Case-Control Study of the Risk Factors for Acquisition of Pseudomonas and Proteus Species during Tigecycline Therapy

Abstract

Tigecycline is an important agent in clinical practice because of its broad-spectrum activity. However, it has no activity against Pseudomonas or Proteus species. We conducted a case-control study to analyze risk factors for the acquisition of Pseudomonas or Proteus spp. during tigecycline therapy. Placement of suction drainage at infected wound sites, ICU stay, and neurologic disease were identified as independent risk factors for the acquisition of Pseudomonas and Proteus spp.

TEXT

Over the past 2 decades, there has been a rapid emergence of multidrug-resistant organisms, which is a major problem in terms of infection control. There is a crucial need for new antibiotics because of the limited treatment options for infections caused by these organisms (1–3). Tigecycline, one of the glycylcycline antibiotics, was designed to overcome resistance mechanisms mediated by efflux pump and ribosomal protection. It has broad-spectrum activity that includes activity against antibiotic-resistant bacteria (4–6). However, the U.S. Food and Drug Administration noted that, in a pooled analysis of 13 clinical trials, tigecycline was significantly associated with an increased risk for all-cause mortality compared to that of other antibiotics used to treat serious infections and announced that it has added a boxed warning about the increased risk for death to the label of tigecycline (7). Nevertheless, the unique spectrum of activity and favorable postantibiotic effect make tigecycline an important antibiotic in clinical practice (1–3, 8–10), particularly for complicated skin and soft tissue infections and the complicated intra-abdominal infections for which it is indicated (1, 3, 8, 10). However, as tigecycline has no activity against Pseudomonas and Proteus species, there are concerns about the possibility of superinfection caused by these organisms (11, 12). We aimed to analyze risk factors for acquisition of Pseudomonas and Proteus spp., organisms intrinsically resistant to tigecycline.

A retrospective case-control study was performed to identify risk factors for acquisition of Pseudomonas and Proteus spp. during tigecycline therapy. Clinical and microbiological data were collected from administrative, pharmacy, and laboratory computerized databases in our hospitals (Samsung Medical Information Systems). Case and control patients were selected from adult patients who received tigecycline for more than 3 days between January 2008 and April 2014 at Samsung Changwon Hospital and Samsung Medical Center (Sungkyunkwan University-affiliated hospitals). Forty-one patients whose microbiological cultures grew Pseudomonas or Proteus spp. during tigecycline therapy were designated cases. For every case, two matched controls were randomly selected from the 628 patients who received tigecycline for more than 3 days during the study period and did not have Pseudomonas or Proteus spp. isolations. Bacterial acquisition was defined as isolation of Pseudomonas or Proteus spp. from clinical specimens and classification as true infection or colonization. When attending physicians switched tigecycline to other antimicrobial agents with better activity against Pseudomonas or Proteus after identifying these isolates, the cases were considered true infections. Other cases, which did not obviously indicate true infections, were regarded as colonization. Data on 41 cases were compared with those on 82 controls. Of the 41 case patients, 26 had Pseudomonas, 13 had Proteus, and 2 had Pseudomonas and Proteus. Baseline characteristics, including age, sex, underlying disease, and type of infection, were recorded. The presence of comorbid conditions, including diabetes, malignancy, and cardiovascular, hepatic, renal, pulmonary, and neurologic diseases, was documented. We used the Charlson weighted comorbidity index to adjust for the severity of illness. Data on medical conditions included duration of hospitalization, duration of hospitalization before tigecycline use, duration of tigecycline usage, intensive care unit (ICU) stay at the start of tigecycline therapy, surgical procedures or intervention procedures within 30 days, indwelling urinary catheter use, Levin tube use, and placement of percutaneous drainage and suction drainage at infected sites. Preceding antimicrobial exposure was defined as at least 1 day of therapy administered during the 30 days prior to tigecycline usage. Bacterial cultures from all possible sources of infection were performed by attending physicians, and controls were selected from patients whose adequate specimens were cultured before and during tigecycline therapy. Student's t test and Mann-Whitney test were used for continuous variables, and chi-square test and Fisher's exact test were used for categorical variables. Variables with P values of <0.05 in univariate analysis were included in the multivariate analysis. Multivariate analysis was performed by using a logistic regression model.

Anatomic sites for cultures that grew Pseudomonas or Proteus isolates in the case group included 15 skin (36.58%), 11 abdomen (26.82%), 7 lung (17.07%), 3 blood (7.31%), and 5 other sites (12.19%). Twenty-six cases (63.41%) were found to be compatible with true infection. For three cases (7.31%), it was not obvious whether they should be classified as true infection or colonization. Twelve cases (29.21%) were suspected of colonization. There were no significant differences in the median age, sex, underlying disease, Charlson weighted comorbidity index, or type of infection between the case and control groups (Table 1). However, 11 patients (26.8%) in the case group had neurologic disease, whereas 5 patients (6%) in the control group had neurologic disease. Table 2 shows the medical conditions of the case and control groups. The average length of hospital stays in the case group was 100.2 days, twice that of the control group. The average durations of hospitalization before tigecycline usage were 33.7 and 21.7 days in cases and controls, respectively. Statistically significant differences in ICU stay, indwelling urinary catheter, and placement of suction drainage at infected sites were also observed between the two groups. Of the 12 patients who had suction drainage systems in the case group, 8 patients had sump, 2 had vacuum, and 2 had suction wound bag systems. We categorized the prior use of antimicrobial agents into 5 groups (Table 2), and there were no statistical differences between cases and controls except for the result that narrow-spectrum, expanded-spectrum, and broad-spectrum cephalosporin administration was higher in controls. The presence of neurologic disease and of indwelling urinary catheter, placement of suction drainage, duration of hospitalization before tigecycline use, and ICU stay were included for multivariate analysis. The independent risk factors found included underlying neurologic disease (odds ratio, 4.30; P = 0.030), ICU stay at the start of therapy (odds ratio, 3.6; P = 0.045), and placement of suction drainage at infected sites (odds ratio, 8.65; P = 0.003) (Table 3). The duration of hospitalization was longer (100.2 days versus 53.8 days, P = 0.001) and the overall mortality during hospitalization was higher in the case group than in the control group (36.6% versus 14.6%, P = 0.020).

TABLE 1.

Demographic and clinical characteristics of patients in the case and control groups

Characteristic	No. of patients (%)a		P value
	Case group (n = 41)	Control group (n = 82)
Demographic
Age, yr (mean ± SD)	59.78 ± 14.88	59.83 ± 13.72	0.99
Male	26 (63.4)	50 (60)	0.85
Underlying disease
Diabetes mellitus	7 (17.1)	25 (30.5)	0.110
Malignancy	23 (56.1)	38 (46.3)	0.308
Cardiovascular disease	7 (17.1)	14 (17.1)	1.000
Liver disease	4 (9.9)	17 (20.7)	0.127
Renal disease	8 (19.5)	18 (22.0)	0.755
Pulmonary disease	1 (2.4)	7 (8.5)	0.196
Neurologic disease	11 (26.8)	5 (6.1)	0.001
CCIb (mean ± SD)	2.80 ± 2.10	2.80 ± 2.47	1.000
Source of acquisition			0.33
Skin and soft tissue infection	19 (46.3)	33 (40.2)
Intra-abdominal infection	21 (51.2)	47 (57.3)
Pneumonia	1 (2.4)	0 (0.0)
Other infections	0 (0.0)	2 (2.4)

^aData are presented as the no. (%) of patients unless indicated otherwise.

^bCCI, Charlson comorbidity index.

TABLE 2.

Medical conditions of the case and control groups

Variable	Case group (n = 41)a	Control group (n = 82)a	P value
Duration of
Hospitalization	100.2 ± 80.01	53.82 ± 33.70	0.001
Hospitalization before the tigecycline use	33.66 ± 34.27	21.71 ± 18.56	0.042
Tigecycline usage	20.80 ± 16.11	17.11 ± 11.59	0.195
Hospital exposure
ICU stayb	18 (43.9)	21 (25.6)	0.040
Surgical proceduresc	25 (61.0)	50 (61.0)	1.000
Intervention proceduresd	17 (41.5)	41 (51.2)	0.307
Indwelling catheter or drainage
Foley catheter	24 (58.5)	31 (39.0)	0.041
Percutaneous drainage	22 (53.7)	50 (61.0)	0.437
Suction drainage systeme	12 (29.3)	4 (4.9)	0.001
Levin tube	18 (43.9)	25 (30.5)	0.141
Combined antibiotic therapy	7 (17.1)	17 (20.7)	0.629
Exposures to antimicrobial agents
Narrow-, expanded-, and broad-spectrum cephalosporins	7 (17.1)	34 (41.5)	0.007
Ampicillin-sulbactam and penicillin	2 (4.9)	11 (13.4)	0.147
Glycopeptides and linezolid	19 (46.3)	40 (48.9)	0.799
Metronidazole	11 (26.9)	15 (18.3)	0.274
Antipseudomonal antibioticsf	33 (80.5)	58 (70.7)	0.245

^aData are presented as means ± SD or number (%) of patients.

^bICU stay at the start of tigecycline therapy.

^cAny surgical procedure under general anesthesia within 30 days prior to the administration of tigecycline.

^dAny intervention procedure except upper or lower GI endoscopy within 30 days prior to the administration of tigecycline.

^eHemovac, sump, or vacuum dressing at infected site.

^fThese include cefepime, piperacillin-tazobactam, carbapenems except ertapenem, colistin, quinolone, and aminoglycoside.

TABLE 3.

Multivariate analysis of risk factors for Pseudomonas or Proteus spp. acquisition

Variable	Adjusted analysis
	OR (95% CI)a	P value
Neurologic disease	4.301 (1.151–16.073)	0.030
Foley insertion	0.862 (0.260–2.860)	0.808
Suction drainage system	8.648 (2.217–33.741)	0.003
Duration of HD before tigecycline use	0.983 (0.954–1.012)	0.240
Duration of hospital stay (days)	1.022 (1.008–1.037)	0.002
ICU stay	3.642 (1.028–12.101)	0.045

^aOR, odds ratio; CI, confidence interval; HD, hospital day.

Prior studies have reported only superinfection rates and etiologies during tigecycline therapy. One study showed a superinfection rate of 23.5% during tigecycline treatment and that Pseudomonas aeruginosa was the most frequently found organism, responsible for 58.3% of superinfections. Other studies found that Acinetobacter baumannii and P. aeruginosa were the two most common superinfection organisms during tigecycline treatment (9, 13, 14). To our knowledge, this is the first study to identify risk factors for acquisition of Pseudomonas or Proteus spp. during tigecycline treatment. Placement of suction drainage at infected wound sites, ICU stay, and underlying neurologic disease were identified as independent risk factors in this study. It is plausible that ICU stay and underlying neurologic disease may be risk factors for acquisition of antimicrobial-resistant pathogens based on previous studies regarding risk factors for antimicrobial resistance. Similarly, our study demonstrated that ICU stay and underlying neurologic disease may be risk factors for acquisition of Pseudomonas and Proteus during tigecycline therapy. However, the finding that the placement of suction drainage increases the possibility of acquisition of resistant organisms was unexpected. Several studies showed negative pressure wound therapy (NPWT) to be helpful for successful wound healing, consequently leading to its widespread use (15–17). Sump drains, which are based upon the same principles as NPWT, can draw fluids from the intra-abdominal cavity through suction and have been proven to be a safe and effective way to drain complicated intra-abdominal fluid or abscess (18, 19). Although previous data have indicated that the placement of suction drainage is positively influential for wound healing, suction drainage in the infected wound may not be sufficiently managed or may even be harmful in terms of the development of resistant pathogens.

Our study has several limitations. First, even though there is the possibility that the risk factors for Pseudomonas superinfection differ from those for Proteus, we did not evaluate risk factors for each pathogen separately due to the limited number of cases. Further studies regarding risk factors for each pathogen and including more patients are warranted. Second, we did not precisely distinguish the patients into true infection (n = 26, 63.4%), undetermined (n = 3, 7.3%), and colonization (n = 12, 29.3%). More data should be collected to achieve higher validity in future studies. Finally, although our findings of higher mortality and longer hospitalization in the case group are interesting, they may simply reflect the severity of illness rather than the consequences of bacterial acquisition. These limitations require further studies to characterize risk factors associated with mortality and duration of hospitalization during tigecycline therapy.

In conclusion, our study suggests that Pseudomonas or Proteus spp. can be acquired during tigecycline therapy, especially in patients with placement of suction drainage at infected wound sites, ICU stay, and neurologic disease.