Cardiac Device Infection Prevention

Cardiac device implantation rates have been rising with an increasing proportion of complex devices.⁽¹⁾ Contemporary therapies for cardiovascular disease have improved survival, resulting in higher rates of implantable cardioverter defibrillators (ICD) and cardiac resynchronisation therapy (CRT) implants, as well as higher rates of generator changes. In England alone the crude implant rate has risen from 77/100,000 population in 2008 to 101/100,000 in 2011 for pacemakers; from 11/100,000 in 2008 to 16/100,000 for defibrillators in 2011; and from 3.1/100,000 in 2008 to 4.6/100,000 in 2011 for CRT. The indication for CRT has also expanded in recent years to include patients with left ventricular systolic dysfunction and atrioventricular block (including those undergoing atrioventricular node ablation)^(2,3) or patients with a significant right ventricular pacing burden.⁽²⁾ Consequently, more patients qualify for CRT upgrade procedures. Quality improvement initiatives such as “Getting It Right First Time” have encouraged cardiologists to ensure patients receive the most appropriate cardiac device at the time of first implant in a hope to minimise the need for subsequent device upgrades and their associated complications.^(4,5) Cardiac device infections are a leading cause of complications, but despite advances in infection prevention policies and implant techniques evidence suggests no improvement in infection rates over the past 20 years.⁽⁶⁾ In this editorial I will be discussing the recently published Prevention of Arrhythmia Device Infection Trial (PADIT) which assessed the use of periprocedural antibiotics in the prevention of cardiac device infections.⁽⁷⁾

Cardiac device infection

Cardiac device infections are a major cause of complications and can result in significant morbidity and mortality [8]. The risk of cardiac device infection is estimated to be 2% in all patients and up to 4% in those at ‘high risk’.^(9–12) Patients with cardiac device infections may require prolonged courses of antibiotics, lengthy hospital admissions and repeat procedures including device extraction.^(6,13) The mortality rate following cardiac device infection is reported to be as high as 35%.⁽¹⁴⁾ The economic burden of cardiac device infection is also significant with an estimated treatment cost ranging from €12,000 per patient with a minor infection to €59,000 per patient with a major infection.⁽¹⁵⁾

The Centers for Disease Control have developed criteria to define surgical site infections.⁽¹⁶⁾ Infections occurring within 1 year of an intervention are considered to be related to the procedure. A primary infection is usually a result of contamination at the time of the procedure, whilst secondary infections are due to bacterial seeding from another source. Cardiac device infections can be classified as a pocket infection, pocket erosion or endocarditis (Box 1). Significant predictors associated with increased risk of cardiac device infection have been identified and are summarised in Box 2.^(2,17,18)

Box 1. Definition of cardiac device infection in the PADIT trial⁽⁷⁾

Box 2. Risk factors associated with increased risk of device infection^{(2, 17, 18)}

Prophylactic antibiotics

Antibiotic prophylaxis has been shown to reduce the risk of cardiac device infection.^(21,22) de Oliveira et al performed a large prospective randomised double-blinded, placebo-controlled trial of 1000 consecutive patients who underwent new cardiac device implant or generator replacement.⁽²²⁾ Patients were randomised to receive intravenous 1g cefazolin (beta-lactam, first generation cephalosporin antibiotic with bactericidal properties) or placebo immediately before the procedure. The study was terminated early after 649 patients were enrolled as there were significantly fewer device infections in the antibiotic group (0.6 %) compared to the placebo group (3.3 %, p=0.016). A subsequent meta-analysis of 15 studies confirmed these findings demonstrating that antibiotic prophylaxis within 1 hour before cardiac device implantation was effective at reducing risk of cardiac device infection.⁽²³⁾ The authors also found that pre-operative antibiotics were more effective at reducing cardiac device infections compared to postoperative antibiotics. Kang et al performed a meta-analysis of 10 studies (most from China) with 5467 patients who underwent cardiac device implantation to assess the efficacy of pocket antibiotic use in prevention of cardiac devices.⁽²⁴⁾ The authors concluded that pocket irrigation of antibiotics significantly reduced the risk of pocket infection (absolute risk 1.48 %) compared to placebo (absolute risk 3.5 %, relative risk 0.34, 95 % confidence interval 0.20-0.58). The efficacy of antibacterial envelope use within the pocket in prevention of cardiac device infection has also been assessed in a recent meta-analysis.⁽²⁵⁾ TYRX™ (Medtronic Inc, Minneapolis, USA) is an antibiotic envelope comprising a polypropylene mesh that releases minocycline and rifampicin within the pocket. In a meta-analysis of five cohort studies the antibiotic envelope was found to significantly reduce the risk of cardiac device infection (odds ratio 0.29, 95 % confidence interval 0.09-0.94, p<0.004). However, it is difficult to draw strong conclusions as the studies included were non randomised and predominantly retrospective. The evidence to date strongly supports the use of peri-operative antibiotics within 1 hour before cardiac device procedures, however, the incremental benefit achieved with pocket irrigation of antibiotics and post-operative antibiotics remained unclear until now.

The PADIT Trial

The PADIT trial was a cluster randomized crossover trial comparing the use of conventional periprocedural antibiotics against incremental periprocedural antibiotics in the prevention of cardiac device infection.⁽⁷⁾ This multicentre study was conducted in 28 centres (24 in Canada, 4 in the Netherlands) and included 19 603 patients enrolled between 2012 and 2015. In this study 12 842 patients (66 %) were deemed ‘high risk’ defined as those with any repeat procedure on an existing pocket (e.g. generator replacement, system revision or upgrade, or any lead procedure) and any cardiac resynchronisation therapy procedure. The primary outcome was 1-year hospitalisation for device infection in ‘high risk’ patients. The conventional treatment comprised a single infusion of cefazolin (intravenous 1-2 g) within 1 hour of skin incision. The incremental treatment included cefazolin (intravenous 1-2 g) within 1 hour before and vancomycin (intravenous 1-1.5 g) within 2 hours before skin incision, intraprocedural bacitracin (50, 000 units diluted in 50ml of saline) pocket irrigation followed by 2 days of postprocedural oral cephalexin (500 mg four times daily) or cephradroxil (1000 mg twice daily). In patients with penicillin allergy Vancomycin (intravenous 1-1.5 g) was given within 2 hours before skin incision and oral Clindamycin (150-400 mg three times daily) for 2 days post-procedure.

The mean age was 72 years and 34% were female. Common comorbidities included heart failure (40 %), diabetes (26 %) and renal insufficiency (17 %). Procedures performed included new permanent pacemaker implant (24 %), new ICD (11 %), new CRT defibrillator (10 %), new CRT pacemaker (2 %), pacemaker generator replacement (25 %), ICD generator replacement (11 %), CRT generator replacement (4 %) and pocket or lead revision (15 %). The procedural duration ranged from under 1 hour (70 %) to more than 2 hours (6 %).

There were no significant differences in 1-year hospitalisation for device infection rates in patient receiving conventional treatment (1.03 %) compared to incremental antibiotic treatment (0.78 %, odds ratio 0.77, 95 % confidence interval 0.56-1.05, p=0.10). In ‘high risk’ patients there was no significant difference in rates of hospitalisation for device infection in the conventional (1.23 %) compared to the incremental treatment group (1.01 %, odds ratio 0.82, 95 % confidence interval 0.59-1.15, p=0.26). A subgroup analysis failed to demonstrate any patient characteristic associated with benefit from incremental antibiotics.

Hospitalisation for device infection in ‘high risk’ patients was predominantly for skin or subcutaneous/pocket infection (87 %), whilst blood stream infection (24 %), endocarditis (26 %) and erosion of skin with device exposure (2 %) were less common. Surgical intervention was required in 90 % of device infection hospitalisations. The risk of hospitalisation for device infection was highest amongst CRT implants and lowest in pacemaker implants.

Main learning outcomes

This well conducted study by Krahn and colleagues was the largest single randomised control study of cardiac device infection to date and has generated a number of useful learning outcomes. Firstly, it was reassuring that overall device infection rates were low – in the region of 0.8-1.2 % - even among ‘high risk’ patients who comprised two thirds of the study population. Hospital infection protocols including a simple, inexpensive, single pre-procedural antibiotic infusion given up to one-hour before skin incision provided a low rate of hospitalisation for device infection. The addition of pocket antibiotics and post-procedural antibiotics did not significantly reduce the device infection risk. Adverse events associated with antibiotic use were extremely low (0.26 %) and were similar between the treatment groups. Although the authors did not conduct a formal economic analysis it is clear that a single infusion of pre-procedural antibiotics would be substantially less expensive compared to incremental antibiotics. While it is possible that the PADIT trial may be underpowered to detect a statistically significant difference with incremental antibiotic use, it may be argued that the number needed to treat to prevent a single infection would not justify incremental antibiotic use. Previous studies have shown that the implementation of infection control protocols can significantly reduce rates of cardiac device infection.^(26,27) Unfortunately, the PADIT trial authors did not report the specific infection prevention policies employed at each centre which may have been informative. An example of a hospital infection prevention policy is shown in Box 3.

The PADIT trial used a cluster crossover design including 28 centres. In a cluster study the individual centres are randomised rather than individual patients. Each institution was randomised to either of the two treatment arms and a randomised crossover was performed every 6 months. For example, a centre would be randomised to use a conventional antibiotic policy in all patients undergoing cardiac device procedures for 6 months. The centre would then change to an incremental antibiotic policy for the following 6 months (first crossover). For the second crossover the centre would again be randomised to either incremental or conventional antibiotics. In total there were four possible randomisations over two years: 1) conventional, incremental, incremental, convention; 2) conventional, incremental, conventional, incremental; 3) incremental, conventional, incremental, conventional; 4) incremental, conventional, conventional, incremental.

The randomised cluster crossover design provides a number of advantages. Firstly, all patients within an institution can be included into the study and individual patient enrolment or patient consent is not necessarily required. This policy was agreed by the ethical review board in all but ten centres. Secondly, adherence to the study protocol was more likely to occur if it was in line with routine institutional practices and policies. In this study compliance in the conventional arm was 99.8 % and 89.4 % in the incremental arm; the predominant reason for non-compliance was failure to administer post-operative antibiotics. Another benefit of a cluster design was the low cost. Remarkably, the authors reported that the 19 000-patient trial only cost $3 million US dollars in total – an average of $135 per patient.

Box 3. Example of an infection prevention policy (Adapted from ^{(2, 8, 26)})

Conclusion

Cardiac device infection is an important complication of cardiac device procedures that can be reduced with pre-procedural antibiotics. The PADIT trial was a large cluster randomized crossover study of over 19 000 patients who underwent cardiac device procedures. The study found that a single pre-procedural infusion of cefazolin (or vancomycin in penicillin allergy) had similar rates of hospitalisation for cardiac device infections as an incremental regime comprising pre-procedural cefazolin and vancomycin, intraprocedural pocket antibiotics and post procedural oral antibiotics. Overall hospitalization rates for cardiac device infection rates were low even in ‘high risk’ patients. Cardiac device implantation centres should utilise infection prevention policies to include a single pre-procedural dose of cefazolin (or vancomycin in penicillin allergy) in all patients undergoing cardiac device procedures; and have mechanisms in place to monitor their local infection rates. The PADIT Trial has provided a contemporary benchmark for 1-year hospitalisation for device infection rates (<1.2 %) which cardiac centres should aim to achieve even in ‘high risk’ populations.

References

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