)	30 (34.9)	16 (31.4)	14 (40.0)	0.410
Gender, male	56 (65.1)	28 (54.9)	28 (80.0)	0.016
Hospital-acquired infection	79 (91.9)	45 (88.2)	34 (97.1)	0.233
ICU-acquired infection	22 (25.6)	13 (25.5)	10 (28.6)	0.751
Underlying disease
Hematologic malignancy	44 (51.8)	29 (56.9)	15 (44.1)	0.249
Solid tumor	32 (37.2)	16 (31.4)	16 (45.7)	0.176
Liver cirrhosis	14 (16.3)	9 (17.6)	5 (14.3)	0.678
Diabetes mellitus	13 (15.1)	8 (15.7)	5 (14.3)	0.859
Cardiovascular disease	16 (18.6)	8 (15.7)	8 (22.9)	0.401
Comorbid conditions
Chemotherapy	47 (54.7)	30 (58.8)	17 (48.6)	0.348
Neutropenia	38 (44.2)	25 (49)	13 (37.1)	0.276
Major surgery	10 (11.6)	5 (9.8)	5 (14.3)	0.734
Invasive procedure	18 (20.9)	10 (9.6)	8 (22.9)	0.716
Immunosuppression	16 (18.6)	8 (15.7)	8 (22.9)	0.401
CRRT/HD	11 (12.8)	9 (17.6)	2 (5.7)	0.187
Mechanical ventilation	14 (16.3)	7 (13.7)	7 (20.0)	0.439
Tracheostomy	9 (10.5)	4 (7.8)	5 (14.3)	0.476
HSCT	8 (9.3)	5 (9.8)	3 (8.6)	1.000
SOT	7 (8.1)	3 (5.9)	4 (11.4)	0.435
Central venous catheter	61 (70.9)	39 (76.5)	22 (62.9)	0.172
Catheter removal	32 (52.5)	21 (53.8)	11 (50.0)	0.773
Time to removal, daysc	3 (1–5)	3 (0–4.75)	3 (1–6.25)	0.431
CCIc	2 (2–3)	2 (2–3)	2 (2–3)	0.539
CCI of ≥3	26 (30.2)	16 (31.4)	10 (28.6)	0.781
Pitt bacteremia scorec	1 (0–3)	1 (0–3)	2 (0–3)	0.678
Pitt bacteremia score of ≥4	16 (18.6)	10 (19.6)	6 (17.1)	0.773
Septic shock	20 (23.3)	13 (25.5)	7 (20.0)	0.554
Source of bacteremia
Definite CRI	17 (19.8)	12 (23.5)	5 (14.3)	0.290
Possible CRI	22 (25.6)	11 (21.6)	11 (31.4)	0.303
IAI	25 (29.1)	14 (27.5)	11 (31.4)	0.690
Pneumonia	14 (16.3)	9 (17.6)	5 (14.3)	0.678
Polymicrobial bacteremia	17 (19.8)	12 (23.5)	5 (14.3)	0.290
Combination therapy	12 (14.0)	9 (17.6)	3 (8.6)	0.345

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^aAbbreviations: IQR, interquartile range; ICU, intensive care unit; CRRT, continuous renal replacement therapy; HD, hemodialysis; HSCT, hematopoietic stem cell transplantation; SOT, solid organ transplantation; CCI, Charlson comorbidity index; CRI, catheter-related infection; IAI, intraabdominal infection.

^bData are presented as the number (%) of patients unless indicated otherwise.

^cData are presented as the median (interquartile range).

The findings of this study suggest that the severity of bacteremia and the site of infection may be more important for the prognosis of S. maltophilia bacteremia than the choice of either levofloxacin or TMP-SMX for treatment, as long as the causative isolates are susceptible to these antibiotics. In our study, adverse events occurred more frequently in patients receiving TMP-SMX than in those receiving levofloxacin. The new fluoroquinolones, such as moxifloxacin and levofloxacin, show superior in vitro activity against S. maltophilia than earlier quinolones, either alone or in combination (10,–12). However, in the use of levofloxacin for treating S. maltophilia infection, induction of resistance is a matter of concern. Rapid emergence of resistance against quinolones has been observed in vitro and in vivo (13, 14). This finding was observed in our study.

The present study has several limitations. First, treatment groups were assigned retrospectively and were not randomized. Second, our study showed good susceptibility of S. maltophilia to TMP-SMX and levofloxacin. Therefore, our results cannot be generalized in areas with a high prevalence of multidrug-resistant S. maltophilia.

In conclusion, patients receiving levofloxacin showed clinical outcomes similar to those receiving TMP-SMX for the treatment of S. maltophilia bacteremia. The patients receiving TMP-SMX experienced a higher rate of adverse events, while induction of resistance was observed in the levofloxacin group. Our data suggest that levofloxacin can be a useful option for treating S. maltophilia infections, although a clinical trial comparing the two treatment regimens is warranted.

ACKNOWLEDGMENTS

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