Infection of Cardiovascular Implantable Electronic Devices: Detection with Sonication, Swab Cultures, and Blood Cultures MARTIN ROHACEK, M.D.,*,† PAUL ERNE, M.D.,* RICHARD KOBZA, M.D.,* GABY E. PFYFFER, PH.D.,‡ RENO FREI, M.D.,§ and MAJA WEISSER, M.D.¶ From the *Division of Cardiology, Department of Medicine, Luzerner Kantonsspital, Lucerne, Switzerland; †Department of Emergency Medicine, University Hospital Basel, Switzerland; ‡Department of Medical Microbiology, Luzerner Kantonsspital, Lucerne, Switzerland; §Division of Clinical Microbiology, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland; and ¶Division of Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
Background: The number of patients with cardiovascular implantable electronic devices (CIEDs) is increasing. The purpose of this study was to compare three methods (sonication, swab cultures, and blood cultures) to detect bacteria in infections of CIEDs. Methods: Patients with pocket infection of CIEDs and/or CIED-associated infective endocarditis were prospectively included. Generators and leads were sonicated together. Swab cultures of the generator pocket and blood cultures were performed. Results: Between January 2009 and September 2012, 18 patients with a CIED infection were recorded, including two definite and four possible CIED-IEs. In 17 patients, blood cultures were performed and the device was analyzed by sonication. A swab culture from the device pocket was performed in 16 cases. Ten (59%) patients received antibiotic therapy before the device was removed. In 15 of 16 cases (94%), bacteria were detected by sonication, while bacteria were detected in only nine (56%) and seven (41%) cases by swab—and blood cultures, respectively. In four cases (24%), sonication was the only method that detected bacteria. The following bacteria were detected by sonication: methicillin-sensitive Staphylococcus aureus (MSSA; n = 6), coagulase-negative staphylococci (CNS; n = 3), Propionibacterium acnes (n = 2), Staphylococcus lugdunensis (n = 1), MSSA/Pseudomonas aeruginosa (n = 1), Bacillus cereus (n = 1), MSSA/P. acnes (n = 1), and P. acnes/CNS (n = 1). All positive swab cultures and all positive blood cultures but one grew the same bacteria as sonication fluid cultures. Conclusion: Sonication can be more sensitive than swab cultures or blood cultures in detecting bacteria in infections of CIEDs. (PACE 2014; 00:1–7) CIED, infection, sonication
Introduction Cardiovascular implantable electronic devices (CIEDs) improve the symptoms and survival of patients with heart diseases.1,2 The use of CIEDs has increased in recent years. Approximately 178,000 pacemakers (PMs) and 67,000 implantable cardioverter defibrillators (ICDs) were implanted in 2004 in the United States, a 145% increase for ICDs and 25% for PMs since 1997.3 A worldwide survey in 2009 found that the Funding: None. Disclosures: None. Address for reprints: Martin Rohacek, M.D., Department of Emergency Medicine, Basel University Hospital, Petersgraben 2, CH-4031 Basel, Switzerland. Fax: 41-61-265-58-31; e-mail: [email protected] Received May 16, 2014; revised August 16, 2014; accepted August 19, 2014.
number of implants had risen from 2005. In the USA, 235,567 new PMs and 133,262 new ICDs were implanted in 2009.4 In previous reports, the rate of infection of devices ranged between 0.19% and 1.6% and increased by 124% from 1990 to 1999.5–8 In another study from the United States, the annual rate of infections rose from 1.53% in 2004 to 2.41% in 2008.9 The most commonly isolated pathogens are coagulasenegative staphylococci (CNS) and Staphylococcus aureus, but a variety of bacteria may cause infection of CIEDs, including Propionibacterium acnes, Pseudomonas aeruginosa, and Enterococcus species.10–13 Infection of CIEDs is associated with high mortality, particularly in CIED-associated infective endocarditis (IE), with concomitant valve involvement.14 Besides removal of the device, appropriate antibiotic treatment is mandatory.15,16 This requires detection of the causative pathogen and its resistance profile, especially if antibiotic
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resistance is increasing and with treatment periods as long as 6 weeks in CIED-associated IE. However, microbiological diagnosis remains challenging, as blood cultures and cultures from swabs may be negative, in particular after initiation of antibiotic therapy. Sonication, initially validated for orthopedic devices,17 is a sensitive method to detect bacteria on foreign bodies. We have recently described the detection of bacteria with sonication and conventional swab culture in 115 explanted CIEDs without clinical signs of infection and in six with clinical signs of infection.18 Here we report the results of sonication, swab cultures, and blood cultures of consecutive cases of infected CIEDs.
agar plates and incubated at 37°C for 7 days. Microorganisms were quantitated (i.e., number of colony-forming units [CFU]/mL sonication fluid) and identified using routine microbiologic techniques. One milliliter was inoculated in 9-mL thioglycolate broth. Growth in broth only was defined as growth after enrichment. Intraoperative swabs from the generator pocket were collected after removal of the device. Cotton-tipped swabs were placed in Amies agar, then inoculated to sheep blood agar, chocolate agar, and MacConkey agar and incubated aerobically for 48 hours. An additional sheep blood agar plate was incubated anaerobically for 5 days. Thioglycolate was used for enrichment. Blood cultures were incubated both aerobically and anaerobically for 72 hours. Organisms were identified by standard microbiological methods.
Methods Study Design and Study Population We performed a prospective observational single center cohort study in a tertiary care hospital in Lucerne, Switzerland, from January 2009 to September 2012. All patients ࣙ18 years, were eligible, if their CIED system had been removed because of infection. Infection was defined as either local infection of the generator pocket (acute inflammation with redness, local warmth, pain, swelling, or purulent drainage intraoperatively or through skin erosion) or CIEDassociated IE, as defined by the Duke criteria.19 Patient records were summarized with a standardized case report form to retrieve demographic, clinical, microbiological, and laboratory data. The study protocol was approved by the local ethics committee.
Outcome Microbiological outcome was defined as any growth of bacteria in cultures from sonication fluid, swab, or blood (sonication positive, swab positive, blood culture positive). After removal or replacement of the device, patients were routinely seen every 6–12 months to control device function and to check for signs of infection. Follow-up lasted until September 2012. Statistical Analysis The statistical analysis was descriptive, without significance testing. Results In 2010, 2,530 patients with CIEDs were followed regularly at our institution. From January 2009 through September 2012, 18 devices were removed in 17 patients because of infection (in one patient, two PM systems had to be removed because of relapse of infection). This corresponds to an approximate incidence of infection of 0.19%. None of these patients were included in the cohort of patients with noninfected devices studied between October 2007 and December 2008.18 Of the 18 devices, two were removed in another hospital, and one of these devices was not sonicated. Thus, 17 devices were analyzed. Baseline characteristics of patients and devices (14 PMs, two ICDs, and one cardiac resynchronization therapy device [CRT]) are summarized in Table I. Risk factors for CIEDassociated infections were found in eight patients with a history of device change, and in one patient with chronic renal failure.16 Of the eight patients with a history of device change, four had a history of CIED infection, one had a revision of the pocket 3 weeks after implantation, and one had diabetes mellitus, a risk factor for bloodstream
Removal of Devices The infected device was removed in the operation theater. Skin was prepared by shaving, followed by application of 50% isopropyl alcohol three times, 1% povidone-iodine solution R (Braunoderm , B. Braun Melsungen AG, Melsungen, Germany), and by draping with sterile cloths. Generators and leads were aseptically removed and placed together in solid air-tight containers. The device was covered with 0.9% NaCl to prevent it from drying out. Microbiological Methods Sonication was performed in the microbiology laboratory of the University Hospital Basel, Switzerland, as described elsewhere.18 Briefly, containers were transported to the microbiology laboratory within 24 hours after removal. After 30 seconds of vortexing, sonication (frequency 40 ± 2 kHz; power density 0.22 ± 0.04 watts/cm2 ) was performed. After repetition of the vortex step, 0.1 mL of the resulting sonicate fluid was inoculated onto aerobic and anaerobic sheep blood
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fluid cultures. In one case of pocket infection, possible endocarditis and concomitant presence of spondylodiscitis, MSSA grew in blood cultures and in the tissue culture of the pocket, while B. cereus (>1,000 CFU/mL) grew in sonication fluid after 6 days of oxacillin, followed by 6 days of combination therapy with oxacillin, rifampicin, and daptomycin. In one case of pocket infection, sonication fluid culture grew P. acnes in addition to MSSA, which also grew in swab culture. In a case of pocket infection and possible endocarditis, P. aeruginosa was detected by sonication and swab culture in addition to MSSA, which also grew in blood cultures. In one case of definite endocarditis, MSSA grew in sonicate fluid and swab culture, while Streptococcus mitis grew in one of four blood culture bottles, in addition to MSSA in four of four bottles. In one case, cultures of all three methods remained sterile. Follow-up was available for all patients until September 2012, with a median followup time of 1.75 years (range 0.16–3.33). Nine patients received a new device after completion of antibiotic therapy; seven did not receive a new device. One patient developed a relapse of infection because not all electrodes could be removed primarily, and the remaining electrodes were removed 4 months later by cardiac surgery. No patient died during the follow-up period.
Table I. Baseline Characteristics of 16 Patients and 17 Devices Age, years, median (range)
65 (35–88)
Male sex, n Chronic heart failure, n Diabetes mellitus, n History of device infection, n Chronic renal failure Pacemaker, n ICD/CRT, n Indwelling time, years, median (range) First device change, n
12 3 1 4 1 14 3 1.3 (0.05–8.25) 9
CRT = cardiac resynchronization therapy device; ICD = implantable cardioverter defibrillator.
infections.20 At the time of implantation of the device, routine antibiotic prophylaxis with cefazolin or cefuroxime had been given to all patients. The median indwelling time was 1.3 years (range 0.05–8.25). Table II outlines clinical, echocardiographic, and microbiological results of 17 clinically diagnosed pocket site infections, two definite CIED-associated IE (vegetations seen on leads or valves with echocardiography), and four possible IE cases according to the Duke Criteria.19 All 17 devices were removed, including the leads, and were sonicated. Intraoperative swab cultures from the pocket were performed, except in one patient, in whom tissue culture of the generator pocket was performed. Blood cultures were taken in all but one case prior to antibiotic therapy. Ten patients (59%) received antibiotic therapy before removal of the device. In 16 of 17 cases (94%), bacteria were detected by sonication, whereas swabs and blood cultures detected bacteria in only nine of 16 (56%) and seven of 17 (41%) cases, respectively. The following bacteria were detected by sonication: methicillin-sensitive S. aureus (MSSA; n = 6), CNS (n = 3), P. acnes (n = 2), Staphylococcus lugdunensis (n = 1), and Bacillus cereus (n = 1). In three patients, two different bacteria were recorded: MSSA/P. aeruginosa (n = 1), MSSA/P. acnes (n = 1), P. acnes/CNS (n = 1). In four cases (24%), sonication was the only method that detected bacteria (one case of MSSA, one P. acnes, one CNS, and one P. acnes/CNS, 50 to >1,000 CFU/mL). In three of these four cases, antibiotic therapy was administered prior to removal of the device. All positive swab cultures (n = 9) and all but one positive blood culture (n = 6) grew the same bacteria as sonication
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Discussion In our study, to compare three methods to detect bacteria in infections of CIEDs, sonication detected bacteria in 94% of all cases, while swab and blood cultures detected bacteria in only 56% and 41%, respectively. In four (24%) cases, sonication was the only method that detected bacteria. Our results are in line with two other studies in which infected CIEDs were sonicated. In one study, sonication was positive in 15 of 16 infected devices, tissue culture in 13, and swab culture in 11 cases.21 Similar results were reported in another study including 20 infected CIEDs.22 An important issue of our study is the lack of a diagnostic gold standard for CIEDrelated infection. The use of a highly sensitive microbiological method such as sonication raises the concern of possible contamination. In orthopedic devices, this led to the definition of a cutoff value.17 For diagnosis of CIEDassociated infection, no such cutoff value for sonication has been defined. Nevertheless, we believe that in the four cases in which bacteria were detected by sonication only, true infection of the device was more likely than contamination or colonization, for the following reasons. First, all cases showed clinical signs of pocket infection.
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Pocket Pocket
Pocket Pocket Pocket
Definite IE
PM* ICD
PM PM PM
PM
PM
Pocket and possible IE Pocket
Pocket and definite IE Pocket and possible IE Pocket and possible IE
Site of Infection
PM
PM*
CRT
PM
CIED
2.5 months
8 years 3 weeks 6 weeks
5 months 6.3 years
6 months
10 months
3 weeks
2 months
3.25 years
Indwelling Time
12 (OX)
0 7 (AMC) 0
0 28 (AMC)
0
21 (PN)
0
0
1 (AMC)
Antibiotic Therapy before Explantation (Days)
No
No No Yes
No No
No
Yes
Yes
Yes
Yes
Fever
TTE: vegetation on lead and valve
TEE: no vegetation No echocardiography No echocardiography
1,000, >1,000), P. acnes (750) CNS, 2 MT (10,40) P. acnes (700) CNS (>1,000)
MSSA (>1,000), P. aeruginosa (>1,000) S. lugdunensis, 2 MT (160,550) MSSA (>1,000)
MSSA (>1,000)
MSSA (>1,000)
Sonication (CFU/mL)
Characteristics of 17 Cases of CIEDs
Table II.
Sterile
CNS (few) P. acnes (few) Sterile
MSSA (moderate) MSSA (few)
MSSA, 2 MT (strong)
S. lugdunensis (few)
MSSA (strong), P. aeruginosa (strong)
MSSA (strong)
MSSA (strong)
Swab Culture (Growth of Bacteria)
MSSA (4/4), S. mitis (1/4)
Sterile Sterile CNS (1/2)
Sterile Sterile
S. lugdunensis (6/6) Sterile
MSSA (10/10)
MSSA (3/4)
MSSA (8/8)
Blood Cultures (Positive Bottles)
Continued
Perforated pocket Revision of pocket 3 weeks after implantation
MT 1: PN sensitive MT 2: PN resistant
Comment
ROHACEK, ET AL.
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Pocket
Pocket
Pocket Pocket
PM
PM
PM ICD
1.3 years 3.75 years
5.6 years
8.25 years
3.75 years
2.8 years
Indwelling Time
1 (AMC) 3 (AMC)
21 (AMC)
35 (CE)
0
6 (OX) 6 (OX, RI, DA)
Yes Yes
No
No
No
Yes
Fever
No echocardiography
1,000), CNS (110)
B. cereus (>1,000)
Sonication (CFU/mL)
Sterile Sterile
Sterile
Sterile
Sterile
Not performed
Swab Culture (Growth of Bacteria)
Sterile Sterile
Sterile
Sterile
Sterile
MSSA (10/10)
Blood Cultures (Positive Bottles)
Device removed in another hospital. Tissue culture from pocket: MSSA. Presence of spondylodiscitis Perforated pocket; recurrence of infection with P. acnes 1.5 years ago Blood cultures taken under antibiotic therapy
Comment
*The marked two cases represent two episodes of CIED-system removal in the same patient. AMC = amoxicillin/clavulanic acid; CE = ceftriaxone; CFU = colony-forming units; CIED = cardiovascular implantable electronic devices; CNS = coagulase-negative staphylococci; CRP = C-reactive protein; CRT = cardiac resynchronization therapy device; DA = daptomycin; IE = infective endocarditis; MSSA = methicillin-sensitive S. aureus; MT = morphotype; OX = oxacillin; PM = pacemaker; PN = penicillin; RI = rifampicin; TEE = transesophageal echocardiography; TTE = transthoracal echocardiography.
Pocket
Pocket and definite IE
Site of Infection
PM
PM
CIED
Antibiotic Therapy before Explantation (Days)
Continued
Table II.
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Second, MSSA, CNS, and P. acnes are known pathogens of CIED infections. Although P. acnes is known as a skin commensal, and can colonize foreign bodies, recent evidence shows that P. acnes can act as a pathogen, causing implant infections such as prosthetic joint infections, infections of cardiovascular and cerebrovascular devices, and of breast implants, through biofilm formation.12,23–25 Third, the counts of detected microorganisms was very high with 700 to >1,000 CFU/mL in these four cases. In the literature no validated cutoff for infection exists. But, in our previous study of 115 clinically noninfected devices, we detected bacteria by sonication in 44 (38%) devices. A cutoff of 10 and 150 CFU/mL led to concordance of sonication with swab culture of 83% and 100%, respectively, assuming colonization rather than contamination. Only a minority of colonized devices showed bacterial growth of >500 CFU/mL in sonication fluid (5 of 27 devices with P. acnes and 1 of 11 devices with CNS).18 Fourth, in our previous study, of 26 negative controls (ICD dummies) only one dummy was contaminated with CNS (30 CFU/mL).18 In this study, one case showed simultaneous growth of CNS (110 CFU/mL) and P. acnes (>1,000 CFU/mL). This amount of CNS is more likely to represent colonization than contamination. Moreover, this case was a recurrent infection with P. acnes, with the first manifestation of P. acnes infection one and a half years previously. Therefore, even though colonization cannot be completely excluded in the four cases, the high amount of bacteria together with the clinical signs is a strong indicator for true infection rather than contamination. Finally, three of four patients were receiving antibiotics at the time of removal of the device. This decreases the chance that bacteria grew when using a less sensitive method, and may explain that swab and blood cultures remained sterile. Discordance of microbiological results was found in four patients. In one case, sonicate fluid grew B. cereus (>1,000 CFU/mL), while MSSA grew in blood cultures and tissue culture of the pocket. The antibiotic therapy, which was administered after blood culture sampling, and which consisted of 6 days of oxacillin and 6 days of oxacillin, rifampicin, and daptomycin, could have been the reason that MSSA did not grow in sonicate fluid and could have led to selection of colonizing B. cereus. In a second case, MSSA grew in sonication fluid and in four of four blood culture bottles. Additionally, Streptococcus mitis grew in one of four blood culture bottles but not in sonication. S. mitis can be a contaminant of blood cultures, as viridans streptococci are thought to be clinically significant in only 21% of cases.26 In
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two cases, an additional bacterium was detected in high amounts in sonication fluid besides a MSSA (P. acnes in the sonicate of one device and P. aeruginosa in sonication fluid and swab culture of another device). Although contamination cannot be excluded, colonization or superinfection is more likely, due to the high levels of bacteria. In one case, cultures from swab and sonication remained sterile, although there were clinical signs of pocket infection. In this case, it remains open, whether it was an infection or not. Blood cultures can be negative in localized infections but are crucial in the diagnosis of CIED-associated IE. Continuous bacteremia is a major Duke criterion for CIED-associated IE and determines the duration of antibiotic therapy.15,16 Therefore, sonication cannot replace blood cultures. On the other hand, sonication could be a more sensitive method than swab cultures and should be considered as an additional method to diagnose pocket infection, especially if devices are removed after the beginning of antibiotic treatment or if blood cultures were not performed. In our study, generators and leads were sonicated together. Since the leads are connected to the generator in the pocket and have direct contact to infected tissue of the pocket, it does not make sense to sonicate generator and leads separately. But, since the leads represent an additional surface for biofilms and can be the only infected part of the device in the case of CIEDassociated IE, we suggest that leads should always be sonicated together with the generator. Our study had several limitations. First, this study included only a small number of cases, which is due to the low incidence of CIEDassociated infections. Second, we did not perform tissue cultures and histological analysis from surrounding tissue. Thus, we could not compare sonication fluid cultures with tissue cultures, and cannot determine if sonication would improve the yield compared to tissue cultures. Further studies are needed, with more cases of infected devices including tissue culture and histology. Finally, there was no diagnostic gold standard for CIEDrelated infection, which was discussed above. In conclusion, sonication could be a more sensitive method than swab and blood cultures to detect bacteria on infected CIEDs, especially in patients receiving antibiotic treatment prior to removal of the device. Therefore, sonication should be considered for inclusion in the diagnosis of infection of cardiac devices, in addition to blood cultures. Acknowledgment: We thank Dr. Rodney Yeates for language editing.
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References 1. Myerburg RJ. Implantable cardioverter-defibrillators after myocardial infarction. N Engl J Med 2008; 359:2245–2253. 2. Holzmeister J, Leclercq C. Implantable cardioverter defibrillators and cardiac resynchronisation therapy. Lancet 2011; 378:722– 730. 3. Zhan CBW, Sedrakyan A, Steiner C. Cardiac device implantation in the United States from 1997 though 2004: A population-based analysis. J Gen Intern Med 2008; 23 Suppl 1:13–19. 4. Mond HG, Proclemer A. The 11th world survey of cardiac pacing and implantable cardioverter-defibrillators: Calendar year 2009—A World Society of Arrhythmia’s project. Pacing Clin Electrophysiol 2011; 34:1013–1027. 5. Cabell CH, Heidenreich PA, Chu VH, Moore CM, Stryjewski ME, Corey GR, Fowler VG, Jr. Increasing rates of cardiac device infections among Medicare beneficiaries: 1990–1999. Am Heart J 2004; 147:582–586. 6. Mela T, McGovern BA, Garan H, Vlahakes GJ, Torchiana DF, Ruskin J, Galvin JM. Long-term infection rates associated with the pectoral versus abdominal approach to cardioverter-defibrillator implants. Am J Cardiol 2001; 88:750–753. 7. Catanchin A, Murdock CJ, Athan E. Pacemaker infections: A 10-year experience. Heart Lung Circ 2007; 16:434–439. 8. Uslan DZ, Sohail MR, St Sauver JL, Friedman PA, Hayes DL, Stoner SM, Wilson WR, et al. Permanent pacemaker and implantable cardioverter defibrillator infection: A population-based study. Arch Intern Med 2007; 167:669–675. 9. Greenspon AJ, Patel JD, Lau E, Ochoa JA, Frisch DR, Ho RT, Pavri BB, et al. 16-Year trends in the infection burden for pacemakers and implantable cardioverter-defibrillators in the United States 1993 to 2008. J Am Coll Cardiol 2011; 58:1001–1006. 10. Baddour LM, Bettmann MA, Bolger AF, Epstein AE, Ferrieri P, Gerber MA, Gewitz MH, et al. Nonvalvular cardiovascular device-related infections. Circulation 2003; 108:2015– 2031. 11. Duval X, Selton-Suty C, Alla F, Salvador-Mazenq M, Bernard Y, Weber M, Lacassin F, et al. Endocarditis in patients with a permanent pacemaker: A 1-year epidemiological survey on infective endocarditis due to valvular and/or pacemaker infection. Clin Infect Dis 2004; 39:68–74. 12. Viola GM, Awan LL, Darouiche RO. Nonstaphylococcal infections of cardiac implantable electronic devices. Circulation 2010; 121:2085–2091. 13. Murdoch DR, Corey GR, Hoen B, Miro JM, Fowler VG, Jr., Bayer AS, Karchmer AW, et al. Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: The International Collaboration on Endocarditis-Prospective Cohort Study. Arch Intern Med 2009; 169:463–473.
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14. Athan E, Chu VH, Tattevin P, Selton-Suty C, Jones P, Naber C, Miro JM, et al. Clinical characteristics and outcome of infective endocarditis involving implantable cardiac devices. JAMA 2012; 307:1727–1735. 15. Baddour LM, Epstein AE, Erickson CC, Knight BP, Levison ME, Lockhart PB, Masoudi FA, et al. Update on cardiovascular implantable electronic device infections and their management: A scientific statement from the American Heart Association. Circulation 2010; 121:458–477. 16. Baddour LM, Cha YM, Wilson WR. Clinical practice. Infections of cardiovascular implantable electronic devices. N Engl J Med 2012; 367:842–849. 17. Trampuz A, Piper KE, Jacobson MJ, Hanssen AD, Unni KK, Osmon DR, Mandrekar JN, et al. Sonication of removed hip and knee prostheses for diagnosis of infection. N Engl J Med 2007; 357:654– 663. 18. Rohacek M, Weisser M, Kobza R, Schoenenberger AW, Pfyffer GE, Frei R, Erne P, et al. Bacterial colonization and infection of electrophysiological cardiac devices detected with sonication and swab culture. Circulation 2010; 121:1691–1697. 19. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: Utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med 1994; 96:200–209. 20. Stoeckle M, Kaech C, Trampuz A, Zimmerli W. The role of diabetes mellitus in patients with bloodstream infections. Swiss Med Wkly 2008; 138:512–519. 21. Mason PK, Dimarco JP, Ferguson JD, Mahapatra S, Mangrum JM, Bilchick KC, Moorman JR, et al. Sonication of explanted cardiac rhythm management devices for the diagnosis of pocket infections and asymptomatic bacterial colonization. Pacing Clin Electrophysiol 2011; 34:143–149. 22. Oliva A, Nguyen BL, Mascellino MT, D’Abramo A, Iannetta M, Ciccaglioni A, Vullo V, et al. Sonication of explanted cardiac implants improves microbial detection in cardiac device infections. J Clin Microbiol 2013; 51:496–502. 23. Zedtwitz-Liebenstein K, Gabriel H, Graninger W. Pacemaker endocarditis due to Propionibacterium acnes. Infection 2003; 31:184–185. 24. Chua AG, Ding J, Schoch PE, Cunha BA. Pacemaker-induced endocarditis due to Propionibacterium acnes. Clin Infect Dis 1998; 27:1541–1542. 25. Chakour M, Revel F, Godreuil C, Plotton C, Aubry A, Koeck JL. [Infectious endocarditis due to Propionibacterium acnes on a mechanical heart valve and cardiac stimulator electrode]. Presse Med 2002; 31:1414. 26. Swenson FJ, Rubin SJ. Clinical significance of viridans streptococci isolated from blood cultures. J Clin Microbiol 1982; 15:725–727.
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Background: The number of patients with cardiovascular implantable electronic devices (CIEDs) is increasing. The purpose of this study was to compare three methods (sonication, swab cultures, and blood cultures) to detect bacteria in infections of CIEDs. Methods: Patients with pocket infection of CIEDs and/or CIED-associated infective endocarditis were prospectively included. Generators and leads were sonicated together. Swab cultures of the generator pocket and blood cultures were performed. Results: Between January 2009 and September 2012, 18 patients with a CIED infection were recorded, including two definite and four possible CIED-IEs. In 17 patients, blood cultures were performed and the device was analyzed by sonication. A swab culture from the device pocket was performed in 16 cases. Ten (59%) patients received antibiotic therapy before the device was removed. In 15 of 16 cases (94%), bacteria were detected by sonication, while bacteria were detected in only nine (56%) and seven (41%) cases by swab—and blood cultures, respectively. In four cases (24%), sonication was the only method that detected bacteria. The following bacteria were detected by sonication: methicillin-sensitive Staphylococcus aureus (MSSA; n = 6), coagulase-negative staphylococci (CNS; n = 3), Propionibacterium acnes (n = 2), Staphylococcus lugdunensis (n = 1), MSSA/Pseudomonas aeruginosa (n = 1), Bacillus cereus (n = 1), MSSA/P. acnes (n = 1), and P. acnes/CNS (n = 1). All positive swab cultures and all positive blood cultures but one grew the same bacteria as sonication fluid cultures. Conclusion: Sonication can be more sensitive than swab cultures or blood cultures in detecting bacteria in infections of CIEDs. (PACE 2014; 00:1–7) CIED, infection, sonication
Introduction Cardiovascular implantable electronic devices (CIEDs) improve the symptoms and survival of patients with heart diseases.1,2 The use of CIEDs has increased in recent years. Approximately 178,000 pacemakers (PMs) and 67,000 implantable cardioverter defibrillators (ICDs) were implanted in 2004 in the United States, a 145% increase for ICDs and 25% for PMs since 1997.3 A worldwide survey in 2009 found that the Funding: None. Disclosures: None. Address for reprints: Martin Rohacek, M.D., Department of Emergency Medicine, Basel University Hospital, Petersgraben 2, CH-4031 Basel, Switzerland. Fax: 41-61-265-58-31; e-mail: [email protected] Received May 16, 2014; revised August 16, 2014; accepted August 19, 2014.
number of implants had risen from 2005. In the USA, 235,567 new PMs and 133,262 new ICDs were implanted in 2009.4 In previous reports, the rate of infection of devices ranged between 0.19% and 1.6% and increased by 124% from 1990 to 1999.5–8 In another study from the United States, the annual rate of infections rose from 1.53% in 2004 to 2.41% in 2008.9 The most commonly isolated pathogens are coagulasenegative staphylococci (CNS) and Staphylococcus aureus, but a variety of bacteria may cause infection of CIEDs, including Propionibacterium acnes, Pseudomonas aeruginosa, and Enterococcus species.10–13 Infection of CIEDs is associated with high mortality, particularly in CIED-associated infective endocarditis (IE), with concomitant valve involvement.14 Besides removal of the device, appropriate antibiotic treatment is mandatory.15,16 This requires detection of the causative pathogen and its resistance profile, especially if antibiotic
doi: 10.1111/pace.12529
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resistance is increasing and with treatment periods as long as 6 weeks in CIED-associated IE. However, microbiological diagnosis remains challenging, as blood cultures and cultures from swabs may be negative, in particular after initiation of antibiotic therapy. Sonication, initially validated for orthopedic devices,17 is a sensitive method to detect bacteria on foreign bodies. We have recently described the detection of bacteria with sonication and conventional swab culture in 115 explanted CIEDs without clinical signs of infection and in six with clinical signs of infection.18 Here we report the results of sonication, swab cultures, and blood cultures of consecutive cases of infected CIEDs.
agar plates and incubated at 37°C for 7 days. Microorganisms were quantitated (i.e., number of colony-forming units [CFU]/mL sonication fluid) and identified using routine microbiologic techniques. One milliliter was inoculated in 9-mL thioglycolate broth. Growth in broth only was defined as growth after enrichment. Intraoperative swabs from the generator pocket were collected after removal of the device. Cotton-tipped swabs were placed in Amies agar, then inoculated to sheep blood agar, chocolate agar, and MacConkey agar and incubated aerobically for 48 hours. An additional sheep blood agar plate was incubated anaerobically for 5 days. Thioglycolate was used for enrichment. Blood cultures were incubated both aerobically and anaerobically for 72 hours. Organisms were identified by standard microbiological methods.
Methods Study Design and Study Population We performed a prospective observational single center cohort study in a tertiary care hospital in Lucerne, Switzerland, from January 2009 to September 2012. All patients ࣙ18 years, were eligible, if their CIED system had been removed because of infection. Infection was defined as either local infection of the generator pocket (acute inflammation with redness, local warmth, pain, swelling, or purulent drainage intraoperatively or through skin erosion) or CIEDassociated IE, as defined by the Duke criteria.19 Patient records were summarized with a standardized case report form to retrieve demographic, clinical, microbiological, and laboratory data. The study protocol was approved by the local ethics committee.
Outcome Microbiological outcome was defined as any growth of bacteria in cultures from sonication fluid, swab, or blood (sonication positive, swab positive, blood culture positive). After removal or replacement of the device, patients were routinely seen every 6–12 months to control device function and to check for signs of infection. Follow-up lasted until September 2012. Statistical Analysis The statistical analysis was descriptive, without significance testing. Results In 2010, 2,530 patients with CIEDs were followed regularly at our institution. From January 2009 through September 2012, 18 devices were removed in 17 patients because of infection (in one patient, two PM systems had to be removed because of relapse of infection). This corresponds to an approximate incidence of infection of 0.19%. None of these patients were included in the cohort of patients with noninfected devices studied between October 2007 and December 2008.18 Of the 18 devices, two were removed in another hospital, and one of these devices was not sonicated. Thus, 17 devices were analyzed. Baseline characteristics of patients and devices (14 PMs, two ICDs, and one cardiac resynchronization therapy device [CRT]) are summarized in Table I. Risk factors for CIEDassociated infections were found in eight patients with a history of device change, and in one patient with chronic renal failure.16 Of the eight patients with a history of device change, four had a history of CIED infection, one had a revision of the pocket 3 weeks after implantation, and one had diabetes mellitus, a risk factor for bloodstream
Removal of Devices The infected device was removed in the operation theater. Skin was prepared by shaving, followed by application of 50% isopropyl alcohol three times, 1% povidone-iodine solution R (Braunoderm , B. Braun Melsungen AG, Melsungen, Germany), and by draping with sterile cloths. Generators and leads were aseptically removed and placed together in solid air-tight containers. The device was covered with 0.9% NaCl to prevent it from drying out. Microbiological Methods Sonication was performed in the microbiology laboratory of the University Hospital Basel, Switzerland, as described elsewhere.18 Briefly, containers were transported to the microbiology laboratory within 24 hours after removal. After 30 seconds of vortexing, sonication (frequency 40 ± 2 kHz; power density 0.22 ± 0.04 watts/cm2 ) was performed. After repetition of the vortex step, 0.1 mL of the resulting sonicate fluid was inoculated onto aerobic and anaerobic sheep blood
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fluid cultures. In one case of pocket infection, possible endocarditis and concomitant presence of spondylodiscitis, MSSA grew in blood cultures and in the tissue culture of the pocket, while B. cereus (>1,000 CFU/mL) grew in sonication fluid after 6 days of oxacillin, followed by 6 days of combination therapy with oxacillin, rifampicin, and daptomycin. In one case of pocket infection, sonication fluid culture grew P. acnes in addition to MSSA, which also grew in swab culture. In a case of pocket infection and possible endocarditis, P. aeruginosa was detected by sonication and swab culture in addition to MSSA, which also grew in blood cultures. In one case of definite endocarditis, MSSA grew in sonicate fluid and swab culture, while Streptococcus mitis grew in one of four blood culture bottles, in addition to MSSA in four of four bottles. In one case, cultures of all three methods remained sterile. Follow-up was available for all patients until September 2012, with a median followup time of 1.75 years (range 0.16–3.33). Nine patients received a new device after completion of antibiotic therapy; seven did not receive a new device. One patient developed a relapse of infection because not all electrodes could be removed primarily, and the remaining electrodes were removed 4 months later by cardiac surgery. No patient died during the follow-up period.
Table I. Baseline Characteristics of 16 Patients and 17 Devices Age, years, median (range)
65 (35–88)
Male sex, n Chronic heart failure, n Diabetes mellitus, n History of device infection, n Chronic renal failure Pacemaker, n ICD/CRT, n Indwelling time, years, median (range) First device change, n
12 3 1 4 1 14 3 1.3 (0.05–8.25) 9
CRT = cardiac resynchronization therapy device; ICD = implantable cardioverter defibrillator.
infections.20 At the time of implantation of the device, routine antibiotic prophylaxis with cefazolin or cefuroxime had been given to all patients. The median indwelling time was 1.3 years (range 0.05–8.25). Table II outlines clinical, echocardiographic, and microbiological results of 17 clinically diagnosed pocket site infections, two definite CIED-associated IE (vegetations seen on leads or valves with echocardiography), and four possible IE cases according to the Duke Criteria.19 All 17 devices were removed, including the leads, and were sonicated. Intraoperative swab cultures from the pocket were performed, except in one patient, in whom tissue culture of the generator pocket was performed. Blood cultures were taken in all but one case prior to antibiotic therapy. Ten patients (59%) received antibiotic therapy before removal of the device. In 16 of 17 cases (94%), bacteria were detected by sonication, whereas swabs and blood cultures detected bacteria in only nine of 16 (56%) and seven of 17 (41%) cases, respectively. The following bacteria were detected by sonication: methicillin-sensitive S. aureus (MSSA; n = 6), CNS (n = 3), P. acnes (n = 2), Staphylococcus lugdunensis (n = 1), and Bacillus cereus (n = 1). In three patients, two different bacteria were recorded: MSSA/P. aeruginosa (n = 1), MSSA/P. acnes (n = 1), P. acnes/CNS (n = 1). In four cases (24%), sonication was the only method that detected bacteria (one case of MSSA, one P. acnes, one CNS, and one P. acnes/CNS, 50 to >1,000 CFU/mL). In three of these four cases, antibiotic therapy was administered prior to removal of the device. All positive swab cultures (n = 9) and all but one positive blood culture (n = 6) grew the same bacteria as sonication
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Discussion In our study, to compare three methods to detect bacteria in infections of CIEDs, sonication detected bacteria in 94% of all cases, while swab and blood cultures detected bacteria in only 56% and 41%, respectively. In four (24%) cases, sonication was the only method that detected bacteria. Our results are in line with two other studies in which infected CIEDs were sonicated. In one study, sonication was positive in 15 of 16 infected devices, tissue culture in 13, and swab culture in 11 cases.21 Similar results were reported in another study including 20 infected CIEDs.22 An important issue of our study is the lack of a diagnostic gold standard for CIEDrelated infection. The use of a highly sensitive microbiological method such as sonication raises the concern of possible contamination. In orthopedic devices, this led to the definition of a cutoff value.17 For diagnosis of CIEDassociated infection, no such cutoff value for sonication has been defined. Nevertheless, we believe that in the four cases in which bacteria were detected by sonication only, true infection of the device was more likely than contamination or colonization, for the following reasons. First, all cases showed clinical signs of pocket infection.
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Pocket Pocket
Pocket Pocket Pocket
Definite IE
PM* ICD
PM PM PM
PM
PM
Pocket and possible IE Pocket
Pocket and definite IE Pocket and possible IE Pocket and possible IE
Site of Infection
PM
PM*
CRT
PM
CIED
2.5 months
8 years 3 weeks 6 weeks
5 months 6.3 years
6 months
10 months
3 weeks
2 months
3.25 years
Indwelling Time
12 (OX)
0 7 (AMC) 0
0 28 (AMC)
0
21 (PN)
0
0
1 (AMC)
Antibiotic Therapy before Explantation (Days)
No
No No Yes
No No
No
Yes
Yes
Yes
Yes
Fever
TTE: vegetation on lead and valve
TEE: no vegetation No echocardiography No echocardiography
1,000, >1,000), P. acnes (750) CNS, 2 MT (10,40) P. acnes (700) CNS (>1,000)
MSSA (>1,000), P. aeruginosa (>1,000) S. lugdunensis, 2 MT (160,550) MSSA (>1,000)
MSSA (>1,000)
MSSA (>1,000)
Sonication (CFU/mL)
Characteristics of 17 Cases of CIEDs
Table II.
Sterile
CNS (few) P. acnes (few) Sterile
MSSA (moderate) MSSA (few)
MSSA, 2 MT (strong)
S. lugdunensis (few)
MSSA (strong), P. aeruginosa (strong)
MSSA (strong)
MSSA (strong)
Swab Culture (Growth of Bacteria)
MSSA (4/4), S. mitis (1/4)
Sterile Sterile CNS (1/2)
Sterile Sterile
S. lugdunensis (6/6) Sterile
MSSA (10/10)
MSSA (3/4)
MSSA (8/8)
Blood Cultures (Positive Bottles)
Continued
Perforated pocket Revision of pocket 3 weeks after implantation
MT 1: PN sensitive MT 2: PN resistant
Comment
ROHACEK, ET AL.
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Pocket Pocket
PM
PM
PM ICD
1.3 years 3.75 years
5.6 years
8.25 years
3.75 years
2.8 years
Indwelling Time
1 (AMC) 3 (AMC)
21 (AMC)
35 (CE)
0
6 (OX) 6 (OX, RI, DA)
Yes Yes
No
No
No
Yes
Fever
No echocardiography
1,000), CNS (110)
B. cereus (>1,000)
Sonication (CFU/mL)
Sterile Sterile
Sterile
Sterile
Sterile
Not performed
Swab Culture (Growth of Bacteria)
Sterile Sterile
Sterile
Sterile
Sterile
MSSA (10/10)
Blood Cultures (Positive Bottles)
Device removed in another hospital. Tissue culture from pocket: MSSA. Presence of spondylodiscitis Perforated pocket; recurrence of infection with P. acnes 1.5 years ago Blood cultures taken under antibiotic therapy
Comment
*The marked two cases represent two episodes of CIED-system removal in the same patient. AMC = amoxicillin/clavulanic acid; CE = ceftriaxone; CFU = colony-forming units; CIED = cardiovascular implantable electronic devices; CNS = coagulase-negative staphylococci; CRP = C-reactive protein; CRT = cardiac resynchronization therapy device; DA = daptomycin; IE = infective endocarditis; MSSA = methicillin-sensitive S. aureus; MT = morphotype; OX = oxacillin; PM = pacemaker; PN = penicillin; RI = rifampicin; TEE = transesophageal echocardiography; TTE = transthoracal echocardiography.
Pocket and definite IE
Site of Infection
PM
PM
CIED
Antibiotic Therapy before Explantation (Days)
Continued
Table II.
SONICATION OF CIEDS
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ROHACEK, ET AL.
Second, MSSA, CNS, and P. acnes are known pathogens of CIED infections. Although P. acnes is known as a skin commensal, and can colonize foreign bodies, recent evidence shows that P. acnes can act as a pathogen, causing implant infections such as prosthetic joint infections, infections of cardiovascular and cerebrovascular devices, and of breast implants, through biofilm formation.12,23–25 Third, the counts of detected microorganisms was very high with 700 to >1,000 CFU/mL in these four cases. In the literature no validated cutoff for infection exists. But, in our previous study of 115 clinically noninfected devices, we detected bacteria by sonication in 44 (38%) devices. A cutoff of 10 and 150 CFU/mL led to concordance of sonication with swab culture of 83% and 100%, respectively, assuming colonization rather than contamination. Only a minority of colonized devices showed bacterial growth of >500 CFU/mL in sonication fluid (5 of 27 devices with P. acnes and 1 of 11 devices with CNS).18 Fourth, in our previous study, of 26 negative controls (ICD dummies) only one dummy was contaminated with CNS (30 CFU/mL).18 In this study, one case showed simultaneous growth of CNS (110 CFU/mL) and P. acnes (>1,000 CFU/mL). This amount of CNS is more likely to represent colonization than contamination. Moreover, this case was a recurrent infection with P. acnes, with the first manifestation of P. acnes infection one and a half years previously. Therefore, even though colonization cannot be completely excluded in the four cases, the high amount of bacteria together with the clinical signs is a strong indicator for true infection rather than contamination. Finally, three of four patients were receiving antibiotics at the time of removal of the device. This decreases the chance that bacteria grew when using a less sensitive method, and may explain that swab and blood cultures remained sterile. Discordance of microbiological results was found in four patients. In one case, sonicate fluid grew B. cereus (>1,000 CFU/mL), while MSSA grew in blood cultures and tissue culture of the pocket. The antibiotic therapy, which was administered after blood culture sampling, and which consisted of 6 days of oxacillin and 6 days of oxacillin, rifampicin, and daptomycin, could have been the reason that MSSA did not grow in sonicate fluid and could have led to selection of colonizing B. cereus. In a second case, MSSA grew in sonication fluid and in four of four blood culture bottles. Additionally, Streptococcus mitis grew in one of four blood culture bottles but not in sonication. S. mitis can be a contaminant of blood cultures, as viridans streptococci are thought to be clinically significant in only 21% of cases.26 In
6
two cases, an additional bacterium was detected in high amounts in sonication fluid besides a MSSA (P. acnes in the sonicate of one device and P. aeruginosa in sonication fluid and swab culture of another device). Although contamination cannot be excluded, colonization or superinfection is more likely, due to the high levels of bacteria. In one case, cultures from swab and sonication remained sterile, although there were clinical signs of pocket infection. In this case, it remains open, whether it was an infection or not. Blood cultures can be negative in localized infections but are crucial in the diagnosis of CIED-associated IE. Continuous bacteremia is a major Duke criterion for CIED-associated IE and determines the duration of antibiotic therapy.15,16 Therefore, sonication cannot replace blood cultures. On the other hand, sonication could be a more sensitive method than swab cultures and should be considered as an additional method to diagnose pocket infection, especially if devices are removed after the beginning of antibiotic treatment or if blood cultures were not performed. In our study, generators and leads were sonicated together. Since the leads are connected to the generator in the pocket and have direct contact to infected tissue of the pocket, it does not make sense to sonicate generator and leads separately. But, since the leads represent an additional surface for biofilms and can be the only infected part of the device in the case of CIEDassociated IE, we suggest that leads should always be sonicated together with the generator. Our study had several limitations. First, this study included only a small number of cases, which is due to the low incidence of CIEDassociated infections. Second, we did not perform tissue cultures and histological analysis from surrounding tissue. Thus, we could not compare sonication fluid cultures with tissue cultures, and cannot determine if sonication would improve the yield compared to tissue cultures. Further studies are needed, with more cases of infected devices including tissue culture and histology. Finally, there was no diagnostic gold standard for CIEDrelated infection, which was discussed above. In conclusion, sonication could be a more sensitive method than swab and blood cultures to detect bacteria on infected CIEDs, especially in patients receiving antibiotic treatment prior to removal of the device. Therefore, sonication should be considered for inclusion in the diagnosis of infection of cardiac devices, in addition to blood cultures. Acknowledgment: We thank Dr. Rodney Yeates for language editing.
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