http://informahealthcare.com/rnf ISSN: 0886-022X (print), 1525-6049 (electronic) Ren Fail, Early Online: 1–6 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/0886022X.2015.1052949
CASE REPORT
Acute renal failure after high-dose antibiotic bone cement: case report and review of the literature Alexia James and Trent Larson
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Banner Health, Mesa, AZ, USA
Abstract
Keywords
High-dose antibiotic-loaded bone cement (ALBC) spacers are commonly used to treat prosthetic joint infections following total hip and knee arthroplasties. This methodology can provide high local antibiotic concentrations while minimizing systemic exposure and toxicity. The occurrence of acute kidney injury (AKI) is rarely reported. Available literature suggests that the rate may be higher than previously thought. We report a case of significant systemic tobramycin absorption with concomitant acute renal failure in a 69-year-old female following the implantation of a high-dose ALBC spacer containing both tobramycin and vancomycin. The tobramycin level 24 h post-surgery was 5.8 mcg/mL. Due to concomitant renal failure, antibiotic clearance was poor and resulted in prolonged exposure to elevated aminoglycoside levels. Recovery of renal function occurred, but clinicians should be vigilant in considering the potential impact ALBC spacers can have on post-operative renal function if antibiotic elution is higher than expected.
Acute kidney injury, arthroplasty, bone cement, knee, prosthesis-related infections, replacement, tobramycin/adverse effects
Introduction It is estimated that over one million combined hip and knee arthroplasties are performed each year in the United States.1,32 With subsequent joint infection rates being reported as high as 3%, two-stage arthroplasty is considered as the treatment of choice to help eradicate this complication.2 This involves high-dose antibiotic-loaded bone cement (ALBC) spacers which can provide local antibiotic concentrations that are higher than what can be achieved with systemic antibiotics alone while having little impact on serum or urine levels.2 Although systemic complications of ALBC spacers are limited, a recent systematic evaluation has shown that significant antibiotic absorption can occur and the incidence of acute kidney injury (AKI) is likely higher than previously thought and may average as high as 5%.1 Many of the studies evaluated within this review showed wide variances depending on the definition of AKI. This is further confounded by many factors which can influence the elution rates of antibiotics from ALBC.2,3 We report another case of acute renal failure that was likely impacted by significant tobramycin absorption following high-dose ALBC spacer placement.
Case report A 69-year-old female was admitted with fever, chills, night sweats and a small wound on the medial side of her left knee, Address correspondence to Alexia James, PharmD, BCPS, Banner Health, 1400 S. Dobson Road, Mesa, AZ 85202, USA. E-mail: [email protected]
History Received 11 February 2015 Revised 7 April 2015 Accepted 13 May 2015 Published online 9 June 2015
which was draining serosanguineous fluid. Approximately one-week prior, the left knee had been aspirated and the patient was started on oral cephalexin. Due to worsening pain and swelling, the patient decided to seek emergent medical care. The patient had four previous knee surgeries; the most recent revision was approximately 8 weeks prior to admission. The patient was admitted and started empirically on intravenous (IV) vancomycin and IV piperacillin–tazobactam. Past medical history included osteoarthritis, hypertension, obesity (113 kg, BMI – 36.0 kg/m2), chronic back pain, breast cancer status post-mastectomy in 2011 (no further radiation or chemotherapy), depression, stress incontinence and a total of four left knee surgeries, including a history of methicillinresistant staphylococcus aureus (MRSA) skin abscess. Home medications consisted of duloxetine, solifenacin, amlodipine, hydrocodone–acetaminophen, lisinopril, morphine and paroxetine. Allergies included oxycodone–acetaminophen and statins. The patient did have a history of acute renal failure secondary to dehydration and medications 19 months prior. Her medications at that time included enalapril, hydrochlorothiazide and sulfamethoxazole/trimethoprim. Serum creatinine (Scr) and blood urea nitrogen (BUN) on admission during that stay were 2.03 mg/dL and 23 mg/dL, respectively. Patient was rehydrated, medications were held and she was subsequently discharged two days later with a Scr of 0.62 mg/dL and BUN of 8 mg/dL. On this admission, white blood cell count was elevated at 11.9 k/mm3, erythrocyte sedimentation rate (ESR) was 98 mm/h, Scr was 0.82 mg/dL and BUN was 11 mg/dL. Reaspiration and bone scan were completed which showed
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diffuse uptake around the femoral and tibial component. The aspiration revealed 85,000 white cells and the culture grew MRSA. Piperacillin–tazobactam was discontinued three days after admission once the culture results were available and the patient was continued on IV vancomycin along with oral rifampin. Orthopedic surgery recommended a resection arthroplasty with irrigation and implantation of an antibiotic bone cement spacer. The patient was taken to surgery five days after admission. Laboratory testing the day of surgery revealed a Scr of 1.0 mg/dL and BUN of 7 mg/dL. The patient had been on vancomycin since admit and was on 1 g intravenous (IV) every 12 h. The trough on the day prior to surgery was 19 mcg/mL, so the dose was subsequently decreased to 750 mg IV every 12 h to minimize the risk of further accumulation. The goal vancomycin trough was targeted at 15–20 mcg/mL for a possible osteomyelitis. Intra-operatively, three bags of Biomet cobalt cement (40 g each) were mixed with a total of 10.8 g of tobramycin and 12 g of vancomycin which was injected into the tibial and femoral molds. A final bag of Biomet cement was mixed with 3.6 g of tobramycin and 4 g of vancomycin to make femoral and tibial stems to cement the tibial and femoral components in place. A left knee resection arthroplasty, extensive debridement of the wound and placement of antibiotic spacers were performed. In the post-anesthesia care unit, the patient’s blood pressure dropped to 68/28 mmHg 40 min after leaving the operating room. Although, no major bleeding was reported, a hemoglobin (Hgb) check showed that the Hgb dropped from 10.2 to 8.5 g/dL. Intravenous hydration with 0.9% sodium chloride was started and two units of blood were transfused. Blood pressure improved, but the patient remained hypotensive for approximately three hours. On post-operative day one, the patient’s Scr had increased to 1.33 mg/dL and the BUN had increased to 11 mg/dL. A vancomycin level was checked the day after surgery and although it was drawn approximately 2.5 h earlier than a true nadir trough based on every 12-h dosing, it was unexpectedly elevated at 30.5 mcg/mL. The dose was held and a subsequent random vancomycin level was checked the next day 25.8 h later, which came back at 23.1 mcg/mL suggesting a calculated 64.3-h vancomycin elimination halflife. Considering these results, vancomycin was permanently discontinued and changed to IV daptomycin every 48 h per renal dosing guidelines and infectious disease recommendations. Due to acute renal failure, the tobramycin level was also checked to determine whether any significant antibiotic elution from the cement spacers might be occurring. The random tobramycin level approximately 24 h post-surgery was 5.8 mcg/mL. No IV tobramycin had been given to this patient. A subsequent tobramycin level was checked approximately 96 h later and it was still 3.8 mcg/mL. The patient did not receive IV contrast or non-steroidal anti-inflammatory drugs. The patient was on lisinopril prior to admission which was stopped two days after surgery. On post-operative day two, the Scr and BUN increased to 2.35 and 17 mg/dL, respectively. Nephrology was consulted and subsequently determined that the nonoliguric AKI was
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likely multifactorial due to acute tubular necrosis (ATN) from IV antibiotics combined with leaching of antibiotics from the cement spacers, transient post-operative hypotension and lisinopril. Scr peaked at 3.3 mg/dL with a BUN of 29 mg/dL one week after surgery. Based on the documented levels, this patient exhibited significant tobramycin absorption and systemic exposure from the ALBC spacer. The post-operative vancomycin trough was also elevated despite the dose being previously reduced. It was considered possible that this was also impacted by concomitant vancomycin leaching from the cement spacers. This is less clear due to the fact that the patient was on systemic IV vancomycin. On further examination of anesthesia records, it was also noted that despite receiving the morning dose of IV vancomycin, the patient was given an additional 1 g IV dose intra-operatively less than five hours later. This would have significantly impacted the results as well. The patient was discharged from the hospital on postoperative day 17 with continued renal impairment and six more weeks of IV daptomycin and oral rifampin. Scr on day of discharge was 3.01 mg/dL with a BUN of 29 mg/dL. Dialysis was not considered necessary and nephrology expected eventual renal recovery. The patient was readmitted two months later and an above the knee amputation was performed due to left septic knee arthritis which was refractory to medical management. On this admission, the Scr was 1.95 mg/dL with a BUN of 17 mg/dL. During a subsequent admission one year later, Scr and BUN showed complete resolution at 0.97 and 16 mg/dL, respectively.
Discussion Addition of antibiotics in bone cement to treat orthopedic infections is a common practice with the goal of delivering high localized concentrations of the antibiotic while minimizing systemic exposure and toxicity compared to systemic antibiotic therapy.1 While vancomycin and aminoglycosides are typically the most common antibiotics used, linezolid, daptomycin, cephalosporins and fluoroquinolones have been utilized.2,3 Amounts of antibiotics used per 40 g of bone cement has been reported up to 8 g for vancomycin, 2 g for gentamicin and 7.2 g for tobramycin.1 It has been reported that 8 g of antibiotic per 40 g of bone cement is the highest ratio that can be introduced and still allow proper molding/forming of the cement.2 Low-dose ALBC has been defined as less than 2 g of antibiotic per 40 g or high-dose when greater than 3.6 g of antibiotic is used per 40 g of cement.4 Others have defined lowdose ALBC as being 1 g of powdered antibiotic per 40 g of bone cement.5 Most commercially available pre-mixed ALBC preparations are considered low-dose and contain 0.5–1 g of antibiotic per 40 g of polymethylmethacrylate (PMMA).6 Lower dose products should be differentiated from high-dose ALBC in that they are indicated for prophylaxis, whereas the latter requires further compounding of antibiotics in to each 40 g cement packet to achieve the desired concentration. It has been shown that at least 3.6 g of antibiotic per 40 g of cement is likely needed to achieve effective elution and antibiotic concentrations to treat musculoskeletal infections.5,7
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DOI: 10.3109/0886022X.2015.1052949
The extent of elution of antibiotics from bone cement is impacted by several factors. These can include the antibiotic used, the amount and number of antibiotics present in the cement, the porosity, type of cement, method of preparation or mixing and the surface area of the spacer.2,3,6,8 It has been shown that generic tobramycin has the potential to elute twice as fast as proprietary tobramycin when mixed in PMMA. It was proposed that this occurred due to the fact that the volume of generic tobramycin powder is more than 3.5 times the volume of proprietary tobramycin for an equivalent 1.2 g dose.9 Hartman et al.’s 2012 review stated that the elution kinetics of antibiotics from acrylic cement followed a biphasic profile with high elution rates early followed by a sustained elution rate over time.6,10 The amount of antibiotic released from cement showed an exponential decline after day one of implantation.11–13 Villanueva-Martı´nez reported in their 2013 review that elution typically occurs in three phases based on Lewis’s data.3,14 This was explained as an initial burst or exponential phase during the first 24 h, followed by a declining phase and a third and final low constant elution phase. The exponential phase depends more on the diffusion area of the spacer surface with porosity and hydrophilicity playing an associated role. All of which impacts the elution rate of the antibiotic from the surface and deep cracks in the cement. Regardless of whether elution rates follow a bi-or tri-phasic pattern, it seems generally well accepted that the initial exponential phase is short-lived and likely drops off rapidly.6,8,14,18 However, there are others that have shown that antibiotic release can occur even up to 4 months postimplantation.15,16 One of the more important issues of using high-dose ALBC, however, is the potential risk of systemic toxicity. The primary goal of this methodology is to provide high local antibiotic concentrations that exceed the minimum-inhibitory concentrations of the microorganism, while maintaining very low systemic exposure versus using intravenous antibiotics.2,16,17 One of the original reviews that concluded high-dose ALBC to be clinically safe was by Springer et al. in 2004. They observed no evidence of acute renal insufficiency, failure or other systemic side effects after treating 34 total knee arthroplasty patients with spacers loaded with an average of 10.5 g of vancomycin and 12.5 g of gentamicin.17 Only one patient was noted to have a transient rise in Scr which resolved quickly. One previous 2002 report of acute renal failure had been documented in the literature by van Raaij et al.19 This patient who underwent a total hip arthroplasty had a systemic tobramycin level of 2.1 mg/L on post-op day six and developed renal failure. The spacer was removed and short-term hemodialysis was subsequently required, but the renal function returned to baseline. In 2004, there was a retrospective study of 34 patients by Evans who reported no renal, vestibular or hearing changes after 2 years of follow-up in 44 patients who received spacers with 4 g of vancomycin and 4.6 g of tobramycin.20 This was followed-up with a study of 50 patients who received knee spacers containing 4.8 g of tobramycin per 40 g of cement. Systemic tobramycin levels were stated to be therapeutic on post-op day one, but undetectable by day three which supports the rapid decline after an initial exponential phase. The authors did report vestibular damage in one
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patient, but it was attributed to a high vancomycin level due to systemic administration.21 Since 2005, there have been numerous cases of acute renal failure that occurred after orthopedic implantation of highdose ALBC,22,23,25–29 low-dose ALBC used for treatment24 and one case after low-dose ALBC used for prophylaxis in a primary total knee arthroplasty.30 Most of these case reports required hemodialysis19,22,24–26,29,30 and explantation of the spacers.19,22,25–29 Some did not require dialysis23,27,28 or undergo spacer removal.24,30 The renal function eventually resolved in most cases, but one case was not clear22 and another still required hemodialysis five months post-explantation.25 In almost all cases there was a documented systemic antibiotic level attributed to bone cement elution that could have played a role in the acute renal failure.19,22–26,28,29 McGlothan and Gosmanova did not report serum antibiotic levels that could be attributed solely to cement leaching, but still considered that the ALBC was the likely cause since the renal function resolved fairly soon after explantation.27 In the low-dose ALBC primary prophylaxis case reported by Lau and Kumar, levels were neither drawn nor was the spacer explanted, but the authors still deemed the gentamicin spacer to be the probable cause with a Naranjo score of 6 out of 10.30 In evaluating these reports, it is worth noting that one of these cases exhibited a serum tobramycin level of 5.5 mcg/mL five months after the implantation,23 while another had a level of 13.4 mcg/mL on post-operative day 17.29 A recent case series of detectable serum tobramycin levels in patients who had renal dysfunction and underwent recent ALBC spacer implantation reported of one patient who had a tobramycin level of 19.8 mcg/mL on post-operative day one.31 These instances demonstrate the duration and extent of which a patient can be exposed to nephrotoxic systemic antibiotic levels after bone cement implantation. Despite these reports, the important question is in regards to the overall rate of nephrotoxicity risk when using high-dose ALBC spacers. When considering that there is an estimated one million joint arthroplasties performed in the United States annually and only 0.25–3% of these result in prosthetic joint infections then even using a conservative 1% infection rate would yield an estimated 10,000 patients per year that may need revisions and be candidates for high-dose ALBC.2,32–35 The collective case reports of AKI published over the past decade are an extremely small percentage of the overall patients who likely received ALBC to treat infections. It is worth noting that a 2006 study which evaluated the underreporting of adverse drug events showed that a median overall under-reporting rate of 94% existed and even when differentiating between all adverse events versus more serious or severe events the under-reporting rate was still high at 85%.36 Considering these rates of under-reporting, it is fairly safe to suggest that for every reported case of acute renal failure that may be associated with ALBC there are likely significantly more occurring nationally. In a retrospective review of over 17,000 arthroplasties by Jafari et al., it was estimated that 0.55% of patients undergoing primary elective total joint arthroplasty will develop acute renal failure.37 However, a recent Australian study reported a much higher rate.38 They retrospectively looked at 425 patients undergoing primary, elective total joint
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arthroplasty and evaluated for AKI based on the RIFLE criteria.42 Despite the authors noting that most studies report the incidence of AKI as being less than 2% in this population, they found that 67 patients (14.8%) developed AKI in their institution. They also found that increasing body mass index (BMI), older age, lower pre-operative glomerular filtration rate and use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin-II receptor blockers (ARB) were risk factors for developing AKI. This still leaves the question as to the rate of AKI in patients who receive subsequent revision and high-dose ALBC implantation. A recent systematic review of the literature by Luu et al. attempted to improve our understanding of this risk.1 Ten observational studies (n ¼ 544) were identified, which reported a wide variance in the incidence of AKI ranging from 2% to 17%, although the definition of AKI was not consistent. The overall rate of AKI was calculated to be 4.8% (26 patients of the total 544). It also attempted to identify risk factors for developing AKI when ALBC was used, but due to the heterogeneity in the data reviewed along with reporting variabilities no association could be made. In a separate Infectious Diseases Society of America (IDSA) conference abstract the incidence of AKI was reported at a very high 46%.39 Upon further evaluation of this abstract, they retrospectively reviewed 109 treatments of 89 patients who received antibiotic containing cement. They only evaluated the incidence of AKI in patients who had a Scr measured both pre- and post-operatively (n ¼ 99). The change in renal function was expressed as the creatinine ratio (CR) of the peak Scr after surgery to the level immediately before surgery. Forty-six of these 99 patients (46%) developed some form of AKI post-operatively defined as a CR 41.2, which can also be stated as more than a 20% rise in the Scr. Among those in which an aminoglycoside was used in the cement, 10 of 88 (11%) developed what was considered a severe AKI (CR 2.0). Five patients (6%) developed a moderate AKI (CR 1.5–1.99) and 28 (32%) had a mild AKI (CR 1.2–1.5). Aminoglycoside doses were significantly correlated with greater renal toxicity. Most cases also recovered normal renal function, but one patient required permanent hemodialysis. Another IDSA poster abstract retrospectively reviewed 85 patients who received antibiotic-impregnated spacers for TKA revisions at Vanderbilt University.40 AKI was defined as a 450% rise in Scr from baseline to a level of 41.4 mg/dL within 90 days of the surgery. The incidence of AKI at 90 days was 16% (n ¼ 14) based on this definition outlined in the methodology. They also noted that 25% (n ¼ 21) experienced a 30% rise in Scr from baseline. Risk factors for developing AKI were not identified. One remaining study that was not reviewed by Luu et al. evaluated 17 patients.41 Eight patients had a pre-operative diagnosis of infection and received high-dose ALBC while nine patients received low-dose ALBC implants for primary prophylaxis. Tobramycin serum concentrations were detected (0.3 mcg/mL) in seven of the eight patients in group one (87.5%), while only one patient (11%) in group two had detectable levels. One patient still had an aminoglycoside level of 0.9 mcg/mL on post-operative day 38. The incidence of AKI was evaluated using a definition of a 0.3 g/dL increase in Scr from baseline as per the Acute Kidney Injury
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Network (AKIN) guidelines.42 Six of 17 patients (35%) met the AKIN criteria for AKI. The available data to date report a wide variance, but it appears to suggest that the risk for AKI after high-dose ALBC is likely higher than what has typically been thought. The real rate will be difficult to determine without well designed prospective trials using a standardized definition of AKI.42–44 Additional risk factors for clinicians to be aware of that are unique to this population have also been unclear, but a recent study identified exposure to ACEI and piperacillin–tazobactam within seven days of surgery to be associated with an increased risk for AKI in the immediate post-operative period when patients undergo ALBC spacer placement.45 This finding with piperacillin–tazobactam is not surprising as its nephrotoxicity risk appears to be more significant than previously appreciated.46–49 We do not believe that the tobramycin was the cause of the AKI alone in our case, but rather a contributing factor. Our patient experienced significant post-operative hypotension for a brief time period and was also on intravenous vancomycin. Despite close monitoring of vancomycin levels by the pharmacokinetic service and pro-actively decreasing the dose to avoid excessive accumulation, elimination rates of the antibiotics decreased dramatically post-operatively due to the AKI, which still resulted in supratherapeutic levels. Our patient had also been exposed to both lisinopril and piperacillin/tazobactam within seven days of surgery, which as stated earlier have recently been reported to be independent risk factors for the development of AKI after ALBC placement.45 When considering the post-operative tobramycin levels it appears that the elution was likely highest in the first 24 h followed by a subsequent decline as suggested by others.3,10,50 Due to the development of AKI, the tobramycin was not well cleared, which allowed for its systemic accumulation. Our highest documented level of 5.8 mcg/mL is significant considering IV tobramycin was not given. A significant concern associated with scenarios like this ALBC elution case is the persistent exposure to aminoglycoside levels 41.0 mcg/mL for an extended period since elevated troughs and plasma concentration–time area under the curve are considered risk factors for aminoglycoside-induced nephrotoxicity.51–55 We postulate that this likely contributed to the prolonged AKI since the spacers were not removed until the subsequent amputation two months later. Hemodialysis was never initiated which would have assisted with systemic aminoglycoside removal when it was at its highest.
Conclusion We report another case of elevated aminoglycoside levels and AKI post-ALBC implantation. Although, this risk has been significantly downplayed by some previous reviews of the subject,4,8,14,17 a thorough consideration of information published over the past decade suggests that the risk of AKI after ALBC implantation may be higher than thought. It has been projected that by 2030 the annual demand for primary total hip and knee arthroplasties in the United States will grow to 572,000 and 3.48 million, respectively. Hip and knee revisions are expected to grow significantly as well which
Antibiotic bone cement and acute renal failure
DOI: 10.3109/0886022X.2015.1052949
could add another estimated 364,900 orthopedic procedures per year.56 True rates of AKI that may occur after implantation of ALBC spacers will likely vary depending on an institution’s local practice, since cements with different properties are often combined with antibiotics of various combinations and concentrations using different mixing techniques. All of which can impact antibiotic elution rates and systemic exposure. As a result, clinicians need to remain aware of the contribution ALBC could have in regards to postoperative renal failure.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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40. Koeth J, Hester S, Jenkins C, et al. Incidence of acute kidney injury following placement of antibiotic-impregnated cement spacers: A retrospective review. Antibacterial Agents and Resistance 2010. IDSA Poster. 41. Kalil GZ, Ernst E, Johnson SJ, et al. Systemic exposure to aminoglycosides following knee and hip arthroplasty with aminoglycoside-loaded bone cement implants. Ann Pharmacother. 2012:46(7–8):929–934. 42. Lopes JA, Jorge S. The RIFLE and AKIN classifications for acute kidney injury: A critical and comprehensive review. Clin Kidney J. 2013;6:8–14. 43. Luo X, Jiang L, Du B, et al. A comparison of different diagnostic criteria of acute kidney injury in critically ill patients. Critical Care. 2014;18(4):R144. 44. Fujii T, Uchino S, Takinami M, Bellomo R. Validation of the kidney disease: Improving global outcomes criteria for AKI and comparison of three criteria in hospitalized patients. Clin J Am Soc Nephrol. 2014;9:848–854. 45. Reed EE, Johnston J, Severing J, Stevenson KB, Deutscher M. Nephrotoxicity risk factors and intravenous vancomycin dosing in the immediate postoperative period following antibiotic impregnated cement spacer placement. Ann Pharmacother. 2014; 48(8):962–969. 46. O’Rourke. Vancomycin plus piperacillin–tazo may trigger acute kidney injury. Pharmacy Practice News. 2012;39:1,13. 47. Gomes DM, Smotherman C, Birch A, et al. Comparison of acute kidney injury during treatment with vancomycin in combination with piperacillin–tazobactam or cefepime. Pharmacotherapy. 2014; 34(7):662–669. 48. Moenster RP, Linneman TW, Finnegan PM, Hand S, Thomas Z, McDonald JR. Acute renal failure associated with vancomycin and
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49.
50.
51. 52. 53.
54.
55. 56.
b-lactams for the treatment of osteomyelitis in diabetics: Piperacillin–tazobactam as compared with cefepime. Clin Microbiol Infect. 2014;20(6):O384–O389. Burgess LD, Drew LH. Comparison of the incidence of vancomycin-induced nephrotoxicity in hospitalized patients with and without concomitant piperacillin–tazobactam. Pharmacotherapy. 2014;34(7):670–676. Minelli EB, Benini A, Magnan B, Bartolozzi P. Release of gentamicin and vancomycin from temporary human hip spacers in two-stage revision of infected arthroplasty. J Antimicrob Chemother. 2004;53(2):329–334. Dahlgren JG, Anderson ET, Hewitt WL. Gentamicin blood levels: A guide to nephrotoxicity. Antimicrob Agents Chemother. 1975; 8(1):58–62. Selby NM, Shaw S, Woodier N, Fluck RJ, Kolhe NV. Gentamicinassociated acute kidney injury. Q J Med. 2009;102:873–880. Raveh D, Kopyt M, Hite Y, Rudensky B, Sonnenblick M, Yinnon AM. Risk factors for nephrotoxicity in elderly patients receiving once-daily aminoglycosides. Q J Med. 2002;95: 291–297. Rybak MJ, Abate BJ, Kang SL, Ruffing MJ, Lerner SA, Drusano GL. Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother. 1999;43(7):1549–1555. Prescott WA, Nagle JL. Extended-interval once-daily dosing of aminoglycosides in adult and pediatric patients with cystic fibrosis. Pharmacotherapy. 2010;30(1):95–108. Kurtz S, Ong K, Lau E, Mowat F, Halpern M. Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint Surg Am. 2007;89: 780–785.
CASE REPORT
Acute renal failure after high-dose antibiotic bone cement: case report and review of the literature Alexia James and Trent Larson
Ren Fail Downloaded from informahealthcare.com by Nyu Medical Center on 06/22/15 For personal use only.
Banner Health, Mesa, AZ, USA
Abstract
Keywords
High-dose antibiotic-loaded bone cement (ALBC) spacers are commonly used to treat prosthetic joint infections following total hip and knee arthroplasties. This methodology can provide high local antibiotic concentrations while minimizing systemic exposure and toxicity. The occurrence of acute kidney injury (AKI) is rarely reported. Available literature suggests that the rate may be higher than previously thought. We report a case of significant systemic tobramycin absorption with concomitant acute renal failure in a 69-year-old female following the implantation of a high-dose ALBC spacer containing both tobramycin and vancomycin. The tobramycin level 24 h post-surgery was 5.8 mcg/mL. Due to concomitant renal failure, antibiotic clearance was poor and resulted in prolonged exposure to elevated aminoglycoside levels. Recovery of renal function occurred, but clinicians should be vigilant in considering the potential impact ALBC spacers can have on post-operative renal function if antibiotic elution is higher than expected.
Acute kidney injury, arthroplasty, bone cement, knee, prosthesis-related infections, replacement, tobramycin/adverse effects
Introduction It is estimated that over one million combined hip and knee arthroplasties are performed each year in the United States.1,32 With subsequent joint infection rates being reported as high as 3%, two-stage arthroplasty is considered as the treatment of choice to help eradicate this complication.2 This involves high-dose antibiotic-loaded bone cement (ALBC) spacers which can provide local antibiotic concentrations that are higher than what can be achieved with systemic antibiotics alone while having little impact on serum or urine levels.2 Although systemic complications of ALBC spacers are limited, a recent systematic evaluation has shown that significant antibiotic absorption can occur and the incidence of acute kidney injury (AKI) is likely higher than previously thought and may average as high as 5%.1 Many of the studies evaluated within this review showed wide variances depending on the definition of AKI. This is further confounded by many factors which can influence the elution rates of antibiotics from ALBC.2,3 We report another case of acute renal failure that was likely impacted by significant tobramycin absorption following high-dose ALBC spacer placement.
Case report A 69-year-old female was admitted with fever, chills, night sweats and a small wound on the medial side of her left knee, Address correspondence to Alexia James, PharmD, BCPS, Banner Health, 1400 S. Dobson Road, Mesa, AZ 85202, USA. E-mail: [email protected]
History Received 11 February 2015 Revised 7 April 2015 Accepted 13 May 2015 Published online 9 June 2015
which was draining serosanguineous fluid. Approximately one-week prior, the left knee had been aspirated and the patient was started on oral cephalexin. Due to worsening pain and swelling, the patient decided to seek emergent medical care. The patient had four previous knee surgeries; the most recent revision was approximately 8 weeks prior to admission. The patient was admitted and started empirically on intravenous (IV) vancomycin and IV piperacillin–tazobactam. Past medical history included osteoarthritis, hypertension, obesity (113 kg, BMI – 36.0 kg/m2), chronic back pain, breast cancer status post-mastectomy in 2011 (no further radiation or chemotherapy), depression, stress incontinence and a total of four left knee surgeries, including a history of methicillinresistant staphylococcus aureus (MRSA) skin abscess. Home medications consisted of duloxetine, solifenacin, amlodipine, hydrocodone–acetaminophen, lisinopril, morphine and paroxetine. Allergies included oxycodone–acetaminophen and statins. The patient did have a history of acute renal failure secondary to dehydration and medications 19 months prior. Her medications at that time included enalapril, hydrochlorothiazide and sulfamethoxazole/trimethoprim. Serum creatinine (Scr) and blood urea nitrogen (BUN) on admission during that stay were 2.03 mg/dL and 23 mg/dL, respectively. Patient was rehydrated, medications were held and she was subsequently discharged two days later with a Scr of 0.62 mg/dL and BUN of 8 mg/dL. On this admission, white blood cell count was elevated at 11.9 k/mm3, erythrocyte sedimentation rate (ESR) was 98 mm/h, Scr was 0.82 mg/dL and BUN was 11 mg/dL. Reaspiration and bone scan were completed which showed
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diffuse uptake around the femoral and tibial component. The aspiration revealed 85,000 white cells and the culture grew MRSA. Piperacillin–tazobactam was discontinued three days after admission once the culture results were available and the patient was continued on IV vancomycin along with oral rifampin. Orthopedic surgery recommended a resection arthroplasty with irrigation and implantation of an antibiotic bone cement spacer. The patient was taken to surgery five days after admission. Laboratory testing the day of surgery revealed a Scr of 1.0 mg/dL and BUN of 7 mg/dL. The patient had been on vancomycin since admit and was on 1 g intravenous (IV) every 12 h. The trough on the day prior to surgery was 19 mcg/mL, so the dose was subsequently decreased to 750 mg IV every 12 h to minimize the risk of further accumulation. The goal vancomycin trough was targeted at 15–20 mcg/mL for a possible osteomyelitis. Intra-operatively, three bags of Biomet cobalt cement (40 g each) were mixed with a total of 10.8 g of tobramycin and 12 g of vancomycin which was injected into the tibial and femoral molds. A final bag of Biomet cement was mixed with 3.6 g of tobramycin and 4 g of vancomycin to make femoral and tibial stems to cement the tibial and femoral components in place. A left knee resection arthroplasty, extensive debridement of the wound and placement of antibiotic spacers were performed. In the post-anesthesia care unit, the patient’s blood pressure dropped to 68/28 mmHg 40 min after leaving the operating room. Although, no major bleeding was reported, a hemoglobin (Hgb) check showed that the Hgb dropped from 10.2 to 8.5 g/dL. Intravenous hydration with 0.9% sodium chloride was started and two units of blood were transfused. Blood pressure improved, but the patient remained hypotensive for approximately three hours. On post-operative day one, the patient’s Scr had increased to 1.33 mg/dL and the BUN had increased to 11 mg/dL. A vancomycin level was checked the day after surgery and although it was drawn approximately 2.5 h earlier than a true nadir trough based on every 12-h dosing, it was unexpectedly elevated at 30.5 mcg/mL. The dose was held and a subsequent random vancomycin level was checked the next day 25.8 h later, which came back at 23.1 mcg/mL suggesting a calculated 64.3-h vancomycin elimination halflife. Considering these results, vancomycin was permanently discontinued and changed to IV daptomycin every 48 h per renal dosing guidelines and infectious disease recommendations. Due to acute renal failure, the tobramycin level was also checked to determine whether any significant antibiotic elution from the cement spacers might be occurring. The random tobramycin level approximately 24 h post-surgery was 5.8 mcg/mL. No IV tobramycin had been given to this patient. A subsequent tobramycin level was checked approximately 96 h later and it was still 3.8 mcg/mL. The patient did not receive IV contrast or non-steroidal anti-inflammatory drugs. The patient was on lisinopril prior to admission which was stopped two days after surgery. On post-operative day two, the Scr and BUN increased to 2.35 and 17 mg/dL, respectively. Nephrology was consulted and subsequently determined that the nonoliguric AKI was
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likely multifactorial due to acute tubular necrosis (ATN) from IV antibiotics combined with leaching of antibiotics from the cement spacers, transient post-operative hypotension and lisinopril. Scr peaked at 3.3 mg/dL with a BUN of 29 mg/dL one week after surgery. Based on the documented levels, this patient exhibited significant tobramycin absorption and systemic exposure from the ALBC spacer. The post-operative vancomycin trough was also elevated despite the dose being previously reduced. It was considered possible that this was also impacted by concomitant vancomycin leaching from the cement spacers. This is less clear due to the fact that the patient was on systemic IV vancomycin. On further examination of anesthesia records, it was also noted that despite receiving the morning dose of IV vancomycin, the patient was given an additional 1 g IV dose intra-operatively less than five hours later. This would have significantly impacted the results as well. The patient was discharged from the hospital on postoperative day 17 with continued renal impairment and six more weeks of IV daptomycin and oral rifampin. Scr on day of discharge was 3.01 mg/dL with a BUN of 29 mg/dL. Dialysis was not considered necessary and nephrology expected eventual renal recovery. The patient was readmitted two months later and an above the knee amputation was performed due to left septic knee arthritis which was refractory to medical management. On this admission, the Scr was 1.95 mg/dL with a BUN of 17 mg/dL. During a subsequent admission one year later, Scr and BUN showed complete resolution at 0.97 and 16 mg/dL, respectively.
Discussion Addition of antibiotics in bone cement to treat orthopedic infections is a common practice with the goal of delivering high localized concentrations of the antibiotic while minimizing systemic exposure and toxicity compared to systemic antibiotic therapy.1 While vancomycin and aminoglycosides are typically the most common antibiotics used, linezolid, daptomycin, cephalosporins and fluoroquinolones have been utilized.2,3 Amounts of antibiotics used per 40 g of bone cement has been reported up to 8 g for vancomycin, 2 g for gentamicin and 7.2 g for tobramycin.1 It has been reported that 8 g of antibiotic per 40 g of bone cement is the highest ratio that can be introduced and still allow proper molding/forming of the cement.2 Low-dose ALBC has been defined as less than 2 g of antibiotic per 40 g or high-dose when greater than 3.6 g of antibiotic is used per 40 g of cement.4 Others have defined lowdose ALBC as being 1 g of powdered antibiotic per 40 g of bone cement.5 Most commercially available pre-mixed ALBC preparations are considered low-dose and contain 0.5–1 g of antibiotic per 40 g of polymethylmethacrylate (PMMA).6 Lower dose products should be differentiated from high-dose ALBC in that they are indicated for prophylaxis, whereas the latter requires further compounding of antibiotics in to each 40 g cement packet to achieve the desired concentration. It has been shown that at least 3.6 g of antibiotic per 40 g of cement is likely needed to achieve effective elution and antibiotic concentrations to treat musculoskeletal infections.5,7
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DOI: 10.3109/0886022X.2015.1052949
The extent of elution of antibiotics from bone cement is impacted by several factors. These can include the antibiotic used, the amount and number of antibiotics present in the cement, the porosity, type of cement, method of preparation or mixing and the surface area of the spacer.2,3,6,8 It has been shown that generic tobramycin has the potential to elute twice as fast as proprietary tobramycin when mixed in PMMA. It was proposed that this occurred due to the fact that the volume of generic tobramycin powder is more than 3.5 times the volume of proprietary tobramycin for an equivalent 1.2 g dose.9 Hartman et al.’s 2012 review stated that the elution kinetics of antibiotics from acrylic cement followed a biphasic profile with high elution rates early followed by a sustained elution rate over time.6,10 The amount of antibiotic released from cement showed an exponential decline after day one of implantation.11–13 Villanueva-Martı´nez reported in their 2013 review that elution typically occurs in three phases based on Lewis’s data.3,14 This was explained as an initial burst or exponential phase during the first 24 h, followed by a declining phase and a third and final low constant elution phase. The exponential phase depends more on the diffusion area of the spacer surface with porosity and hydrophilicity playing an associated role. All of which impacts the elution rate of the antibiotic from the surface and deep cracks in the cement. Regardless of whether elution rates follow a bi-or tri-phasic pattern, it seems generally well accepted that the initial exponential phase is short-lived and likely drops off rapidly.6,8,14,18 However, there are others that have shown that antibiotic release can occur even up to 4 months postimplantation.15,16 One of the more important issues of using high-dose ALBC, however, is the potential risk of systemic toxicity. The primary goal of this methodology is to provide high local antibiotic concentrations that exceed the minimum-inhibitory concentrations of the microorganism, while maintaining very low systemic exposure versus using intravenous antibiotics.2,16,17 One of the original reviews that concluded high-dose ALBC to be clinically safe was by Springer et al. in 2004. They observed no evidence of acute renal insufficiency, failure or other systemic side effects after treating 34 total knee arthroplasty patients with spacers loaded with an average of 10.5 g of vancomycin and 12.5 g of gentamicin.17 Only one patient was noted to have a transient rise in Scr which resolved quickly. One previous 2002 report of acute renal failure had been documented in the literature by van Raaij et al.19 This patient who underwent a total hip arthroplasty had a systemic tobramycin level of 2.1 mg/L on post-op day six and developed renal failure. The spacer was removed and short-term hemodialysis was subsequently required, but the renal function returned to baseline. In 2004, there was a retrospective study of 34 patients by Evans who reported no renal, vestibular or hearing changes after 2 years of follow-up in 44 patients who received spacers with 4 g of vancomycin and 4.6 g of tobramycin.20 This was followed-up with a study of 50 patients who received knee spacers containing 4.8 g of tobramycin per 40 g of cement. Systemic tobramycin levels were stated to be therapeutic on post-op day one, but undetectable by day three which supports the rapid decline after an initial exponential phase. The authors did report vestibular damage in one
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patient, but it was attributed to a high vancomycin level due to systemic administration.21 Since 2005, there have been numerous cases of acute renal failure that occurred after orthopedic implantation of highdose ALBC,22,23,25–29 low-dose ALBC used for treatment24 and one case after low-dose ALBC used for prophylaxis in a primary total knee arthroplasty.30 Most of these case reports required hemodialysis19,22,24–26,29,30 and explantation of the spacers.19,22,25–29 Some did not require dialysis23,27,28 or undergo spacer removal.24,30 The renal function eventually resolved in most cases, but one case was not clear22 and another still required hemodialysis five months post-explantation.25 In almost all cases there was a documented systemic antibiotic level attributed to bone cement elution that could have played a role in the acute renal failure.19,22–26,28,29 McGlothan and Gosmanova did not report serum antibiotic levels that could be attributed solely to cement leaching, but still considered that the ALBC was the likely cause since the renal function resolved fairly soon after explantation.27 In the low-dose ALBC primary prophylaxis case reported by Lau and Kumar, levels were neither drawn nor was the spacer explanted, but the authors still deemed the gentamicin spacer to be the probable cause with a Naranjo score of 6 out of 10.30 In evaluating these reports, it is worth noting that one of these cases exhibited a serum tobramycin level of 5.5 mcg/mL five months after the implantation,23 while another had a level of 13.4 mcg/mL on post-operative day 17.29 A recent case series of detectable serum tobramycin levels in patients who had renal dysfunction and underwent recent ALBC spacer implantation reported of one patient who had a tobramycin level of 19.8 mcg/mL on post-operative day one.31 These instances demonstrate the duration and extent of which a patient can be exposed to nephrotoxic systemic antibiotic levels after bone cement implantation. Despite these reports, the important question is in regards to the overall rate of nephrotoxicity risk when using high-dose ALBC spacers. When considering that there is an estimated one million joint arthroplasties performed in the United States annually and only 0.25–3% of these result in prosthetic joint infections then even using a conservative 1% infection rate would yield an estimated 10,000 patients per year that may need revisions and be candidates for high-dose ALBC.2,32–35 The collective case reports of AKI published over the past decade are an extremely small percentage of the overall patients who likely received ALBC to treat infections. It is worth noting that a 2006 study which evaluated the underreporting of adverse drug events showed that a median overall under-reporting rate of 94% existed and even when differentiating between all adverse events versus more serious or severe events the under-reporting rate was still high at 85%.36 Considering these rates of under-reporting, it is fairly safe to suggest that for every reported case of acute renal failure that may be associated with ALBC there are likely significantly more occurring nationally. In a retrospective review of over 17,000 arthroplasties by Jafari et al., it was estimated that 0.55% of patients undergoing primary elective total joint arthroplasty will develop acute renal failure.37 However, a recent Australian study reported a much higher rate.38 They retrospectively looked at 425 patients undergoing primary, elective total joint
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arthroplasty and evaluated for AKI based on the RIFLE criteria.42 Despite the authors noting that most studies report the incidence of AKI as being less than 2% in this population, they found that 67 patients (14.8%) developed AKI in their institution. They also found that increasing body mass index (BMI), older age, lower pre-operative glomerular filtration rate and use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin-II receptor blockers (ARB) were risk factors for developing AKI. This still leaves the question as to the rate of AKI in patients who receive subsequent revision and high-dose ALBC implantation. A recent systematic review of the literature by Luu et al. attempted to improve our understanding of this risk.1 Ten observational studies (n ¼ 544) were identified, which reported a wide variance in the incidence of AKI ranging from 2% to 17%, although the definition of AKI was not consistent. The overall rate of AKI was calculated to be 4.8% (26 patients of the total 544). It also attempted to identify risk factors for developing AKI when ALBC was used, but due to the heterogeneity in the data reviewed along with reporting variabilities no association could be made. In a separate Infectious Diseases Society of America (IDSA) conference abstract the incidence of AKI was reported at a very high 46%.39 Upon further evaluation of this abstract, they retrospectively reviewed 109 treatments of 89 patients who received antibiotic containing cement. They only evaluated the incidence of AKI in patients who had a Scr measured both pre- and post-operatively (n ¼ 99). The change in renal function was expressed as the creatinine ratio (CR) of the peak Scr after surgery to the level immediately before surgery. Forty-six of these 99 patients (46%) developed some form of AKI post-operatively defined as a CR 41.2, which can also be stated as more than a 20% rise in the Scr. Among those in which an aminoglycoside was used in the cement, 10 of 88 (11%) developed what was considered a severe AKI (CR 2.0). Five patients (6%) developed a moderate AKI (CR 1.5–1.99) and 28 (32%) had a mild AKI (CR 1.2–1.5). Aminoglycoside doses were significantly correlated with greater renal toxicity. Most cases also recovered normal renal function, but one patient required permanent hemodialysis. Another IDSA poster abstract retrospectively reviewed 85 patients who received antibiotic-impregnated spacers for TKA revisions at Vanderbilt University.40 AKI was defined as a 450% rise in Scr from baseline to a level of 41.4 mg/dL within 90 days of the surgery. The incidence of AKI at 90 days was 16% (n ¼ 14) based on this definition outlined in the methodology. They also noted that 25% (n ¼ 21) experienced a 30% rise in Scr from baseline. Risk factors for developing AKI were not identified. One remaining study that was not reviewed by Luu et al. evaluated 17 patients.41 Eight patients had a pre-operative diagnosis of infection and received high-dose ALBC while nine patients received low-dose ALBC implants for primary prophylaxis. Tobramycin serum concentrations were detected (0.3 mcg/mL) in seven of the eight patients in group one (87.5%), while only one patient (11%) in group two had detectable levels. One patient still had an aminoglycoside level of 0.9 mcg/mL on post-operative day 38. The incidence of AKI was evaluated using a definition of a 0.3 g/dL increase in Scr from baseline as per the Acute Kidney Injury
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Network (AKIN) guidelines.42 Six of 17 patients (35%) met the AKIN criteria for AKI. The available data to date report a wide variance, but it appears to suggest that the risk for AKI after high-dose ALBC is likely higher than what has typically been thought. The real rate will be difficult to determine without well designed prospective trials using a standardized definition of AKI.42–44 Additional risk factors for clinicians to be aware of that are unique to this population have also been unclear, but a recent study identified exposure to ACEI and piperacillin–tazobactam within seven days of surgery to be associated with an increased risk for AKI in the immediate post-operative period when patients undergo ALBC spacer placement.45 This finding with piperacillin–tazobactam is not surprising as its nephrotoxicity risk appears to be more significant than previously appreciated.46–49 We do not believe that the tobramycin was the cause of the AKI alone in our case, but rather a contributing factor. Our patient experienced significant post-operative hypotension for a brief time period and was also on intravenous vancomycin. Despite close monitoring of vancomycin levels by the pharmacokinetic service and pro-actively decreasing the dose to avoid excessive accumulation, elimination rates of the antibiotics decreased dramatically post-operatively due to the AKI, which still resulted in supratherapeutic levels. Our patient had also been exposed to both lisinopril and piperacillin/tazobactam within seven days of surgery, which as stated earlier have recently been reported to be independent risk factors for the development of AKI after ALBC placement.45 When considering the post-operative tobramycin levels it appears that the elution was likely highest in the first 24 h followed by a subsequent decline as suggested by others.3,10,50 Due to the development of AKI, the tobramycin was not well cleared, which allowed for its systemic accumulation. Our highest documented level of 5.8 mcg/mL is significant considering IV tobramycin was not given. A significant concern associated with scenarios like this ALBC elution case is the persistent exposure to aminoglycoside levels 41.0 mcg/mL for an extended period since elevated troughs and plasma concentration–time area under the curve are considered risk factors for aminoglycoside-induced nephrotoxicity.51–55 We postulate that this likely contributed to the prolonged AKI since the spacers were not removed until the subsequent amputation two months later. Hemodialysis was never initiated which would have assisted with systemic aminoglycoside removal when it was at its highest.
Conclusion We report another case of elevated aminoglycoside levels and AKI post-ALBC implantation. Although, this risk has been significantly downplayed by some previous reviews of the subject,4,8,14,17 a thorough consideration of information published over the past decade suggests that the risk of AKI after ALBC implantation may be higher than thought. It has been projected that by 2030 the annual demand for primary total hip and knee arthroplasties in the United States will grow to 572,000 and 3.48 million, respectively. Hip and knee revisions are expected to grow significantly as well which
Antibiotic bone cement and acute renal failure
DOI: 10.3109/0886022X.2015.1052949
could add another estimated 364,900 orthopedic procedures per year.56 True rates of AKI that may occur after implantation of ALBC spacers will likely vary depending on an institution’s local practice, since cements with different properties are often combined with antibiotics of various combinations and concentrations using different mixing techniques. All of which can impact antibiotic elution rates and systemic exposure. As a result, clinicians need to remain aware of the contribution ALBC could have in regards to postoperative renal failure.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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