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Antibiotic Prophylaxis by Teicoplanin and Risk of Acute Kidney Injury in Cardiac Surgery
Antibiotic Prophylaxis by Teicoplanin and Risk of Acute Kidney Injury in Cardiac Surgery Daniel P. Olsson, MD,* Martin J. Holzmann, MD, PhD,*† and Ulrik Sartipy, MD, PhD‡§ Objective: To investigate the risk of acute kidney injury (AKI) associated with antibiotic prophylaxis with teicoplanin in cardiac surgery. Design: Observational cohort study. Data were gathered from patient charts and national registers. Setting: University hospital. Participants: All adult patients who underwent cardiac surgery at the authors’ institution between January 1, 2010 and July 31, 2013 were eligible for the study. Interventions: The risk for AKI associated with teicoplanin prophylaxis was estimated by multivariate logistic regression. Measurements and Main Results: The primary endpoint, AKI, was defined according to the Acute Kidney Injury Network criteria stage 1, as an increase of postoperative serum creatinine by Z 26 μmol/L (Z0.3 mg/dL) or a relative increase of Z 50% compared to the preoperative value. The authors included 2,809 patients, and 1,056 (38%) received a combination of teicoplanin and cloxacillin for antibiotic prophylaxis. The remaining 1,753 (62%) patients received
only cloxacillin and constituted the control group. AKI occurred in 32% (n ¼ 343) in the teicoplanin group compared to 29% (n ¼ 517) in the control group. There was a significant association between antibiotic prophylaxis with teicoplanin and AKI; multivariate adjusted odds ratio (OR): 1.41 (95% confidence interval [CI] 1.18-1.70). There was a dose-dependent relationship; 600 mg OR: 1.48 (95% CI 1.171.87), and 400 mg OR: 1.34 (95% CI 1.06-1.71). The findings were confirmed in several subgroup analyses; men (OR: 1.27; 95% CI 1.03-1.56); women (OR: 1.90; 95% CI 1.30-2.80); normal renal function (OR: 1.31; 95% CI 1.07-1.60), and reduced renal function (OR: 1.80; 95% CI 1.13-2.85). Conclusions: Antibiotic prophylaxis with teicoplanin was associated with an increased risk of AKI after cardiac surgery. The relative risk of AKI was higher in women and in patients with impaired renal function. & 2015 Elsevier Inc. All rights reserved.
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acute kidney injury associated with antibiotic prophylaxis with teicoplanin in cardiac surgery. The hypothesis was that patients who received teicoplanin would have a higher risk for AKI compared to patients who received cloxacillin.
NTIBIOTIC PROPHYLAXIS IS STANDARD practice in cardiac surgery to prevent postoperative infections, but there is wide variation regarding antibiotic choice and duration of treatment.1,2 The glycopeptides teicoplanin and vancomycin are used frequently in cardiac surgery, mainly because of the effectiveness against methicillin-or beta-lactam-resistant bacteria.3 Teicoplanin is a possible alternative to vancomycin because of its excellent tissue penetration, 1-dose regimen, long half-time, and fewer nephrotoxic effects.4–6 However, both teicoplanin and vancomycin have been described as nephrotoxic.6 A randomized controlled trial compared the efficacy of teicoplanin and cefazolin for prophylaxis of surgical infections following elective cardiac surgery, and although safety endpoints were included in the study protocol, the risk of acute kidney injury (AKI) was not specifically addressed.7 AKI after cardiac surgery is common and is associated with increased short- and long-term mortality, mediastinitis, myocardial infarction, and heart failure.8–10 At present, there is no effective pharmacologic treatment of AKI,11 and, thus, prevention of AKI in patients undergoing cardiac surgery is critical. The objective of this study was to investigate the risk of
From the *Department of Medicine, Karolinska Institutet; †Department of Emergency Medicine, Karolinska University Hospital; ‡Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital; and §Department of Molecular Medicine and Surgery, Karolinska Institutet Stockholm, Sweden. Supported by unrestricted research grants from the Mats Kleberg Foundation. Address reprint request to Ulrik Sartipy, MD, PhD, Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. E-mail: Ulrik.Sartipy@ karolinska.se © 2015 Elsevier Inc. All rights reserved. 1053-0770/2601-0001$36.00/0 http://dx.doi.org/10.1053/j.jvca.2014.08.010 626
KEY WORDS: cardiac surgical procedure, prophylaxis, teicoplanin, acute kidney injury
antibiotic
METHODS
The study was approved by the Regional Ethical Review Board, Stockholm, Sweden (2012/1336-31/1). The need for patient consent was waived. All adult patients who underwent cardiac surgery at Karolinska University Hospital between January 1, 2010 and July 31, 2013 were eligible for the study (n ¼ 3,469). Information regarding patient characteristics and outcomes was gathered from patient charts and the SWEDEHEART (the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) registry.12 The exclusion criteria and number of patients are presented in Figure 1. The authors excluded patients who underwent pericardiectomy, surgery for postinfarction ventricular septum rupture, trauma, heart transplantation or left ventricular assist device implantation, or surgery on the aortic arch or descendent aorta; had active infectious endocarditis; underwent emergency procedures; had preoperative dialysis or estimated glomerular filtration rate (eGFR) o15 mL/min/1.73m2; those who died within the same day of surgery; or had missing information on teicoplanin treatment. Cardiopulmonary bypass was performed with centrifugal pumps with a flow rate of 2.4 L/m2 or more. From January 1, 2010 to December 5, 2011, the standard regimen for antibiotic prophylaxis during cardiac surgery was cloxacillin, 2 grams, given just before surgery and during surgery right after cardiopulmonary bypass, and thereafter every 8th hour over 48 hours. After December 5, 2011, the institutional policy for antibiotic prophylaxis was changed to a combination of teicoplanin and cloxacillin. Teicoplanin was administered intravenously right
Journal of Cardiothoracic and Vascular Anesthesia, Vol 29, No 3 (June), 2015: pp 626–631
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TEICOPLANIN PROPHYLAXIS IN CARDIAC SURGERY
Fig 1. Exclusion criteria among all adult patients who underwent cardiac surgery at Karolinska University Hospital between January 1, 2010 and July 31, 2013. Procedures performed in low volumes included pericardiectomy, ventricular septum rupture repair after myocardial infarction, trauma, left ventricular reconstruction, heart transplantation, and surgery for thoracoabdominal aortic aneurysms.
before the start of the operation. The recommended teicoplanin dose was 400 mg for patients o 80 kg and 600 mg in patients 4 80 kg. Patients with penicillin allergy were treated with clindamycin, 600 mg intravenously, instead of cloxacillin. From December 1, 2011, all patients’ charts were accessed to verify if the patients had received teicoplanin and to confirm the dose administered. The exposure in this study was treatment with the combination of teicoplanin and cloxacillin, and the control group consisted of patients treated only with cloxacillin. The primary outcome was AKI, and was defined using preand postoperative serum creatinine values. Preoperative serum creatinine samples normally were taken within 24 hours before surgery. The postoperative serum creatinine value was the highest value during the postoperative stay. Acute kidney injury was defined according to Acute Kidney Injury Network classification stage 1 as an increase of postoperative serum
creatinine by Z 26 mmol/L or a relative increase of Z 50% compared to the preoperative value.13 Glomerular filtration rates were calculated using the simplified Modification of Diet in Renal Disease study equation.14 Chronic kidney disease was defined according to the American National Kidney Foundation guidelines as a glomerular filtration rate o60 mL/min/1.73 m2.15 Left ventricular function was assessed from echocardiography before surgery and was categorized as normal (ejection fraction 4 50%), reduced (ejection fraction 30%-50%), or severely reduced (ejection fraction o 30%). Diagnosis of diabetes and chronic obstructive pulmonary disease was made on the basis of patients’ (CK-MB) ongoing pharmacologic treatment. Postoperative creatine kinase MB was the highest value within the first day after surgery. Preoperative hemoglobin concentration samples normally were taken within 24 hours before surgery. Peripheral vascular disease was defined as previous surgery on the carotid artery, iliac artery, abdominal aorta, or presence of claudication. Patient characteristics were described with frequencies and percentages for categoric variables. Continuous variables were described with means and standard deviations. Logistic regression was used to study the association between teicoplanin and AKI. Odds ratios (OR) of developing AKI were calculated with 95% confidence intervals (CI) and were reported as crude, adjusted for age and sex, and multivariate adjusted. The final multivariate-adjusted model was constructed after considering all baseline characteristics and primary interaction terms. The following variables were included in the final model: Age, sex, eGFR, left ventricular ejection fraction, diabetes mellitus, deep hypothermic circulatory arrest, chronic obstructive pulmonary disease, preoperative hemoglobin concentration, postoperative CK-MB, and body mass index. The continuous variables age, eGFR, hemoglobin concentration, body mass index, and CKMB were modelled using restricted cubic splines with 3 knots. Left ventricular ejection fraction was used as a 3-level categoric variable (normal, reduced, and severely reduced). The authors also performed several sensitivity analyses to assess the robustness of their results. First, serum creatinine was included in the multivariate models instead of eGFR as a measure of preoperative renal function. Then, the eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) formula.16 Because postoperative deep surgical site infections are related to AKI, the authors reanalyzed their data after excluding patients who developed deep sternal wound infections. The authors performed 4 prespecified subgroup analyses. The relative risk of AKI in patients treated with teicoplanin was analyzed separately in men and women, in patients with normal or reduced preoperative renal function (eGFR 460 or o60 mL/min/1.73 m2), in patients who received low or high dose of teicoplanin (400 mg or 600 mg), and, finally, according to type of surgical procedure (isolated coronary artery bypass surgery versus other type of procedure). Data management and statistical analyses were performed using Stata 13.1 (StataCorp, College Station, TX). RESULTS
A total of 2,809 consecutive patients were included in the study (Fig 1). Of these, 1,056 (38%) received antibiotic
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Table 1. Baseline and Operative Characteristics of the Study Population in Relation to Treatment With Teicoplanin All Patients
Number of patients and (%) Age (SD), yr Female sex (%) eGFR (SD), mL/min/1.73 m2 Preop. SCr (SD), μmol/L Preop. SCr (SD), mg/dL Diabetes mellitus (%) Peripheral vascular disease (%) Hemoglobin (SD), g/L COPD (%) Recent myocardial infarction (%) Prior stroke (%) Left ventricular function Ejection fraction 4 0.5 (%) Ejection fraction 0.3-0.5 (%) Ejection fraction o 0.3 (%) Type of surgery Isolated CABG (%) Isolated valve surgery (%) Other (%) Cardiopulmonary bypass (%) Deep hypothermic circulatory arrest (%) CK-MB postop day 1 (SD), μg/L
2809 66 731 82 87 0.98 575 246 137 262 634 200
(100) (12) (26) (22) (24) (0.28) (21) (8.8) (15) (9.3) (23) (7.1)
Control
1,056 66 460 80 88 1.00 360 151 136 169 407 120
1,864 (66) 775 (28) 170 (6.1)
1,177 (67) 454 (26) 122 (6.7)
1225 901 683 2795 53 22
770 571 412 1744 26 22
(44) (32) (24) (99.5) (1.9) (30)
Teicoplanin
(38) (12) (26) (23) (25) (0.28) (21) (8.6) (15) (9.6) (23) (6.9)
1,753 66 271 84 84 0.95 215 95 138 93 227 80
(62) (11) (26) (21) (23) (0.26) (20) (9.0) (15) (8.8) (22) (7.6)
687 (65) 321 (31) 48 (4.6)
(44) (33) (24) (99.5) (1.5) (26)
455 330 271 1051 27 22
(43) (31) (26) (99.5) (2.6) (36)
p Value
0.277 0.735 o0.001 o0.001 o0.001 0.911 0.728 0.005 0.462 0.291 0.466 0.257 0.010 0.009 0.665 0.467 0.196 0.884 0.043 0.479
NOTE. Age, glomerular filtration rate, and serum creatinine values are given as means with standard deviations. Acute kidney injury was classified according to the Acute Kidney Injury Network classification stage 1: Z 26 μmol/L or Z 50% increase in serum creatinine. Abbreviations: CABG, coronary artery bypass grafting; CK-MB, creatine kinase MB; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; Preop, preoperatively; Postop, postoperatively; SCr, serum creatinine; SD, standard deviation.
prophylaxis with teicoplanin and the remaining 1,753 (62%) patients constituted the control group. During the study period, when teicoplanin was part of the standard protocol for cardiac surgery antibiotic prophylaxis, 139 patients (11.6%) did not receive teicoplanin. Of these 139 patients, 78% received cloxacillin, 22% clindamycin, 1% cloxacillin þ imipenem, and they were included in the control group. Baseline and operative characteristics in the teicoplanin group and the control group are shown in Table 1. The unadjusted and multivariate adjusted risks for AKI in patients treated with teicoplanin compared with the control group are shown in Table 2. Among patients treated with teicoplanin, 343 (32%) patients developed AKI compared to 517 (29%) patients in the control group; unadjusted OR 1.15 (95% CI 0.98-1.36). After multivariate adjustment, there was an independent and statistically significant association between antibiotic prophylaxis with teicoplanin and AKI; adjusted OR 1.40 (95% CI 1.17-1.68). The relationship between age, hemoglobin, eGFR, CK-MB, and the multivariate-adjusted ORs and 95% CIs for AKI are shown in Figure 2. Death within 30 days occurred in 9 (0.85 %) patients in the teicoplanin group and in 29 (1.65 %) patients in the control group (p ¼ 0.075). Deep sternal wound infections requiring surgical exploration occurred in 12 (1.14 %) patients in the teicoplanin group and in 34 (1.94%) patients in the control group (p ¼ 0.104). Multivariate analyses for the secondary outcomes were not performed because of the low number of events. There was a statistically significant association between teicoplanin prophylaxis and AKI in both men (OR: 1.27; 95%
CI 1.03-1.56) and women (OR: 1.90; 95% CI 1.30-2.80), as shown in Table 3. There was a statistically significant association between teicoplanin prophylaxis and AKI in patients with normal renal function (eGFR 4 60 mL/min/ 1.73 m2); OR 1.31 (95% CI 1.07 to 1.60), and in patients with reduced renal function (eGFR 15 to 60 mL/min/1.73 m2); OR 1.80 (95% CI 1.13 to 2.85) as shown in Table 4. There was a dose-dependent relationship between teicoplanin and AKI. The OR for AKI was 1.34 (95% CI 1.05-1.70) in patients who were treated with 400-mg doses of teicoplanin, and the OR was 1.46 (1.15-1.84) in patients treated with 600-mg doses, compared to the control group. In patients undergoing isolated coronary artery bypass grafting (CABG), the odds ratio for Table 2. Risk for Acute Kidney Injury Following Cardiac Surgery With Teicoplanin Antibiotic Prophylaxis All patients
Number of patients (%) Number of events (%)
2,809 (100) 860 (31)
Crude Adjustment for age and sex Multivariate adjustment†
Control*
Teicoplanin
1,753 (62) 1,056 (38) 517 (29) 343 (32) Odds Ratio (95% CI) 1.0 1.15 (0.98-1.36) 1.0 1.20 (1.01-1.42) 1.0 1.40 (1.18-1.68)
Abbreviations: CI, confidence interval. *Reference category †Multivariate adjustment was made for: Age, sex, estimated glomerular filtration rate, left ventricular ejection fraction, diabetes mellitus, deep hypothermic circulatory arrest, chronic obstructive pulmonary disease, preoperative hemoglobin concentration, creatine kinase MB, and body mass index.
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TEICOPLANIN PROPHYLAXIS IN CARDIAC SURGERY
Fig 2. The graph shows the relationship between age, hemoglobin, estimated glomerular filtration rate, creatine kinase (CK-MB), and the multivariate adjusted ORs and 95% CIs for acute kidney injury. All continuous variables were modeled by restricted cubic splines with three knots in a logistic regression model. The reference levels were set at 50 years (age), 130 g/L (hemoglobin), 90 mL/min per 1.73 m2 (estimated glomerular filtration rate), and 20 lg/L (CK-MB) for the estimation of odds ratios. The logistic model was adjusted for treatment group (teicoplanin or control), age, sex, estimated glomerular filtration rate, left ventricular ejection fraction, diabetes, deep hypothermic circulatory arrest, chronic obstructive pulmonary disease, hemoglobin, CK-MB, and body mass index.
Table 3. Risk for Acute Kidney Injury Following Cardiac Surgery With Teicoplanin Stratified By Sex All Patients
Men Number of patients (%) Number of events (%) Crude Multivariate adjustment† Women Number of patients Number of events Crude Multivariate adjustment†
2,078 (100) 651 (31)
731 (100) 209 (29)
Control*
Teicoplanin
1,293 (62) 785 (38) 399 (31) 252 (32) Odds Ratio (95% CI) 1.00 1.06 (0.88-1.28) 1.00 1.27 (1.03-1.56) 460 (63) 271 (37) 118 (26) 91 (34) Odds Ratio (95% CI) 1.00 1.47 (1.06-2.03) 1.00 1.90 (1.30-2.80)
Abbreviation: CI, confidence interval. *Reference category †Multivariate adjustment was made for: Age, estimated glomerular filtration rate, left ventricular ejection fraction, diabetes mellitus, deep hypothermic circulatory arrest, chronic obstructive pulmonary disease, preoperative hemoglobin concentration, postoperative creatine kinase MB, and body mass index.
Table 4. Risk for Acute Kidney Injury Following Cardiac Surgery With Teicoplanin Stratified By Preoperative Renal Function All Patients
eGFR 460 mL/min/1.73 m2 Number of patients (%) 2,365 (100) Number of events (%) 619 (26) Crude Multivariate adjustment† eGFR 15-60 mL/min/1.73 m2 Number of patients 444 (100) Number of events 241 (54) Crude Multivariate adjustment†
Control*
Teicoplanin
1,423 (60) 942 (40) 348 (24) 271 (29) Odds Ratio (95% CI) 1.00 1.25 (1.04-1.50) 1.00 1.31 (1.07-1.60) 330 (74) 114 (26) 169 (51) 72 (63) Odds Ratio (95% CI) 1.00 1.63 (1.05-2.53) 1.00 1.80 (1.13-2.85)
Abbreviations: CI, confidence interval; eGFR, estimated glomerular filtration rate *Reference category †Multivariate adjustment was made for: Age, sex, left ventricular ejection fraction, diabetes mellitus, deep hypothermic circulatory arrest, chronic obstructive pulmonary disease, preoperative hemoglobin concentration, postoperative creatine kinase MB, and body mass index.
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OLSSON ET AL
AKI was 1.31 (95% CI 0.99-1.73) after multivariate adjustment; and in patients undergoing a procedure other than isolated CABG, the odds ratio for AKI was 1.50 (95% CI 1.18-1.92) in patients who received teicoplanin. The authors repeated the multivariate analyses and replaced the assessment of preoperative renal function with eGFR according to the CKD-EPI formula, and also with serum creatinine, and the results essentially were unchanged; adjusted OR 1.40 (95% CI 1.16-1.68) and OR 1.37 (95% CI 1.15-1.65), respectively. The authors also repeated the analysis after excluding patients with deep sternal wound infection, because these patients are at high risk for AKI, and the results were very similar; adjusted OR 1.43 (95% CI 1.19-1.72). DISCUSSION
The main finding of this study was that antibiotic prophylaxis with teicoplanin during cardiac surgery was associated with an increased risk of AKI. Supplementary subgroup analyses confirmed the authors’ findings in men and women and in patients with reduced renal function. The authors also found a dosedependent relationship with a higher risk of AKI in patients treated with a higher dose of teicoplanin. The authors’ finding was robust to different estimations of renal function and also to exclusion of patients with postoperative deep sternal wound infection, as demonstrated in sensitivity analyses. Acute kidney injury after heart surgery is associated with increased short- and long-term mortality, risk of myocardial infarction and heart failure.9,10 Even minimal increases of 0 to 26 mmol/L in postoperative serum creatinine are associated with increased short- and long-term mortality.17,18 Tolpin et al18 found that a subclinical change in serum creatinine between 0 and 0.2 mg/dL was associated independently with 30-day all-cause mortality in patients with normal renal function or preoperative renal insufficiency undergoing CABG. The authors’ group recently reported that a minimal increase in serum creatinine (0-0.3 mg/dL) was associated independently with long-term allcause mortality and cardiovascular outcomes, regardless of preoperative renal function in more than 25,000 patients who underwent CABG.17 Acute kidney injury also is associated with development of chronic kidney disease.19 The negative influence on renal function associated with antibiotic prophylaxis with teicoplanin, therefore, should be taken into consideration when developing protocols for antibiotic prophylaxis in cardiac surgery. The authors found certain risk groups that were more susceptible to AKI: Female patients and patients with impaired preoperative renal function (eGFRo 60 mL/min/1.73m2). The mechanism by which the glycopeptides teicoplanin and vancomycin potentially impair renal function largely is unknown though some studies suggest that vancomycin causes oxidative stress.20 Teicoplanin is largely excreted in the urine unmetabolized. In healthy patients approximately 50% of the administered dose is excreted in the urine within the first
48 hours and 80% within 16 days.21 There have been several reports on biopsy-confirmed acute tubular necrosis and interstitial nephritis in humans after vancomycin treatment.22,23 A meta-analysis comparing the nephrotoxic effects of teicoplanin and vancomycin found teicoplanin safer.6 This also has been shown in a study on rats.5 Cephalosporins today are used widely as primary prophylaxis in cardiac surgery. The most frequent agents in surgical site infections after cardiac surgery are Staphylococcus aureus, coagulase-negative staphylococci and Enterobacteriaceae.24 In animal models, beta-lactams have been found to be more effective against endocarditis from methicillin-susceptible gram-positive bacteria than glycopeptides.25 At times glycopeptides are used as adjuvant, often due to the concern about methicillin-resistant staphylococci.3 One disadvantage of using aminoglycosides is the risk of resistance development.3 The authors’ study identified a clinically important side effect of teicoplanin prophylaxis in cardiac surgery, which previously was not reported. The observed higher risk for AKI should be included in the risk-benefit analysis regarding choice of antibiotic prophylactic regimen in cardiac surgery. The authors identified patient subgroups with particularly high risk for AKI after antibiotic prophylaxis with teicoplanin, and in their opinion it would be reasonable to consider an alternative treatment strategy in women with impaired renal function. Study Limitations The main limitation of this study was that treatment allocation was not randomized. However, selection bias should be minimized by that fact that patients were included consecutively during the study period, and the protocol for antibiotic prophylaxis was determined by institutional directives. Therefore, teicoplanin prophylaxis was introduced from one day to another. Because it was a single-center study, there were minimal differences in pre-, peri-, and postoperative care. The authors addressed potential selection bias by multivariate regression adjustment, but still there may be unmeasured or unknown factors related to the outcome for which they were not able to account. Because of study design, the authors had no possibility to make statements regarding causality or mechanisms. Because the study included patients who had surgery during a period of 4 years, the authors cannot rule out that minor changes in the perioperative or surgical care may have influenced the results. Another limitation was that the authors did not have information regarding cardiopulmonary bypass times. CONCLUSIONS
Teicoplanin was associated with an increased risk of acute kidney injury. The risk of acute kidney injury was higher in women and in patients with decreased glomerular filtration rate.
REFERENCES 1. Edwards FH, Engelman RM, Houck P, et al: The Society of Thoracic Surgeons Practice Guideline Series: Antibiotic prophylaxis in cardiac surgery, Part I: Duration. Ann Thorac Surg 81:397-404, 2006 2. Engelman R, Shahian D, Shemin R, et al: The Society of Thoracic Surgeons practice guideline series: Antibiotic prophylaxis in
cardiac surgery, Part II: Antibiotic choice. Ann Thorac Surg 83: 1569-1576, 2007 3. Zanetti G, Platt R: Antibiotic prophylaxis for cardiac surgery: does the past predict the future? Clin Infect Dis 38:1364-1366, 2004
TEICOPLANIN PROPHYLAXIS IN CARDIAC SURGERY
4. Mini E, Nobili S, Periti P: Does surgical prophylaxis with teicoplanin constitute a therapeutic advance? J Chemother 12(suppl):40-55, 2000 5. Yoshiyama Y, Yazaki T, Kanke M, et al: Nephrotoxicity of teicoplanin in rats. Jpn J Antibiot 53:660-666, 2000 6. Svetitsky S, Leibovici L, Paul M: Comparative efficacy and safety of vancomycin versus teicoplanin: systematic review and metaanalysis. Antimicrob Agents Chemother 53:4069-4079, 2009 7. Saginur R, Croteau D, Bergeron MG: Comparative efficacy of teicoplanin and cefazolin for cardiac operation prophylaxis in 3027 patients. The ESPRIT Group. J Thorac Cardiovasc Surg 120: 1120-1130, 2000 8. Dasta JF, Kane-Gill SL, Durtschi AJ, et al: Costs and outcomes of acute kidney injury (AKI) following cardiac surgery. Nephrol Dial Transplant 23:1970-1974, 2008 9. Rydén L, Ahnve S, Bell M, et al: Acute kidney injury after coronary artery bypass grafting and long-term risk of myocardial infarction and death. Int J Cardiol 172:190-195, 2014 10. Olsson D, Sartipy U, Braunschweig F, et al: Acute kidney injury following coronary artery bypass surgery and long-term risk of heart failure. Circ Heart Fail 6:83-90, 2013 11. Okusa MD, Molitoris BA, Palevsky PM, et al: Design of clinical trials in acute kidney injury: a report from an NIDDK workshop–prevention trials. Clin J Am Soc Nephrol 7:851-855, 2012 12. Jernberg T, Attebring MF, Hambraeus K, et al: The Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART). Heart 96:1617-1621, 2010 13. Mehta RL, Kellum JA, Shah SV, et al: Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 11:R31, 2007 14. Levey AS, Bosch JP, Lewis JB, et al: A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461-470, 1999
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15. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 39: S1-266, 2002 16. Levey AS, Stevens LA, Schmid CH, et al: A new equation to estimate glomerular filtration rate. Ann Intern Med 150:604 612, 2009 17. Liotta M, Olsson D, Sartipy U, et al: Minimal changes in postoperative creatinine values and early and late mortality and cardiovascular events after coronary artery bypass grafting. Am J Cardiol 113:70-75, 2014 18. Tolpin DA, Collard CD, Lee V-V, et al: Subclinical changes in serum creatinine and mortality after coronary artery bypass grafting. J Thorac Cardiovasc Surg 143:682-688, 2012 19. Coca SG, Singanamala S, Parikh CR: Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int 81:442-448, 2012 20. Celik I, Cihangiroglu M, Ilhan N, et al: Protective effects of different antioxidants and amrinone on vancomycin-induced nephrotoxicity. Basic Clin Pharmacol Toxicol 97:325-332, 2005 21. Buniva G, Del Favero A, Bernareggi A, et al: Pharmacokinetics of 14C-teicoplanin in healthy volunteers. J Antimicrob Chemother 21 Suppl A:23-28, 1988 22. Codding CE, Ramseyer L, Allon M, et al: Tubulointerstitial nephritis due to vancomycin. Am J Kidney Dis 14:512-515, 1989 23. Wu C-Y, Wang J-S, Chiou Y-H, et al: Biopsy proven acute tubular necrosis associated with vancomycin in a child: case report and literature review. Ren Fail 29:1059-1061, 2007 24. Lepelletier D, Perron S, Bizouarn P, et al: Surgical-site infection after cardiac surgery: incidence, microbiology, and risk factors. Infect Control Hosp Epidemiol 26:466-472, 2005 25. Chambers HF, Sande MA: Teicoplanin versus nafcillin and vancomycin in the treatment of experimental endocarditis caused by methicillin-susceptible or -resistant Staphylococcus aureus. Antimicrob Agents Chemother 26:61-64, 1984
only cloxacillin and constituted the control group. AKI occurred in 32% (n ¼ 343) in the teicoplanin group compared to 29% (n ¼ 517) in the control group. There was a significant association between antibiotic prophylaxis with teicoplanin and AKI; multivariate adjusted odds ratio (OR): 1.41 (95% confidence interval [CI] 1.18-1.70). There was a dose-dependent relationship; 600 mg OR: 1.48 (95% CI 1.171.87), and 400 mg OR: 1.34 (95% CI 1.06-1.71). The findings were confirmed in several subgroup analyses; men (OR: 1.27; 95% CI 1.03-1.56); women (OR: 1.90; 95% CI 1.30-2.80); normal renal function (OR: 1.31; 95% CI 1.07-1.60), and reduced renal function (OR: 1.80; 95% CI 1.13-2.85). Conclusions: Antibiotic prophylaxis with teicoplanin was associated with an increased risk of AKI after cardiac surgery. The relative risk of AKI was higher in women and in patients with impaired renal function. & 2015 Elsevier Inc. All rights reserved.
A
acute kidney injury associated with antibiotic prophylaxis with teicoplanin in cardiac surgery. The hypothesis was that patients who received teicoplanin would have a higher risk for AKI compared to patients who received cloxacillin.
NTIBIOTIC PROPHYLAXIS IS STANDARD practice in cardiac surgery to prevent postoperative infections, but there is wide variation regarding antibiotic choice and duration of treatment.1,2 The glycopeptides teicoplanin and vancomycin are used frequently in cardiac surgery, mainly because of the effectiveness against methicillin-or beta-lactam-resistant bacteria.3 Teicoplanin is a possible alternative to vancomycin because of its excellent tissue penetration, 1-dose regimen, long half-time, and fewer nephrotoxic effects.4–6 However, both teicoplanin and vancomycin have been described as nephrotoxic.6 A randomized controlled trial compared the efficacy of teicoplanin and cefazolin for prophylaxis of surgical infections following elective cardiac surgery, and although safety endpoints were included in the study protocol, the risk of acute kidney injury (AKI) was not specifically addressed.7 AKI after cardiac surgery is common and is associated with increased short- and long-term mortality, mediastinitis, myocardial infarction, and heart failure.8–10 At present, there is no effective pharmacologic treatment of AKI,11 and, thus, prevention of AKI in patients undergoing cardiac surgery is critical. The objective of this study was to investigate the risk of
From the *Department of Medicine, Karolinska Institutet; †Department of Emergency Medicine, Karolinska University Hospital; ‡Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital; and §Department of Molecular Medicine and Surgery, Karolinska Institutet Stockholm, Sweden. Supported by unrestricted research grants from the Mats Kleberg Foundation. Address reprint request to Ulrik Sartipy, MD, PhD, Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. E-mail: Ulrik.Sartipy@ karolinska.se © 2015 Elsevier Inc. All rights reserved. 1053-0770/2601-0001$36.00/0 http://dx.doi.org/10.1053/j.jvca.2014.08.010 626
KEY WORDS: cardiac surgical procedure, prophylaxis, teicoplanin, acute kidney injury
antibiotic
METHODS
The study was approved by the Regional Ethical Review Board, Stockholm, Sweden (2012/1336-31/1). The need for patient consent was waived. All adult patients who underwent cardiac surgery at Karolinska University Hospital between January 1, 2010 and July 31, 2013 were eligible for the study (n ¼ 3,469). Information regarding patient characteristics and outcomes was gathered from patient charts and the SWEDEHEART (the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) registry.12 The exclusion criteria and number of patients are presented in Figure 1. The authors excluded patients who underwent pericardiectomy, surgery for postinfarction ventricular septum rupture, trauma, heart transplantation or left ventricular assist device implantation, or surgery on the aortic arch or descendent aorta; had active infectious endocarditis; underwent emergency procedures; had preoperative dialysis or estimated glomerular filtration rate (eGFR) o15 mL/min/1.73m2; those who died within the same day of surgery; or had missing information on teicoplanin treatment. Cardiopulmonary bypass was performed with centrifugal pumps with a flow rate of 2.4 L/m2 or more. From January 1, 2010 to December 5, 2011, the standard regimen for antibiotic prophylaxis during cardiac surgery was cloxacillin, 2 grams, given just before surgery and during surgery right after cardiopulmonary bypass, and thereafter every 8th hour over 48 hours. After December 5, 2011, the institutional policy for antibiotic prophylaxis was changed to a combination of teicoplanin and cloxacillin. Teicoplanin was administered intravenously right
Journal of Cardiothoracic and Vascular Anesthesia, Vol 29, No 3 (June), 2015: pp 626–631
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Fig 1. Exclusion criteria among all adult patients who underwent cardiac surgery at Karolinska University Hospital between January 1, 2010 and July 31, 2013. Procedures performed in low volumes included pericardiectomy, ventricular septum rupture repair after myocardial infarction, trauma, left ventricular reconstruction, heart transplantation, and surgery for thoracoabdominal aortic aneurysms.
before the start of the operation. The recommended teicoplanin dose was 400 mg for patients o 80 kg and 600 mg in patients 4 80 kg. Patients with penicillin allergy were treated with clindamycin, 600 mg intravenously, instead of cloxacillin. From December 1, 2011, all patients’ charts were accessed to verify if the patients had received teicoplanin and to confirm the dose administered. The exposure in this study was treatment with the combination of teicoplanin and cloxacillin, and the control group consisted of patients treated only with cloxacillin. The primary outcome was AKI, and was defined using preand postoperative serum creatinine values. Preoperative serum creatinine samples normally were taken within 24 hours before surgery. The postoperative serum creatinine value was the highest value during the postoperative stay. Acute kidney injury was defined according to Acute Kidney Injury Network classification stage 1 as an increase of postoperative serum
creatinine by Z 26 mmol/L or a relative increase of Z 50% compared to the preoperative value.13 Glomerular filtration rates were calculated using the simplified Modification of Diet in Renal Disease study equation.14 Chronic kidney disease was defined according to the American National Kidney Foundation guidelines as a glomerular filtration rate o60 mL/min/1.73 m2.15 Left ventricular function was assessed from echocardiography before surgery and was categorized as normal (ejection fraction 4 50%), reduced (ejection fraction 30%-50%), or severely reduced (ejection fraction o 30%). Diagnosis of diabetes and chronic obstructive pulmonary disease was made on the basis of patients’ (CK-MB) ongoing pharmacologic treatment. Postoperative creatine kinase MB was the highest value within the first day after surgery. Preoperative hemoglobin concentration samples normally were taken within 24 hours before surgery. Peripheral vascular disease was defined as previous surgery on the carotid artery, iliac artery, abdominal aorta, or presence of claudication. Patient characteristics were described with frequencies and percentages for categoric variables. Continuous variables were described with means and standard deviations. Logistic regression was used to study the association between teicoplanin and AKI. Odds ratios (OR) of developing AKI were calculated with 95% confidence intervals (CI) and were reported as crude, adjusted for age and sex, and multivariate adjusted. The final multivariate-adjusted model was constructed after considering all baseline characteristics and primary interaction terms. The following variables were included in the final model: Age, sex, eGFR, left ventricular ejection fraction, diabetes mellitus, deep hypothermic circulatory arrest, chronic obstructive pulmonary disease, preoperative hemoglobin concentration, postoperative CK-MB, and body mass index. The continuous variables age, eGFR, hemoglobin concentration, body mass index, and CKMB were modelled using restricted cubic splines with 3 knots. Left ventricular ejection fraction was used as a 3-level categoric variable (normal, reduced, and severely reduced). The authors also performed several sensitivity analyses to assess the robustness of their results. First, serum creatinine was included in the multivariate models instead of eGFR as a measure of preoperative renal function. Then, the eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) formula.16 Because postoperative deep surgical site infections are related to AKI, the authors reanalyzed their data after excluding patients who developed deep sternal wound infections. The authors performed 4 prespecified subgroup analyses. The relative risk of AKI in patients treated with teicoplanin was analyzed separately in men and women, in patients with normal or reduced preoperative renal function (eGFR 460 or o60 mL/min/1.73 m2), in patients who received low or high dose of teicoplanin (400 mg or 600 mg), and, finally, according to type of surgical procedure (isolated coronary artery bypass surgery versus other type of procedure). Data management and statistical analyses were performed using Stata 13.1 (StataCorp, College Station, TX). RESULTS
A total of 2,809 consecutive patients were included in the study (Fig 1). Of these, 1,056 (38%) received antibiotic
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Table 1. Baseline and Operative Characteristics of the Study Population in Relation to Treatment With Teicoplanin All Patients
Number of patients and (%) Age (SD), yr Female sex (%) eGFR (SD), mL/min/1.73 m2 Preop. SCr (SD), μmol/L Preop. SCr (SD), mg/dL Diabetes mellitus (%) Peripheral vascular disease (%) Hemoglobin (SD), g/L COPD (%) Recent myocardial infarction (%) Prior stroke (%) Left ventricular function Ejection fraction 4 0.5 (%) Ejection fraction 0.3-0.5 (%) Ejection fraction o 0.3 (%) Type of surgery Isolated CABG (%) Isolated valve surgery (%) Other (%) Cardiopulmonary bypass (%) Deep hypothermic circulatory arrest (%) CK-MB postop day 1 (SD), μg/L
2809 66 731 82 87 0.98 575 246 137 262 634 200
(100) (12) (26) (22) (24) (0.28) (21) (8.8) (15) (9.3) (23) (7.1)
Control
1,056 66 460 80 88 1.00 360 151 136 169 407 120
1,864 (66) 775 (28) 170 (6.1)
1,177 (67) 454 (26) 122 (6.7)
1225 901 683 2795 53 22
770 571 412 1744 26 22
(44) (32) (24) (99.5) (1.9) (30)
Teicoplanin
(38) (12) (26) (23) (25) (0.28) (21) (8.6) (15) (9.6) (23) (6.9)
1,753 66 271 84 84 0.95 215 95 138 93 227 80
(62) (11) (26) (21) (23) (0.26) (20) (9.0) (15) (8.8) (22) (7.6)
687 (65) 321 (31) 48 (4.6)
(44) (33) (24) (99.5) (1.5) (26)
455 330 271 1051 27 22
(43) (31) (26) (99.5) (2.6) (36)
p Value
0.277 0.735 o0.001 o0.001 o0.001 0.911 0.728 0.005 0.462 0.291 0.466 0.257 0.010 0.009 0.665 0.467 0.196 0.884 0.043 0.479
NOTE. Age, glomerular filtration rate, and serum creatinine values are given as means with standard deviations. Acute kidney injury was classified according to the Acute Kidney Injury Network classification stage 1: Z 26 μmol/L or Z 50% increase in serum creatinine. Abbreviations: CABG, coronary artery bypass grafting; CK-MB, creatine kinase MB; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; Preop, preoperatively; Postop, postoperatively; SCr, serum creatinine; SD, standard deviation.
prophylaxis with teicoplanin and the remaining 1,753 (62%) patients constituted the control group. During the study period, when teicoplanin was part of the standard protocol for cardiac surgery antibiotic prophylaxis, 139 patients (11.6%) did not receive teicoplanin. Of these 139 patients, 78% received cloxacillin, 22% clindamycin, 1% cloxacillin þ imipenem, and they were included in the control group. Baseline and operative characteristics in the teicoplanin group and the control group are shown in Table 1. The unadjusted and multivariate adjusted risks for AKI in patients treated with teicoplanin compared with the control group are shown in Table 2. Among patients treated with teicoplanin, 343 (32%) patients developed AKI compared to 517 (29%) patients in the control group; unadjusted OR 1.15 (95% CI 0.98-1.36). After multivariate adjustment, there was an independent and statistically significant association between antibiotic prophylaxis with teicoplanin and AKI; adjusted OR 1.40 (95% CI 1.17-1.68). The relationship between age, hemoglobin, eGFR, CK-MB, and the multivariate-adjusted ORs and 95% CIs for AKI are shown in Figure 2. Death within 30 days occurred in 9 (0.85 %) patients in the teicoplanin group and in 29 (1.65 %) patients in the control group (p ¼ 0.075). Deep sternal wound infections requiring surgical exploration occurred in 12 (1.14 %) patients in the teicoplanin group and in 34 (1.94%) patients in the control group (p ¼ 0.104). Multivariate analyses for the secondary outcomes were not performed because of the low number of events. There was a statistically significant association between teicoplanin prophylaxis and AKI in both men (OR: 1.27; 95%
CI 1.03-1.56) and women (OR: 1.90; 95% CI 1.30-2.80), as shown in Table 3. There was a statistically significant association between teicoplanin prophylaxis and AKI in patients with normal renal function (eGFR 4 60 mL/min/ 1.73 m2); OR 1.31 (95% CI 1.07 to 1.60), and in patients with reduced renal function (eGFR 15 to 60 mL/min/1.73 m2); OR 1.80 (95% CI 1.13 to 2.85) as shown in Table 4. There was a dose-dependent relationship between teicoplanin and AKI. The OR for AKI was 1.34 (95% CI 1.05-1.70) in patients who were treated with 400-mg doses of teicoplanin, and the OR was 1.46 (1.15-1.84) in patients treated with 600-mg doses, compared to the control group. In patients undergoing isolated coronary artery bypass grafting (CABG), the odds ratio for Table 2. Risk for Acute Kidney Injury Following Cardiac Surgery With Teicoplanin Antibiotic Prophylaxis All patients
Number of patients (%) Number of events (%)
2,809 (100) 860 (31)
Crude Adjustment for age and sex Multivariate adjustment†
Control*
Teicoplanin
1,753 (62) 1,056 (38) 517 (29) 343 (32) Odds Ratio (95% CI) 1.0 1.15 (0.98-1.36) 1.0 1.20 (1.01-1.42) 1.0 1.40 (1.18-1.68)
Abbreviations: CI, confidence interval. *Reference category †Multivariate adjustment was made for: Age, sex, estimated glomerular filtration rate, left ventricular ejection fraction, diabetes mellitus, deep hypothermic circulatory arrest, chronic obstructive pulmonary disease, preoperative hemoglobin concentration, creatine kinase MB, and body mass index.
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Fig 2. The graph shows the relationship between age, hemoglobin, estimated glomerular filtration rate, creatine kinase (CK-MB), and the multivariate adjusted ORs and 95% CIs for acute kidney injury. All continuous variables were modeled by restricted cubic splines with three knots in a logistic regression model. The reference levels were set at 50 years (age), 130 g/L (hemoglobin), 90 mL/min per 1.73 m2 (estimated glomerular filtration rate), and 20 lg/L (CK-MB) for the estimation of odds ratios. The logistic model was adjusted for treatment group (teicoplanin or control), age, sex, estimated glomerular filtration rate, left ventricular ejection fraction, diabetes, deep hypothermic circulatory arrest, chronic obstructive pulmonary disease, hemoglobin, CK-MB, and body mass index.
Table 3. Risk for Acute Kidney Injury Following Cardiac Surgery With Teicoplanin Stratified By Sex All Patients
Men Number of patients (%) Number of events (%) Crude Multivariate adjustment† Women Number of patients Number of events Crude Multivariate adjustment†
2,078 (100) 651 (31)
731 (100) 209 (29)
Control*
Teicoplanin
1,293 (62) 785 (38) 399 (31) 252 (32) Odds Ratio (95% CI) 1.00 1.06 (0.88-1.28) 1.00 1.27 (1.03-1.56) 460 (63) 271 (37) 118 (26) 91 (34) Odds Ratio (95% CI) 1.00 1.47 (1.06-2.03) 1.00 1.90 (1.30-2.80)
Abbreviation: CI, confidence interval. *Reference category †Multivariate adjustment was made for: Age, estimated glomerular filtration rate, left ventricular ejection fraction, diabetes mellitus, deep hypothermic circulatory arrest, chronic obstructive pulmonary disease, preoperative hemoglobin concentration, postoperative creatine kinase MB, and body mass index.
Table 4. Risk for Acute Kidney Injury Following Cardiac Surgery With Teicoplanin Stratified By Preoperative Renal Function All Patients
eGFR 460 mL/min/1.73 m2 Number of patients (%) 2,365 (100) Number of events (%) 619 (26) Crude Multivariate adjustment† eGFR 15-60 mL/min/1.73 m2 Number of patients 444 (100) Number of events 241 (54) Crude Multivariate adjustment†
Control*
Teicoplanin
1,423 (60) 942 (40) 348 (24) 271 (29) Odds Ratio (95% CI) 1.00 1.25 (1.04-1.50) 1.00 1.31 (1.07-1.60) 330 (74) 114 (26) 169 (51) 72 (63) Odds Ratio (95% CI) 1.00 1.63 (1.05-2.53) 1.00 1.80 (1.13-2.85)
Abbreviations: CI, confidence interval; eGFR, estimated glomerular filtration rate *Reference category †Multivariate adjustment was made for: Age, sex, left ventricular ejection fraction, diabetes mellitus, deep hypothermic circulatory arrest, chronic obstructive pulmonary disease, preoperative hemoglobin concentration, postoperative creatine kinase MB, and body mass index.
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AKI was 1.31 (95% CI 0.99-1.73) after multivariate adjustment; and in patients undergoing a procedure other than isolated CABG, the odds ratio for AKI was 1.50 (95% CI 1.18-1.92) in patients who received teicoplanin. The authors repeated the multivariate analyses and replaced the assessment of preoperative renal function with eGFR according to the CKD-EPI formula, and also with serum creatinine, and the results essentially were unchanged; adjusted OR 1.40 (95% CI 1.16-1.68) and OR 1.37 (95% CI 1.15-1.65), respectively. The authors also repeated the analysis after excluding patients with deep sternal wound infection, because these patients are at high risk for AKI, and the results were very similar; adjusted OR 1.43 (95% CI 1.19-1.72). DISCUSSION
The main finding of this study was that antibiotic prophylaxis with teicoplanin during cardiac surgery was associated with an increased risk of AKI. Supplementary subgroup analyses confirmed the authors’ findings in men and women and in patients with reduced renal function. The authors also found a dosedependent relationship with a higher risk of AKI in patients treated with a higher dose of teicoplanin. The authors’ finding was robust to different estimations of renal function and also to exclusion of patients with postoperative deep sternal wound infection, as demonstrated in sensitivity analyses. Acute kidney injury after heart surgery is associated with increased short- and long-term mortality, risk of myocardial infarction and heart failure.9,10 Even minimal increases of 0 to 26 mmol/L in postoperative serum creatinine are associated with increased short- and long-term mortality.17,18 Tolpin et al18 found that a subclinical change in serum creatinine between 0 and 0.2 mg/dL was associated independently with 30-day all-cause mortality in patients with normal renal function or preoperative renal insufficiency undergoing CABG. The authors’ group recently reported that a minimal increase in serum creatinine (0-0.3 mg/dL) was associated independently with long-term allcause mortality and cardiovascular outcomes, regardless of preoperative renal function in more than 25,000 patients who underwent CABG.17 Acute kidney injury also is associated with development of chronic kidney disease.19 The negative influence on renal function associated with antibiotic prophylaxis with teicoplanin, therefore, should be taken into consideration when developing protocols for antibiotic prophylaxis in cardiac surgery. The authors found certain risk groups that were more susceptible to AKI: Female patients and patients with impaired preoperative renal function (eGFRo 60 mL/min/1.73m2). The mechanism by which the glycopeptides teicoplanin and vancomycin potentially impair renal function largely is unknown though some studies suggest that vancomycin causes oxidative stress.20 Teicoplanin is largely excreted in the urine unmetabolized. In healthy patients approximately 50% of the administered dose is excreted in the urine within the first
48 hours and 80% within 16 days.21 There have been several reports on biopsy-confirmed acute tubular necrosis and interstitial nephritis in humans after vancomycin treatment.22,23 A meta-analysis comparing the nephrotoxic effects of teicoplanin and vancomycin found teicoplanin safer.6 This also has been shown in a study on rats.5 Cephalosporins today are used widely as primary prophylaxis in cardiac surgery. The most frequent agents in surgical site infections after cardiac surgery are Staphylococcus aureus, coagulase-negative staphylococci and Enterobacteriaceae.24 In animal models, beta-lactams have been found to be more effective against endocarditis from methicillin-susceptible gram-positive bacteria than glycopeptides.25 At times glycopeptides are used as adjuvant, often due to the concern about methicillin-resistant staphylococci.3 One disadvantage of using aminoglycosides is the risk of resistance development.3 The authors’ study identified a clinically important side effect of teicoplanin prophylaxis in cardiac surgery, which previously was not reported. The observed higher risk for AKI should be included in the risk-benefit analysis regarding choice of antibiotic prophylactic regimen in cardiac surgery. The authors identified patient subgroups with particularly high risk for AKI after antibiotic prophylaxis with teicoplanin, and in their opinion it would be reasonable to consider an alternative treatment strategy in women with impaired renal function. Study Limitations The main limitation of this study was that treatment allocation was not randomized. However, selection bias should be minimized by that fact that patients were included consecutively during the study period, and the protocol for antibiotic prophylaxis was determined by institutional directives. Therefore, teicoplanin prophylaxis was introduced from one day to another. Because it was a single-center study, there were minimal differences in pre-, peri-, and postoperative care. The authors addressed potential selection bias by multivariate regression adjustment, but still there may be unmeasured or unknown factors related to the outcome for which they were not able to account. Because of study design, the authors had no possibility to make statements regarding causality or mechanisms. Because the study included patients who had surgery during a period of 4 years, the authors cannot rule out that minor changes in the perioperative or surgical care may have influenced the results. Another limitation was that the authors did not have information regarding cardiopulmonary bypass times. CONCLUSIONS
Teicoplanin was associated with an increased risk of acute kidney injury. The risk of acute kidney injury was higher in women and in patients with decreased glomerular filtration rate.
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