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NDT Advance Access originally published online on January 18, 2006
Nephrology Dialysis Transplantation 2006 21(5):1328-1333; doi:10.1093/ndt/gfk078
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Dialysis and Transplantation

Favourable outcomes in episodes of Pseudomonas bacteraemia when associated with tunnelled cuffed catheters (TCCs) in chronic haemodialysis patients

Ladan Golestaneh, Jeffrey Laut, Stuart Rosenberg, Meilin Zhang and Michele H. Mokrzycki

Montefiore Medical Center, Department of Medicine, Division of Nephrology, Albert Einstein College of Medicine, Bronx, NY, USA

Correspondence and offprint requests to: Ladan Golestaneh, Montefiore Medical Center, Department of Medicine, Division of Nephrology, Albert Einstein College of Medicine, Bronx, NY, USA. Email: lgolesta{at}montefiore.org



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Pseudomonas is regarded as a particularly lethal bacterial isolate. High mortality rates have been reported in episodes of Pseudomonas sepsis when associated with visceral infections as seen in immunosuppressed, hospitalized patients. In comparison, lower mortality rates have been reported with catheter-associated Pseudomonas bacteraemia in non-dialysis patients. The purpose of this study was to determine the risk factors and the outcomes for episodes of Pseudomonas bacteraemia associated with the use of tunnelled cuffed haemodialysis catheters (TCCs) in a chronic out-patient population.

Methods. We performed a prospective observational study in seven chronic haemodialysis units over a 2.5 year period. Patients who were diagnosed as having their initial TCC-associated bacteraemia within the study period were followed for 3 months. All episodes of Pseudomonas TCC bacteraemia were identified, and univariate analyses were performed to compare Pseudomonas bacteraemia with non-Pseudomonas bacteraemia.

Results. During the study period, 219 episodes of TCC bacteraemia were identified; 18 had a Pseudomonas isolate (8%). Pseudomonas bacteraemia episodes were associated with a significantly higher risk of not receiving appropriate initial antibiotics (odds ratio = 3.6, P = 0.02). There were no deaths in the Pseudomonas bacteraemia group, whereas 19% died in the non-Pseudomonas group. The TCC was removed in 89% of Pseudomonas bacteraemias. There were no significant risk factors for acquiring a Pseudomonas isolate, and no difference in recurrent bacteraemia or infectious complication rates between the groups.

Conclusions. In haemodialysis patients with a TCC-associated Pseudomonas bacteraemia, outcomes are remarkably good. This may be because the source of Pseudomonas infection was removed in most cases. Initial antibiotic coverage lacking anti-Pseudomonas activity was not associated with increased mortality.

Keywords: bacteraemia; catheter; Gram negative bacilli; haemodialysis; Pseudomonas



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Infection is a major complication of TCC (tunnelled cuffed catheter) use, and the mean incidence of TCC-associated bacteraemia is three episodes per 1000 TCC days [1–5]. Physicians regard Pseudomonas isolates as particularly lethal. In the existing literature, Pseudomonas bacteraemia has been associated with a mortality rate as high as 60% [6–10]; however, these studies included non-catheter primary sources of infection, such as pneumonia and urosepsis. Furthermore, most studies were performed in hospitalized populations with a high percentage of immunocompromised patients. We recently reported that Staphylococcus aureus and TCC salvage were important risk factors for adverse outcomes after an initial episode of TCC bacteraemia [11,12]. There is a paucity of data regarding the risk factors, mortality and complication rates for episodes of TCC-associated Pseudomonas bacteraemia in chronic haemodialysis (HD) patients. To identify the risk factors and determine the outcomes associated with Pseudomonas TCC bacteraemia in the chronic HD population, we performed a prospective multi-centred study comparing episodes of Pseudomonas vs non-Pseudomonas TCC bactaeremia.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Patients, study design and data collection
The patient population included all chronic HD patients dialysing using a TCC at seven out-patient chronic HD centres. Five centres were affiliated with Montefiore Medical Center, Bronx, NY (combined average census of ~600 patients) and two were located in Connecticut, Hartford Hospital and East Hartford Dialysis Center (combined average census of 334 patients). The prevalence of TCC use in the Bronx was 34% and in Hartford was 26%. The duration of the study was 2.5 years.

All TCC patients who had positive blood cultures were identified and evaluated further to determine the source of bacteraemia. A bacteraemic episode was determined to be TCC related when blood cultures taken from the TCC turned positive during a period in which an exit/tunnel infection was also present or when other primary sources of bacteraemia were absent (by physical examination, urinalysis and chest radiograph). Criteria for drawing blood cultures included fever and/or chills. A designated research nurse situated at each HD unit identified patients who met the criteria for TCC bacteraemia and followed them weekly for 3 months. The date of entry into the study (baseline period) was the date of first positive blood cultures. If a subsequent episode of bacteraemia occurred with the same isolate, after having been determined cured by the presence of negative blood cultures and/or clinical evaluation, it was considered to be a recurrent bacteraemia. Bacteraemia with a different isolate was also recorded.

The 3 month follow-up period was selected based on that used in all previous published series (i.e: 45–90 day follow-up) [5,11–13]. If bacteraemia occurred after the 3 month follow-up period following the initial bacteraemic episode, then it was considered to be a second, unrelated episode of bactaeremia and was excluded from the analysis. Only first bacteraemic episodes were included in the analysis. Clinical decision making and treatment were determined by the patient's nephrologist. None of the HD units use antibiotic protocols.

Demographic and clinical data were collected prospectively using in-patient and out-patient charts. These included data regarding age, gender, race, cause of end-stage renal disease (ESRD), recent use of intravenous iron (within 1 month of bacteraemia) and the presence of diabetes mellitus. Data regarding TCC management during bacteraemia, and TCC survival 3 months post-bacteraemia were recorded. The respective clinical laboratory used for standard patient care, in each dialysis unit, performed microbiological testing. This included identification and antibiotic sensitivity of the isolate. Laboratory data were retrieved by accessing the hospital computer database and the dialysis chart. These included hepatitis B and C serologies, human immunodeficiency virus (HIV) status, ferritin, transferrin saturation, complete blood count, serum albumin and blood cultures. We also collected data regarding TCC exit/tunnel appearance, initial and subsequent antibiotic therapy, hospitalization, documentation of secondary metastatic infection and/or death. We compared demographic data in patients with a Pseudomonas isolate with those with a non-Pseudomonas organism. Isolates in the Pseudomonas family included the following: Pseudomonas aeruginosa, Pseudomonas cepacia and Stenotrophomonas maltophilia [14]. Non-Pseudomonas isolates included all other microorganisms.

All catheters were tunnelled, cuffed, dual-lumen, silastic catheters used only for HD. Standard catheter care consisted of cleansing the catheter site with povidone–iodine solution alone or povidone–iodine followed by isopropyl alcohol. An antiseptic solution, Exsept (Alcavis international, Gaithersburg, MD), is then applied and the site is covered with a transparent, oxygen-permeable dressing (OpSite TM Smith and Nephew Ltd, Largo, CA) with or without the application of gauze. Catheter dressings were changed three times weekly by HD staff. At Hartford Hospital, the TCC dressing was changed weekly using an antimicrobial dressing containing chlorhexidine gluconate (Biopatch TM, Johnson and Johnson, Somerville, NJ).

The four strategies of managing a TCC-related bacteraemia used are as follows: TCC salvage (S; the TCC is not removed and antibiotic therapy is administered); exchange of TCC for a guidewire (W; without waiting for negative blood cultures); immediate removal of the TCC with delayed reinsertion (DR) after a minimum of 1 week after blood culture turned negative; and TCC removal with use of functioning arteriovenous access (arteriovenous fistula or graft) (D).

To determine outcomes according to microbiological isolate, we compared the Pseudomonas vs non-Pseudomonas bacteraemic episodes. Treatment failure was defined as recurrent bacteraemia with the same organism or death from sepsis. Secondary outcomes included bacteraemia with a different isolate, secondary infectious complications and death. Univariate analyses were performed. Infectious complications included endocarditis, septic arthritis, osteomyelitis, septic emboli, abscess and septic thrombophlebitis. All continuous variables are reported as the mean±SEM and were analysed using a two-tailed independent t-test (P = 0.05). Categorical variables were evaluated using {chi}2 analysis for comparisons between groups (Fisher's exact test, P = 0.05).



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Patient demographic and laboratory data
In the 2.5 year study period, 219 episodes of TCC bacteraemia were identified, and in 18 (8%) cases a member of the Pseudomonas family was isolated (P.aeruginosa, n = 9; S.maltophilia, n = 8; and P.cepacia, n = 1). The individual isolates of the Pseudomonas family had similar antibiotic sensitivities. Data for all 18 cases of Pseudomonas bacteraemia are provided in Table 1. As illustrated in Tables 2 and 3, there were no statistically significant differences with regard to demographic, laboratory data or TCC management between those patients in whom Pseudomonas was isolated vs those with a non-Pseudomonas isolate, except for viral status. Patients in the Pseudomonas group had a higher rate of hepatitis B and C co-infection. Two patients had active liver disease, one had chronic hepatitis as evidenced by increased transaminases, and the other had liver cirrhosis. In addition, in the Pseudomonas group, one patient had metastatic cancer and one patient was on corticosteroids.


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  		Table 1. Data for 18 cases of Pseudomonas TCC bacteraemia

 

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  		Table 2. Patient demographic and laboratory data

 

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  		Table 3. Mode of TCC management

 
As illustrated in Table 3, when Pseudomonas was isolated, the most common mode of TCC management was immediate removal with delayed reinsertion (DR) (Pseudomonas 56% vs non-Pseudomonas 41%). TCC salvage (S) was attempted in only 11% of Pseudomonas bacteraemia. There was no difference in the number of days between when blood cultures were obtained and catheter removal between the Pseudomonas group and the non-Pseudomonas group (Pseudomonas 5.69±0.32 vs non-Pseudomonas 4.26±1.02, P = 0.18). Pseudomonas bacteraemia was more likely to be associated with multiple isolates (Pseudomonas 28% vs non-Pseudomonas 12%, P = 0.06); however, this was not statistically significant. The empiric antibiotics administered were found to be inappropriate in 28% of Pseudomonas bacteraemia vs 10% of non-Pseudomonas bacteraemia [odds ratio (OR) 3.6, 95% confidence interval (CI) 1.2–11.1, P = 0.02]. The reasons why empiric antibiotics were deemed inappropriate were (i) resistance to the selected aminoglycoside in three cases; and (ii) the absence of Gram-negative antibiotic coverage in two cases. The likelihood that subsequent antibiotic selection (after the identification and sensitivities of the isolate were available) was inappropriate, was independent of the microbiological isolate (Pseudomonas 11% vs non-Pseudomonas 16%, P = NS). There were no protocols for antibiotic use in any of the dialysis units, and antibody selection was left to the discretion of the attending nephrologist.

There were no significant differences in the rates of treatment failure or infectious complications between those with Pseudomonas as compared with all other isolates combined. There was no difference between the Pseudomonas and non-Pseudomonas groups with regard to treatment failure (defined as recurrent bacteraemia with the same organism and/or death from sepsis), infectious complications, bacteraemia with a different isolate and death from any cause. There was a significantly higher incidence of treatment failure in the Pseudomonas group (17%) compared with other Gram-negative isolates (2%), but no difference when compared with S.aureus or other Gram positives. Treatment failure (recurrent bacteraemia or death from sepsis) occurred in three episodes of Pseudomonas TCC bacteraemia. The modes of TCC management for these three episodes of treatment failure were: DR (TCC removal with delayed reinsertion), S (leaving TCC in and treating with antibiotics) and O (TCC removal with use of another arteriovenous access). In the non-Pseudomonas group, TCC salvage was significantly associated with treatment failure (data not shown). There were no deaths in the Pseudomonas group, whereas there were 15 deaths (7%) in the non-Pseudomonas group (P = 0.6).



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
The mortality associated with Pseudomonas bacteraemia is largely determined by the primary source of infection and underlying immune status of the patient. There were no deaths associated with Pseudomonas TCC bacteraemia in this chronic out-patient HD population. The high mortality rates previously associated with Pseudomonas bacteraemia occurred in a predominantly hospitalized, immunocompromised population, and primary sources of Pseudomonas were non-catheter sources such as pneumonia, urosepsis and severe sepsis [6–10].

The genus Pseuodomonas represents organisms with similar rRNA homologies. The genomic classification of Stenotrophomonas (previously known as Xanthomonas) has been a circuitous one. The new classification is based on DNA–rRNA hybridizations, cellular fatty acid composition and growth parameters. Despite technical differences amongst the different genomes of Pseudomonas, there are some basic clinical commonalities. Clinically, both Pseudomonas and Stenotrophomonas are found in water, soil and on plants. They have an ability to survive in aqueous environments and behave similarly when associated with nosocomial infections. Strenotrophomonas is a significant nosocomial pathogen with risk factors that include mechanical ventilation and the use of central venous catheters. Pseudomonas cepacia is well recognized as a nosocomial pathogen and leads to infections in patients with indwelling catheters, urinary tract infections and respiratory tract infections. All genera survive in a variety of hostile environments and they have similar morphologies. Stenotrophomonas had been shown to develop resistance very quickly, but susceptibility testing is the same as that used for Pseudomonas. The same susceptibility testing applied to Pseudomonas is applied to all species. In fact, although the species grouped under the Pseudomonas family differ in certain aspects, including virulence, frequently organisms that are defined under one species have different morbidity and mortality rates [14].

Despite this relatively large series of TCC bacteraemia, only 8% were with a Pseudomonas isolate. None of the patients with a Pseudomonas isolate was hospitalized prior to their bacteraemia. There were no identifiable demographic or laboratory risk factors for acquiring a Pseudomonas isolate.

TCC salvage, in which the catheter is left in and antibiotics are administered, has been shown to be associated with a higher treatment failure rate (all isolates) [11,12]. Bacteria that are often embedded in the biofilm can be resistant to antibiotic treatment unless the TCC is removed. In an article by Bouza et al. [13], TCC salvage is acceptable in certain circumstances. These include: difficult to replace catheters, blood sterile within 48 h, no signs of tunnel or metastatic infection and a haemodynamically stable patient. In the present study, the infected TCC was removed in 89% of Pseudomonas bacteraemia episodes, which may explain the low treatment failure rate. There were too few patients in the Pseudomonas group to determine if there were significant differences in the outcomes associated with each TCC management strategy. A larger study comparing guidewire exchange vs immediate removal (with DR) in Pseudomonas TCC bacteraemia is needed. The association of TCC salvage and higher treatment failure rates in non-Pseudomonas TCC-associated bacteraemia has been reported by us and others [11,12].

Whether polymicrobial Pseudomonas bacteraemias are associated with higher mortality is controversial. In intensive care unit (ICU) patients, Ibrahim et al. report a higher prevalence of multiple pathogens in patients with Pseudomonas bacteraemia who died during the hospitalization compared with survivors (20 vs 12%; P = 0.009) [9]. In contrast, others report no increase in mortality when multiple organisms are isolated [7]. In the present study, Pseudomonas bacteraemia was polymicrobial in 28% of cases and there were no deaths. In other series, the prevalence of multiple isolates in episodes of Pseudomonas bacteraemia was 19% [6,8].

Pseudomonas is frequently not treated appropriately in the initial days of bacteraemia [10]. In the present study, the likelihood of not receiving appropriate initial antibiotics was almost 4-fold higher in cases of Pseudomonas bacteraemia. Two of five cases were due to the administration of antibiotics with Gram-positive coverage as sole therapy; the remaining cases were associated with aminoglycoside resistance. Despite this disadvantage, there was no increase in mortality. Similar findings were reported in two other series of Pseudomonas bacteraemia. Both studies failed to demonstrate a relationship between the administration of inappropriate empiric antibiotics and a higher mortality [6,10]. In contrast to the above findings, Kang et al. reported a 4.6-fold higher 30 day mortality when Pseudomonas bacteraemia was treated with ineffective empiric antibiotics in the ICU [7]. In this series of 139 patients with Pseudomonas bacteraemia, 65% received ineffective empiric antibiotics. The majority of patients had pneumonia or sepsis, a more severe clinical presentation.

In the present study, treatment with inappropriate definitive (after identification and sensitivities are available) antibiotics was not associated with an increased mortality. This may be due to immediate catheter removal (the primary source of infection) as an initial management step. What made antibiotics ‘inappropriate’ was determined by the antibiotic sensitivity reports of the microbiological organism isolated. Aliaga et al. reported similar findings in their review of 125 episodes of Pseudomonas bacteraemia in which 20% were treated with inappropriate definitive antibiotics without a significant increase in mortality [8]. In contrast, four studies report a higher mortality in patients who receive inappropriate definitive antibiotics [15–19].

Aminoglycoside monotherapy is associated with a significantly higher mortality (48–71%) in Pseudomonas bacteraemia [15,16,18,19]. Chen et al. report a lower mortality in patients treated by adding a ß-lactam antibiotic to an aminoglycoside (C), compared with aminoglycoside therapy alone (S), (C 22 vs S 48%) [17].

Whether adding an aminoglycoside to a ß-lactam regimen vs ß-lactam sole treatment confers a survival advantage in Pseudomonas bacteraemia is controversial. Hilf et al. reported lower mortality rates when combination (ß-lactam based) antibiotics were administered when compared with single ß-lactam antibiotic therapy (combination 27% vs single 47%, P<0.02) [16]. Others have failed to show a similar survival advantage, except in cases of septic shock where combination antibiotics confer an improved cure rate (46 vs 25%) [6,15,18]. In our study, the percentage of Pseudomonas bacteraemia episodes for which combination antibiotics were administered was 83%.

In conclusion, the outcomes in TCC-associated Pseudomonas bacteraemia are remarkably good, with results being more favourable than when Pseudomonas bacteraemia is associated with more invasive visceral infections. Empiric antibiotic therapy coverage lacking anti-Pseudomonas coverage has not been associated with an increased mortality for episodes of TCC bacteraemia in which Pseudomonas is subsequently isolated. Furthermore, Pseudomonas isolates represent a relatively small percentage of all isolates. For episodes of TCC-associated Pseudomonas bacteraemia, removal of the infected TCC is recommended, with either a period of delayed reinsertion or exchange for a guidewire.



   Acknowledgments
 
We thank Maria Coco, MD, John D’Avella, Peter Durkin, PA, Manash DasGupta, MD, Dulce Eleazar, RN, Robert Feingold, MD, Vaughn Folkert, MD, Michael Guccione, MD, Jeffrey Laut, MD, Joel Neugarten, MD, Sushil Sagar, MD, Ann Starnovich, RN and the Aetna Foundation.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 29. 4.05
Accepted in revised form: 23.12.05


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