Relationship between oral bacteria and hemodialysis access infection

Vol. 98 No. 4 October 2004

ORAL MEDICINE

Editor: Martin S. Greenberg

Relationship between oral bacteria and hemodialysis access infection Galib Shariff, DDS,a Michael T. Brennan, DDS, MHS,b M. Louise Kent, RN,c Philip C. Fox, DDS,d David Weinrib, MD,e Patrick Burgess, MD, PhD,f and Peter B. Lockhart, DDS,g Charlotte, NC CAROLINAS MEDICAL CENTER

Objective. Controversy exists concerning the association between oral bacteria and infection of hemodialysis (HD) shunts. The purpose of this study was to determine the extent to which oral bacteria are associated with vascular access site infections in a group of HD patients. Study design. Microbial blood culture data for 87 HD patients were collected: 53 via chart review (retrospective), and 34 with newly suspected vascular access infections (prospective). The primary outcome was the nature (i.e., species) of the bacteria recovered from blood cultures of subjects with vascular access infection, specifically those bacteria considered to be oral flora. Results. The predominant bacteria reported to cause HD vascular access infections were Staphylococcus (48.6%) and Enterococcus (17.6%) species. Most infections occurred in hemodialysis catheters (89%) compared with AV grafts (11%) and AV fistulas (0%). The subclavian venous access (41%) and the internal jugular venous access (38.9%) were more commonly infected than other sites. None of the bacteria identified by blood cultures were considered to be oral flora. Conclusion. The results suggest that oral bacteria rarely, if ever, cause vascular access infections in hemodialysis patients. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;98:418-22)

End-stage renal disease (ESRD) is among the more common chronic ailments in the United States. In 1991, approximately 200,000 Americans were being treated for ESRD and the incidence of new cases is increasing at more than 41,000 per year.1 Infections are a major cause of morbidity and mortality in chronic hemodialysis (HD) patients. The rate of vascular access infection (VAI) is estimated at 3.3/100 patient months,2 and VAI account for 10% of infectious deaths.3 These infections can have devastating consequences, including sepsis with multiorgan failure, endocarditis, and septic arthritis. Although a

Resident, Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC. b Residency Director, Department of Oral Medicine. c Clinical Coordinator, Department of Oral Medicine. d Visiting Scientist, Department of Oral Medicine. e Faculty Physician, Department of Internal Medicine. f Metrolina Nephrology, Department of Nephrology. g Chairman, Department of Oral Medicine. Received for publication Oct 15, 2003; returned for revision Dec 15, 2003; accepted for publication Apr 19, 2004. Available online 24 August 2004. 1079-2104/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.tripleo.2004.04.026

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virtually any bacterial species can cause dialysis accesserelated infection, one of the most common and clinically important pathogens is Staphylococcus aureus.3 Other pathogens involved in VAI are Streptococcus and Enterococcus species, and other gram-positive bacteria, as well as gram-negative rods and fungi (Table I). Because many of these organisms also exist in multiple sites, such as the upper and lower aerodigestive tract and the skin, it is often difficult to determine the source of the causative organisms.4 It is clear that HD patients are at increased risk for infection, but the role of oral bacteria has yet to be defined. The literature reveals a long list of oral bacteria identified in blood cultures following various dental procedures, but when compared with bacteria reported to cause VAI, there is little overlap.4 Nevertheless, it is common for HD patients to receive antimicrobial prophylaxis prior to invasive dental procedures. The current standard of care in medical1,5,6 and dental practice7-9 assumes that antimicrobial prophylaxis will decrease the risk of developing a dialysis access site infection or a more significant complication such as infective endocarditis.10-12 However, there are no prospective data or clinical trials to support this practice.

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The American Heart Association guidelines do not address HD patients or other noncardiac conditions.8 Furthermore, the current National Kidney Foundatione Dialysis Outcome Quality Initiative (NKF-DOQI) for vascular access care does not mention the use of prophylactic antibiotics prior to invasive dental procedures.13 Despite the poorly defined indications for prophylactic antibiotic coverage for HD patients prior to dental treatment, it still remains the standard of care in most communities.9 The primary purpose of this study was to determine the extent to which oral bacteria are associated with vascular access site infections in a group of HD patients. METHODS HD patients from the kidney dialysis unit (KDU) at Carolinas Medical Center with suspected VAI were included in this study. This study was approved by an Institutional Review Board. Culture data, type of vascular access (AV graft, AV fistula, or catheter), and location of vascular access (subclavian vein, internal jugular vein, femoral vein) were collected. Prior to administration of antibiotics, 2 sets of aerobic and anaerobic BACTEC blood cultures (current standard of care) were obtained from the access site in the usual manner. Data from HD patients were collected retrospectively and prospectively. Patients who met the inclusion criteria were those undergoing HD and diagnosed with a VAI. Exclusion criteria included patients undergoing peritoneal dialysis, and those who received antibiotics prior to blood samples being obtained for microbiological analysis. Retrospective For the retrospective component of the study, a list of patients with suspected VAI were provided to us by the KDU. The list included patients from July 2001 to November 2001. Medical charts of patients with a suspected diagnosis of VAI were reviewed for relevant data. Standard protocol called for incubating blood cultures for a maximum of 5 days. Prospective For the prospective component, patients with a likely diagnosis of VAI were identified during visits to the KDU from November 2001 to July 2002. The medical charts were reviewed as in the retrospective study, however, blood cultures were incubated for a maximum of 10 days in an effort to identify slow growing bacteria such as the HACEK group (Haemophilus aprophilus/ paraphrophilis, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae). Blood cultures were held for 10 days

Shariff et al 419

Table I. Bacteria reported as pathogens in vascular access infections from previous studies

Pathogens Gram-positive cocci Streptococci species Streptococcus viridans Streptococcus oralis Streptococcus salivarius Gemella morbillorum Staphylococcus aureus Staphylococcus epidermidis Coagulase-negative Staphylococci Enterococcus species Enterococcus faecalis Gram-positive rods Corynebacterium diphtheriae Listeria monocytogenes Gram-negative rods Acinetobacter species Aeromonas species Bacteroides species Bacteroides fragilis Citrobacter species Enterobacter species Enterobacter cloacae Escherichia coli Escherichia species Klebsiella species Klebsiella pneumoniae Morganella species Proteus species Proteus mirabilis Pseudomonas aeruginosa Salmonella Serratia species Serratia marcescens Stenotrophomonas species Stenotrophomonas maltophilia Yersinia enterolitica Fungi Aspergillus species Candida species Candida albicans

Presence in the oral cavity*14,25

References

+++ +++ ++++ ++++ +++ ++ ++ ++

2,26,27

+ +

2,20,23,26

+ +

22

+ + +++ +++ + + + + + + + + + + + + + + + + +

2,22,23,26

+ +++ +++

2

5 21 28 5 2,5,16,20,22,23,26-29 21,29 2,5,16,20,22,23,26-29

5,22

21,29

2 16 21 2,26 2,23,26 20,22 2,5,21-23,27,29 26 2,5,23,26 22 2 2,5,16 22,27 2,5,20,22,26,27 20,29 23,26 16,27 2,26 21 29

2 16

*Refers to likelihood of presence of microorganism in the oral cavity: 1111, likely oral flora; 111, possible oral flora; 11, unlikely oral flora; 1, rarely/not oral flora.

when microbial growth was not observed at 5 days. If microbial growth was observed at 5 days, it was deemed unlikely that further meaningful data would be obtained by holding cultures for an additional 5 days. The microbiological data from both aspects of the study were analyzed for the incidence and nature of the bacteria. Individual bacteria were classified as either (1) likely oral flora, (2) possible oral flora, (3) unlikely oral flora, or (4) rarely/not oral flora. These classifications were made based on recent microbiology publications.

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420 Shariff et al Table II. Anatomical location of vascular access infections Number (%) Location Subclavian Internal jugular Femoral Forearm Axillary Unknown

Retrospective study (n = 49) 21 20 3 3 0 2

(42.8) (40.8) (6.1) (6.1) (4.1)

Prospective study (n = 23) 7 8 2 2 1 3

(30.4) (34.7) (8.7) (8.7) (4.3) (13.0)

Total (N = 72) 28 28 5 5 1 5

(38.9) (38.9) (6.9) (6.9) (1.3) (6.9)

Once categorization was completed, each identified bacteria was reviewed by an infectious disease consultant at Carolinas Medical Center for accuracy.14,15 VAI was diagnosed if 1 or more of the following criteria occurred.16 Local signs of infection—warmth, tenderness, erythema, loculated fluid, purulent drainage—or a positive culture from the site, with or without bacteremia. Bacteremia but no local sign of access infection. Other sources of bacteremia have been ruled out leaving vascular access as the most likely source. The primary outcome variable was the proportion of HD patients with VAI from a bacteria considered likely or possibly from the mouth. Descriptive statistics were utilized to report the incidence and nature of microbial flora cultured from VAI. RESULTS Retrospective Of the 53 medical charts reviewed, 21 patients (40%) were excluded from the analysis: 20 did not meet the inclusion criteria, and 1 patient’s blood culture results were unavailable. The remaining 32 patients had 49 suspected episodes of VAI. Of the 49 episodes of VAI, 46 (94%) involved a catheter, 3 (6%) involved an AV graft, and none involved an AV fistula. The vast majority of VAI involved the subclavian and internal jugular sites (Table II). In 4 (8%) infectious episodes, microbial growth was not observed after holding the blood cultures for 5 days. Eight infectious episodes (16%) were polymicrobial, and 11 patients (34%) had more than one VAI episode. Staphylococci (44.5%) and Enterococci (16.7%) were the most common bacteria cultured (Table III). Prospective For the prospective aspect of the study, 34 patients presented to the KDU with a suspected VAI. Fifteen patients (44%) were excluded from the analysis for not

meeting the definition of VAI. The remaining 19 patients (56%) had a total of 23 episodes of VAI. Four patients had more than 1 infectious episode, and 1 patient’s infection was polymicrobial. Three (13%) infectious episodes lacked microbial growth. Of the 23 episodes of VAI, 18 (78%) involved infection of a catheter, 3 (13%) involved infection of an AV graft, none involved an AV fistula, 1 involved both a catheter and a graft, and in 1 instance the access type was unknown. Staphylococci (62%) and Enterococci (19%) were the predominant bacteria causing VAI (Table III). In this study, holding blood cultures for 10 days did not influence the microbiological outcome. The combined results of the retrospective and prospective bacterial data for VAI allowed for the analysis of 87 HD patients. Fifty-one (59%) met the criteria for a VAI, for a total of 72 episodes of VAI for the combined group. The majority of VAI were associated with subclavian and internal jugular sites (Table II) along with 64 (89%) VAI involving HD catheters and 8 (11%) involving AV grafts. No VAI were associated with AV fistulas. A cumulative assessment of the retrospective and prospective microbial data emphasized the predominance of Staphylococcus bacteria, which were found in 36 (49%) of cases. The combined bacterial flora analyzed in this study were classified as unlikely (49%) or rarely/not oral bacteria (51%) (Table IV); none was classified as likely or possible oral flora. DISCUSSION Bacteremia originating from the oral cavity is common and has the potential to cause distant site infections (DSI), but the extent to which oral bacteria cause hemoaccess site infections is unclear. The medical literature consists primarily of retrospective data and case reports that lack adequate historical and demographic data, information on the extent of odontogenic disease, and the invasiveness of any associated dental procedures.1,5,6 Furthermore, because normal daily activities, such as chewing foods and brushing teeth, frequently cause bacteremia, these case studies fail to prove a causal relationship between dental procedures and DSI.4,17 Our methodology for determining the extent to which oral bacteria are associated with VAI in HD patients included both retrospective and prospective data collection. The main difference between these 2 methods was our holding negative blood cultures for a full 10 days in the prospective study. Since this had no impact on the nature of bacteria cultured, the data could be analyzed separately and combined. These data confirm that the predominant microorganisms associated with HD VAI are nonoral in origin.

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Shariff et al 421

Table III. Microorganisms implicated in vascular access infections Number (%) Microorganisms Gram-positive cocci Staphylococcus aureus Coagulase-negative Staphylococcus Staphylococcus species Staphylococcus epidermidis Enterococcus spp. Enterococcus faecalis Enterococcus faecium Gram-negative rods Klebsiella pneumoniae Serratia marcescens Enterobacter cloacae Stenotrophomonas maltophilia Achromobacter xylosoxidans Escherichia coli Proteus mirabilis Pantoea agglomerans Flavobacterium breve Burkholderia picketti Gram-positive rods Corynebacterium jejuni

Retrospective (n = 52)

Prospective (n = 21)

12 (23.0) 10 (19.2) 1 (1.9)

7 (33.3) 5 (23.8) 1 (4.8)

1 (1.9) 8 (15.1) 1 (1.9) 3 3 3 2 2 2 2 1 1

4 (19)

(5.7) (5.7) (5.7) (3.7) (3.8) (3.8) (3.8) (1.9) (1.9)

1 (4.8) 1 (4.8) 1 (4.8)

1 (4.8) 1 (1.9)

The predominant organisms recovered were staphylococcal species. The reason for the high incidence of S aureus bacteremia may be related to a chronic carrier state often found in this patient population, resulting in staphylococcal VAI due to autoinoculation. Approximately 75% of patients undergoing HD are carriers of S aureus in the anterior nares and intertriginous regions (ie, axillae, groin, perineum).15 In addition, recent reports18,19 indicate an increasing of oral S aureus carriage in the elderly and patients with rheumatoid arthritis. Two other predominant organisms implicated in access infections in this study (coagulasenegative Staphylococcus and E faecalis) colonize the skin and GI tract respectively and are not considered as likely constituents of the oral flora. As reported previously, the present study demonstrated the majority of VAI involved HD catheters20-22 and was more commonly associated with the subclavian vein and internal jugular vein. Forearm access sites were seldom associated with VAI. Although these results are consistent with the latest NKF-DOQI guidelines they should be interpreted with caution, because these guidelines also state that femoral vein placement of catheters is associated with higher infection rates compared with other sites.13 Long-term tunneled access (subclavian and internal jugular) have more days at risk and therefore more absolute numbers of infection, however a nontunneled femoral vein access has a higher incidence of infection per 1000 days of use, but is typically a short-term access in hospitalized patients.

Total (N = 74) 19 15 1 1 1 12 1

(25.7) (20.3) (1.4) (1.4) (1.4) (16.2) (1.4)

3 4 4 3 2 2 2 1 1 1

(4.1) (5.4) (5.4) (4.1) (2.7) (2.7) (2.7) (1.4) (1.4) (1.4)

1 (1.4)

Table IV. Classification of microorganisms involved in vascular access infections from the present study Oral flora

Number (%)

Likely Possible Unlikely Rarely/Not

0 0 36 (49%) 38 (51%)

Because we did not measure incidence of infection per 1000 days of use, this study could not make appropriate estimates of the actual incidence of infection. The limitations of the present study include a relatively small sample size. Additionally, we did not assess systemic factors such as severity of oral disease, underlying immunocompromised status, and functional status.16,20,21,23,24 However, the absence of oral flora in the list of organisms cultured from infected patients in this study suggest that the burden of proof for demonstrating a relationship between oral flora and VAI rests with those who would recommend antibiotic coverage. The results of this study demonstrate that oral bacterial flora are rarely, if ever, associated with hemdialysis vascular access infections. Therefore, it is highly unlikely that antibiotic prophylaxis prior to invasive dental procedures will prevent cases of VAI. In fact, the routine use of antibiotic prophylaxis in this patient population not only increases healthcare costs, but more importantly places the patient at an increased risk for adverse drug reactions and the development of

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422 Shariff et al resistant bacterial strains. Definitive data to determine the efficacy and necessity of the current standard of care would be a prospective randomized clinical trial of HD patients, with and without antibiotic prophylaxis. The results of the present study argue that such a trial would be acceptable ethically. The authors wish to acknowledge Amy Costner and Bertha Price from the Kidney Dialysis Unit at Carolinas Medical Center for their generous assistance with this project. REFERENCES 1. Anderson JE, Chang ASY, Anstadt MP. Polytetrafluoroethylene hemoaccess site infections. ASAIO J 2000;46:S18-21. 2. D’Agata EMC, Mount DB, Thayer V, Schaffner W. Hospitalacquired infections among chronic hemodialysis patients. Am J Kidney Dis 2000;35:1083-8. 3. Sexton DJ. Vascular access infections in patients undergoing dialysis with special emphasis on the role and treatment of Staphylococcus aureus. Infect Dis Clin North Am 2001;15: 731-42. 4. Lockhart PB, Durack DT. Oral microflora as a cause of endocarditis and other distant site infections. Infect Dis Clin North Am 1999;13:833-50. 5. Fong IW, Capellan JM, Simbul M, Angel J. Infection of arteriovenous fistulas created for chronic haemodialysis. Scan J Infect Dis 1992;25:215-20. 6. Ellison RT III, Blaser MJ. Infectious diseases. In: Schrier RW, editor. Current medical therapy. 2nd ed. New York: Raven Press; 1989. p. 256-7. 7. Naylor GD, Hall EH, Terezhalmy GT. The patient with chronic renal failure who is undergoing dialysis or renal transplantation: another consideration for antimicrobial prophylaxis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1988;65:116-21. 8. Tong DC, Rothwell BR. Antibiotic prophylaxis in dentistry: a review and practice recommendations. J Am Dent Assoc 2000; 131:366-74. 9. Mealey BL. Periodontal implications: medically compromised patients. Ann Periodontol 1996;1:256-321. 10. Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. JAMA 1997;277:1794-1801. 11. Mohamed M, Habte-Gabr E, Mueller W. Infected arteriovenous hemodialysis graft presenting as left and right infective endocarditis. Am J Nephrol 1995;15:521-3. 12. Robinson DL, Fowler VG, Sexton DJ, Corey RG, Conton PJ. Bacterial endocarditis in hemodialysis patients. Am J Kidney Dis 1997;30:521-4. 13. NKF-DOQI clinical practice guidelines for vascular access. National Kidney FoundationeDialysis Outcomes Quality Initiative. Am J Kidney Dis 1997;30:S150-91. 14. Appendix B: compendium of important bacterial pathogens of humans. In: Burton GRW, Engelkirk PG, editors. Microbiology for the health sciences. 6th ed. Baltimore: Lippincott Williams & Wilkins; 2000. p. 450-2. 15. Sheagren JN, Schaberg DR. Staphylococci. In: Gorbach SL, Bartlett JG, Blacklow NR, editors. Infectious diseases. Philadelphia: Saunders; 1992. p. 1397.

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Reprint requests: Dr. Galib Shariff, DDS Department of Dentistry and Oral Medicine Foothills Medical Center AC-129, 1403 29 St. N.W. Calgary, Alberta Canada T2N 2T9 [email protected]