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A retrospective analysis to estimate target trough concentration of vancomycin for febrile neutropenia in patients with hematological malignancy
Clinica Chimica Acta 440 (2015) 183–187
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
A retrospective analysis to estimate target trough concentration of vancomycin for febrile neutropenia in patients with hematological malignancy Yosuke Suzuki a,⁎, Issei Tokimatsu b, Yuko Morinaga a, Yuhki Sato a, Kuniko Takano c, Kazuhiro Kohno c, Masao Ogata c, Kazufumi Hiramatsu b, Hiroki Itoh a, Jun-ichi Kadota b a b c
Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Oita 879-5593, Japan Department of Respiratory Medicine and Infectious Diseases, Oita University, Faculty of Medicine, Hasama-machi, Oita 879-5593, Japan Department of Medical Oncology and Hematology, Oita University, Faculty of Medicine, Hasama-machi, Oita 879-5593, Japan
a r t i c l e
i n f o
Article history: Received 17 September 2014 Received in revised form 25 November 2014 Accepted 25 November 2014 Available online 2 December 2014 Keywords: Vancomycin Therapeutic drug monitoring Febrile neutropenia Hematological malignancy
a b s t r a c t Background: The target trough concentration of vancomycin in patients with febrile neutropenia has not been reported. The aim of this study was to estimate the target trough concentration for febrile neutropenia in patients with hematological malignancy. Methods: In this retrospective, single-center, observational cohort study, 63 hospitalized patients with hematological malignancy who were treated with vancomycin for febrile neutropenia due to bacteriologically documented or presumptive Gram-positive infections were analyzed. Results: A significant difference in the first trough concentration of vancomycin was observed between the response and non-response groups, and between the nephrotoxicity and non-nephrotoxicity groups. Multiple logistic regression analyses identified the first trough concentration as the only independent variable associated with clinical efficacy and nephrotoxicity of vancomycin. The areas under the ROC curves were 0.72 and 0.83 for clinical efficacy and nephrotoxicity, respectively. The cut-off values of the first trough concentration were 11.1 μg/ml for clinical efficacy (sensitivity 60%, specificity 87%) and 11.9 μg/ml for nephrotoxicity (sensitivity 77%, specificity 82%). Conclusions: These results suggest a relationship of trough vancomycin concentration with clinical efficacy and incidence of nephrotoxicity. We propose a target trough vancomycin concentration of around 11.5 μg/ml for febrile neutropenia in patients with hematological malignancy. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Immediate initiation of empirical antibiotic therapy is the standard of care for patients with febrile neutropenia [1], but no single regimen is ideal. Vancomycin is an option for selected patients such as those with hemodynamic instability, pneumonia, clinically evident catheterrelated infection, skin and soft tissue infections, severe mucositis while on empirical ceftazidime treatment after fluoroquinolone prophylaxis, and known colonization with methicillin-resistant Staphylococcus aureus (MRSA) [1]. In general, therapeutic drug monitoring (TDM) of vancomycin is important to improve clinical outcome and to avoid adverse effects such as nephrotoxicity and development of resistance [2,3]. Recent vancomycin therapeutic monitoring guidelines recommend more aggressive vancomycin dosing regimens and maintaining vancomycin trough concentrations between 15 and 20 μg/ml [2,3], in order to maintain an area under the serum concentration–time curve (AUC)/MIC ratio [4–6] at or ⁎ Corresponding author. Tel.: +81 97 586 6113; fax: +81 97 586 6119. E-mail address: [email protected] (Y. Suzuki).
http://dx.doi.org/10.1016/j.cca.2014.11.027 0009-8981/© 2014 Elsevier B.V. All rights reserved.
above 400 [7,8]. On the other hand, a recent prospective multicenter trial suggests that vancomycin trough concentration higher than 15 μg/ml at steady state is a risk factor for nephrotoxicity [9]. Thus, it is necessary to maintain vancomycin trough concentrations between 15 and 20 μg/ml with careful attention to nephrotoxicity. In febrile neutropenia, however, the target trough concentration of vancomycin has not been reported. Thus, the optimal vancomycin dosage in febrile neutropenic patients remains unclear. In this study, we analyzed the correlation of the first trough concentration with clinical efficacy and safety, and estimate the target trough concentration of vancomycin for febrile neutropenia in patients with hematological malignancy. 2. Patients and methods 2.1. Patients Medical records were reviewed to identify hospitalized patients with hematological malignancy treated with vancomycin for febrile neutropenia due to bacteriologically documented or presumptive
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Y. Suzuki et al. / Clinica Chimica Acta 440 (2015) 183–187
Gram-positive infections at Oita University Hospital between June 2005 and April 2014. Patients who had received prophylactic antifungal agents such as triazole (fluconazole or itraconazole) and candin (micafungin), and remained febrile after at least 3 days of treatment with anti-Gram-negative antibiotics such as broad spectrum penicillin (tazobactam/piperacillin), fourth generation cephem (cefepime), carbapenem (meropenem or doripenem) and fluoroquinolone (ciprofloxacin or levofloxacin) before initiation of vancomycin therapy were included in the study. Patients who were younger than 12 years of age, patients who were hemodialyzed, patients who co-administered other anti-MRSA agents, and patients with Gram-negative bacteremia were excluded. Febrile neutropenia was defined as an axillary temperature of ≥ 37.5 °C sustained for 1 h, with an absolute neutrophil count of b500 cells/mm3 or b1000 cells/mm3 with an anticipated decline to 500 cells/mm3 in the next 48 h [10]. Axillary body temperatures were measured N 4 times a day. Serum trough concentration of vancomycin was obtained from routine TDM data. The following clinical data recorded during vancomycin therapy were collected: gender; age; body weight; and laboratory data including absolute neutrophil count, hemoglobin, platelet count, serum creatinine and blood urea nitrogen. Creatinine clearance was calculated according to the Cockcroft– Gault equation [11]. This study was approved by the Ethics Committee of Oita University Hospital. Since blood samples were collected as part of the routine patient care for TDM and laboratory testing, written informed consent was not necessary.
2.5. Analysis of factors associated with clinical efficacy and nephrotoxicity For the analysis of factors related to clinical efficacy and nephrotoxicity, univariate and multiple logistic regression analyses were performed using patient background, laboratory data and co-administered drugs as independent variables. Co-administered drugs were analyzed when they were used in more than 10 patients. 2.6. Determination of target range of serum trough vancomycin concentrations To evaluate the diagnostic accuracy of the first trough concentration of vancomycin, receiver operating characteristic (ROC) curve and area under the ROC curve (AUCROC) were analyzed. The first trough concentration of vancomycin showing the highest accuracy and specificity for efficacy or safety was defined as the cut-off value. 2.7. Statistics Data are expressed as mean ± standard deviation (SD). Differences between two groups were analyzed by paired t test, 2-sided Student's t test or Welch's t test. A p b 0.05 was considered statistically significant. Statistical analyses were performed using the R software version 2.15.2 (http://www.r-project.org) and Predictive Analysis Software (PASW) Statistics ver 21 (SPSS Inc.). 3. Results
2.2. Drug concentration monitoring Vancomycin was infused intravenously over 1 to 2 h. Blood sampling for the measurement of the first trough concentration at steady state was performed between 2 and 6 days after the initiation of vancomycin therapy [2]. Venous blood samples were collected within an hour before the next administration of vancomycin. A vancomycin assay was performed as a routine laboratory test at Oita University Hospital. Serum vancomycin concentrations were determined by a particle enhanced turbidimetric inhibition immunoassay based on Dimension® Xpand (Siemens Inc.). With this method, the limit of detection was 0.8 μg/ml and the coefficient of variation was b 5% for routine clinical TDM. Furthermore, the measurement error was less than 10% in serum containing creatinine 30 mg/dl and urea 500 mg/dl. 2.3. Evaluation of clinical efficacy Treatment outcome was classified as cure (defervescence within 72 h after initiation of vancomycin therapy, sustained for at least 48 h, and improvement of signs and symptoms of infection), improvement (defervescence within 72 h after initiation of vancomycin therapy and improvement of signs and symptoms of infection), minor response (defervescence within 144 h after initiation of vancomycin therapy and improvement tendency of signs and symptoms of infection) or failure (no defervescence within 144 h after initiation of vancomycin therapy and persistence or progression of clinical signs and symptoms of infection, or administration of any additional antibacterial agent for persistent fever, lack of improvement, progressive infection, or new bacterial infection). Defervescence was defined as a maximum axillary temperature of ≤37.0 °C. Response to vancomycin treatment was defined as the achievement of cure or improvement, and non-response was defined as minor response or failure. 2.4. Evaluation of nephrotoxicity Occurrence of nephrotoxicity was defined as an increase in serum creatinine level of 0.5 mg/dl or an increase of 50%, whichever was greater, between 2 and 10 days after initiation of vancomycin therapy [12].
A review of patient records identified 76 patients who satisfied the selection criteria, and 13 patients who met exclusion criteria were excluded. Table 1 shows the characteristics of 63 patients on the first day of vancomycin administration. Acute leukemia accounted for a substantial fraction of the underlying disease (acute myeloid leukemia, 44.4%; acute lymphoblastic leukemia, 12.7%). Most (84.1%) patients had absolute neutrophil counts of b 100 cells/mm3 at the first day of vancomycin administration. Fever of unknown origin and oral mucositis related infection were the most common etiologies (46.0% and 30.2%, respectively). A wide variety of anti-Gram-negative antibiotics and antifungal agents were administered. The first trough concentration of vancomycin was 10.7 ± 6.8 μg/ml, showing large variability. Of the 63 patients, 25 were assessed as showing clinical response (response group) and 38 as showing no response (non-response group). As shown in Fig. 1a, a significant difference in the first trough concentration of vancomycin was observed between the response and non-response groups (p = 0.016). Univariate and multiple logistic regression analyses by stepwise selection identified the first trough concentration as the only independent variable associated with efficacy. The odds ratio (95% confidence interval) was 1.10 (1.01–1.20) (p = 0.026). Fig. 2a shows the optimal ROC curve for predicting response to vancomycin using the first trough vancomycin concentration. The AUCROC was 0.72 and the cut-off value of the first trough concentration for clinical efficacy was 11.1 μg/ml (sensitivity 60%, specificity 87%). Nephrotoxicity was observed in 13 patients. The durations of vancomycin treatment were 9.5 ± 4.8 and 8.7 ± 3.5 days in patients with and without nephrotoxicity, respectively, and did not differ significantly between 2 groups (p = NS). Nephrotoxicity occurred 5.8 ± 2.7 days after initiation of vancomycin, and was significantly later than the time of blood sampling for TDM (2.7 ± 0.9 days) (p = 0.0061). As shown in Fig. 1b, a significant difference in the first trough concentration of vancomycin was observed between the nephrotoxicity and non-nephrotoxicity groups (p = 0.0047). In univariate logistic regression analysis for clinical factors associated with nephrotoxicity, the p values for the first trough concentration (p b 0.0001), blood urea nitrogen (p = 0.0011) and use of opioids (p = 0.078) were less than 0.10. Multiple logistic regression analysis by stepwise selection using the first trough concentration, blood urea nitrogen and use of opioids
Y. Suzuki et al. / Clinica Chimica Acta 440 (2015) 183–187 Table 1 Patient characteristics at the first day of vancomycin administration. Characteristic
Value
No. of subjects Males/females Age (y) Body weight (kg) Underlying disease Acute leukemia Acute myeloid leukemia Acute lymphoblastic leukemia Adult T-cell leukemia Diffuse large B-cell lymphoma Multiple myeloma Myelodysplasia Hodgkin lymphoma Other Hematopoietic stem cell transplant Autologous Allogeneic Absolute neutrophil count (cells/mm3) b100 100–500 N500 Duration of neutropenia (day) Hemoglobin (g/dl) Platelet count (/μl) Blood urea nitrogen (mg/dl) Serum creatinine (mg/dl) Creatinine clearancea (ml/min) Infections Fever of uncertain origin Oral mucositis related Bacteremiab Staphylococcus aureus Staphylococcus epidermidis Streptococci Enterococcus faecalis Other Enterococci Corynebacteria Vascular-catheter related Pneumonia Anti-infective treatment started before initiation of vancomycin Broad spectrum penicillins Tazobactam/Piperacillin Cephalosporins Cefepime Carbapenems Meropenem Doripenem Aminoglycosides Amikacin Fluoroquinolones Ciprofloxacin Levofloxacin Antifungal Amphotericin B Fluconazole Itraconazole Voriconazole Micafungin Antiviral Acyclovir Other co-administered drugs during vancomycin therapyd Proton pump inhibitor Granulocyte colony stimulating factor Calcineurin inhibitor Loop diuretic Benzodiazepine Acetaminophen Antihistamine Opioids Non-steroid anti-inflammatory drug Steroid Recombinant thrombomodulin Calcium inhibitor
63 43/20 50.9 ± 14.2 [25–78] 55.6 ± 7.9 [37.8–78.3]
28 8 10 6 4 3 1 3 3 42 53 10 0 7.4 ± 6.6 [1–40] 8.6 ± 1.4 [5.1–12.7] 25,332 ± 18,066 [2900–92,000] 17.6 ± 12.1 [6.3–85.2] 0.65 ± 0.28 [0.30–1.66] 113.1 ± 40.6 [38.0–209.9] 29 19 9 2 5 1 4 1 1 3 3
3 7 47 12 4 1 25 4 10 11 4 39 41
58 47 34 33 29 24 22 21 20 17 16 12
185
Table 1 (continued) Characteristic
Value
Duration of vancomycin therapy (day) Time of blood sampling for first TDMc (day) First trough concentration of vancomycin (μg/ml)
8.9 ± 3.8 [4–25] 2.7 ± 0.9 [2–6] 10.7 ± 6.8 [2.5–34.4]
Data are expressed as numbers or mean ± S.D. [Range]. a Creatinine clearance was calculated according to the Cockcroft–Gault equation. b Some patients were infected with more than 1 pathogen. c TDM: therapeutic drug monitoring. d Drugs administered in N10 patients.
identified the first trough concentration as the only independent variable of vancomycin-related nephrotoxicity. The odds ratio (95% confidence interval) was 1.21 (1.08–1.36) (p = 0.00092). Fig. 2b shows the optimal ROC curve for predicting nephrotoxicity using the first trough concentration of vancomycin. The AUCROC was 0.83 and the cut-off value of the first trough concentration for nephrotoxicity was 11.9 μg/ml (sensitivity 77%, specificity 82%). 4. Discussion In this study, we attempted to set the target trough concentration of vancomycin for febrile neutropenia in patients with hematological malignancy. It is reported that 80% patients with hematologic malignancies develop fever associated with neutropenia during more than 1 chemotherapy cycle [13]. Gram-positive bacteria have become more common in the epidemiologic spectrum of bloodstream isolates from febrile neutropenic patients [14,15] because of increased use of indwelling plastic venous catheters, which may facilitate colonization by and entry of Gram-positive skin flora [15,16]. Thus, vancomycin is needed for febrile neutropenia suspected to be caused by Gram-positive infections, especially MRSA infection. This study enrolled only patients who had received prophylactic anti-fungal agents and who had remained febrile and neutropenic despite treatment with anti-Gram-negative antibiotics for more than 3 days before initiation of vancomycin. Therefore, this study presumably evaluated the clinical efficacy of vancomycin against Gram-positive infections. Some prospective studies suggested that the inclusion of glycopeptides in the initial empiric antibiotic regimen has no benefit because they do not improve the interval to defervescence or mortality rate in febrile neutropenic patients [17,18]. However, Ramphal et al. reported that the addition of vancomycin resulted in defervescence in some febrile neutropenia patients in whom fever persisted after ceftazidime monotherapy [19]. Consistent with their finding, the use of vancomycin achieved defervescence in approximately 40% of our febrile neutropenic patients in whom anti-Gram-negative antibiotics failed to achieve defervescence. This result suggests that vancomycin may be appropriate when fever persists despite treatment with antibiotics for Gramnegative infections. On the other hand, nephrotoxicity was observed in 13 patients (20.6%) in this study. According to a review, nephrotoxicity associated with vancomycin therapy was observed in 2–28% of patients [20]. Patients with hematological malignancy are at high risk of renal failure associated with serious clinical condition and multiple co-administered medications, which may account for the relatively high incidence of nephrotoxicity. First, our study showed significant differences in the first trough concentration of vancomycin between the response and non-response groups and between the nephrotoxicity and non-nephrotoxicity groups. These findings suggest that trough concentration of vancomycin may be associated with clinical efficacy and nephrotoxicity in febrile neutropenic patients with hematological malignancy. Second, multiple logistic regression analysis identified the first trough concentration of vancomycin as the only independent variable associated with both clinical efficacy and nephrotoxicity. This is the first report on the association of trough vancomycin concentration with clinical
Y. Suzuki et al. / Clinica Chimica Acta 440 (2015) 183–187
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p = 0.016
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0.8 0.6 0.4 0.2 0
0
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efficacy and nephrotoxicity in febrile neutropenic patients with hematological malignancy, although such association has been reported in patients with bacteremia [7], lower respiratory tract infection [8] and pneumonia [21–23]. Finally, the cut-off trough concentrations of vancomycin were estimated to be 11.1 μg/ml for clinical efficacy and 11.9 μg/ml for nephrotoxicity in febrile neutropenic patients with hematological malignancy. Therefore, we propose that the trough concentration should be targeted within a narrow range at approximately 11.5 μg/ml when vancomycin is used for the treatment of febrile neutropenia in patients with hematological malignancy. The cut-off trough level of 11.1 μg/ml for clinical efficacy estimated in this study is lower than those recommended in recent guidelines (15 to 20 μg/ml) [2,3], suggesting that less vancomycin exposure is required to achieve clinical response in patients with febrile neutropenia. One possible reason is a low prevalence of deep infection by MRSA in febrile neutropenic patients [24]. Like clinical efficacy, the cut-off trough level of 11.9 μg/ml for nephrotoxicity is also lower than the recommended levels. Febrile neutropenic patients with hematological malignancy are at high risk of nephrotoxicity associated with serious clinical condition and multiple co-administered medications. Thus, even a normal level of vancomycin exposure may trigger nephrotoxicity in these patients. This is the first report proposing to target trough concentration of vancomycin within a narrow range centering at 11.5 μg/ml, and this finding may
Sensitivity
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0.6 0.4
40
Trough concentration of vancomycin (μg/mL)
0.2 30 0
0.2
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20
Figure 2. Receiver operating characteristic curves for predicting clinical efficacy (a) and nephrotoxicity (b) using the first trough concentration of vancomycin.
10
0
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p = 0.0047
40
Trough concentration of vancomycin (μg/mL)
0
30
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Figure 1. Trough concentrations of vancomycin in response and non-response groups (a) and in nephrotoxicity and non-nephrotoxicity groups (b). Bar indicates the mean value.
contribute to proper use of vancomycin for febrile neutropenia in patients with hematological malignancy. Our study has some limitations. First, occurrence of nephrotoxicity was defined as an increase in serum creatinine level only, while other markers of kidney damage such as proteinuria were not considered in this study. More refined study using a combination of useful markers reflecting kidney damage may be useful to evaluate an association of trough concentration of vancomycin with occurrence of nephrotoxicity. Second, there were only 9 patients with bacteremia in this study. Further study of a larger number of patients with bacteremia may be helpful to correlate MIC, trough vancomycin concentration, treatment response, and nephrotoxicity. Finally, this study analyzed only Japanese patients with hematological malignancy in a single center. Further large-scale study including patients in multiple centers and different countries is required to verify whether this target trough concentration of vancomycin is applicable to other patient cohorts. In conclusion, the present study suggests a relationship of trough vancomycin concentration with clinical efficacy and incidence of nephrotoxicity, and proposes a target trough concentration of around 11.5 μg/ml for febrile neutropenic in patients with hematological malignancy.
References [1] Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011;52:427–31.
Y. Suzuki et al. / Clinica Chimica Acta 440 (2015) 183–187 [2] Matsumoto K, Takesue Y, Ohmagari N, et al. Practice guidelines for therapeutic drug monitoring of vancomycin: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring. J Infect Chemother 2013;19:365–80. [3] Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2009;66:82–98. [4] Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998;26:1–10. [5] Craig WA. Basic pharmacodynamics of antibacterials with clinical applications to the use of beta-lactams, glycopeptides, and linezolid. Infect Dis Clin North Am 2006;17: 479–501. [6] Rybak MJ. The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin Infect Dis 2006;42:S35–9. [7] Kullar R, Davis SL, Levine DP, Rybak MJ. Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia: support for consensus guidelines suggested targets. Clin Infect Dis 2011;52:975–81. [8] Moise-Broder PA, Forrest A, Birmingham MC, Schentag JJ. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet 2004;43:925–42. [9] Bosso JA, Nappi J, Rudisill C, et al. Relationship between vancomycin trough concentrations and nephrotoxicity: a prospective multicenter trial. Antimicrob Agents Chemother 2011;55:5475–9. [10] Masaoka T. Evidence-based recommendations for antimicrobial use in febrile neutropenia in Japan: executive summary. Clin Infect Dis 2004;39:S49–52. [11] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41. [12] Lodise TP, Lomaestro B, Graves J, Drusano GL. Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents Chemother 2008;52:1330–6. [13] Klastersky J. Management of fever in neutropenic patients with different risks of complications. Clin Infect Dis 2004;39:S32–7. [14] Wisplinghoff H, Seifert H, Wenzel RP, Edmond MB. Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies
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and solid neoplasms in hospitals in the United States. Clin Infect Dis 2003;36: 1103–10. Zinner SH. Changing epidemiology of infections in patients with neutropenia and cancer: emphasis on gram-positive and resistant bacteria. Clin Infect Dis 1999;29: 490–4. Hughes WT, Armstrong D, Bodey GP, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002;34:730–51. Cometta A, Kern WV, De Bock R, et al. Vancomycin versus placebo for treating persistent fever in patients with neutropenic cancer receiving piperacillin–tazobactam monotherapy. Clin Infect Dis 2003;37:382–9. de la Rubia J, Montesinos P, Martino R, et al. Imipenem/cilastatin with or without glycopeptide as initial antibiotic therapy for recipients of autologous stem cell transplantation: results of a Spanish multicenter study. Biol Blood Marrow Transplant 2009;15:512–6. Ramphal R, Bolger M, Oblon DJ, et al. Vancomycin is not an essential component of the initial empiric treatment regimen for febrile neutropenic patients receiving ceftazidime: a randomized prospective study. Antimicrob Agents Chemother 1992;36: 1062–7. Wong-Beringer A, Joo J, Tse E, Beringer P. Vancomycin-associated nephrotoxicity: a critical appraisal of risk with high-dose therapy. Int J Antimicrob Agents 2011;37: 95–101. Jeffres MN, Isakow W, Doherty JA, Micek ST, Kollef MH. A retrospective analysis of possible renal toxicity associated with vancomycin in patients with health careassociated methicillin-resistant Staphylococcus aureus pneumonia. Clin Ther 2007; 29:1107–15. Suzuki Y, Kawasaki K, Sato Y, et al. Is peak concentration needed in therapeutic drug monitoring of vancomycin? A pharmacokinetic–pharmacodynamic analysis in patients with methicillin-resistant Staphylococcus aureus pneumonia. Chemotherapy 2012;58:308–12. Wunderink RG, Niederman MS, Kollef MH, et al. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis 2012;54:621–9. Jaksic B, Martinelli G, Perez-Oteyza J, Hartman CS, Leonard LB, Tack KJ. Efficacy and safety of linezolid compared with vancomycin in a randomized, double-blind study of febrile neutropenic patients with cancer. Clin Infect Dis 2006;42:597–607.
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
A retrospective analysis to estimate target trough concentration of vancomycin for febrile neutropenia in patients with hematological malignancy Yosuke Suzuki a,⁎, Issei Tokimatsu b, Yuko Morinaga a, Yuhki Sato a, Kuniko Takano c, Kazuhiro Kohno c, Masao Ogata c, Kazufumi Hiramatsu b, Hiroki Itoh a, Jun-ichi Kadota b a b c
Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Oita 879-5593, Japan Department of Respiratory Medicine and Infectious Diseases, Oita University, Faculty of Medicine, Hasama-machi, Oita 879-5593, Japan Department of Medical Oncology and Hematology, Oita University, Faculty of Medicine, Hasama-machi, Oita 879-5593, Japan
a r t i c l e
i n f o
Article history: Received 17 September 2014 Received in revised form 25 November 2014 Accepted 25 November 2014 Available online 2 December 2014 Keywords: Vancomycin Therapeutic drug monitoring Febrile neutropenia Hematological malignancy
a b s t r a c t Background: The target trough concentration of vancomycin in patients with febrile neutropenia has not been reported. The aim of this study was to estimate the target trough concentration for febrile neutropenia in patients with hematological malignancy. Methods: In this retrospective, single-center, observational cohort study, 63 hospitalized patients with hematological malignancy who were treated with vancomycin for febrile neutropenia due to bacteriologically documented or presumptive Gram-positive infections were analyzed. Results: A significant difference in the first trough concentration of vancomycin was observed between the response and non-response groups, and between the nephrotoxicity and non-nephrotoxicity groups. Multiple logistic regression analyses identified the first trough concentration as the only independent variable associated with clinical efficacy and nephrotoxicity of vancomycin. The areas under the ROC curves were 0.72 and 0.83 for clinical efficacy and nephrotoxicity, respectively. The cut-off values of the first trough concentration were 11.1 μg/ml for clinical efficacy (sensitivity 60%, specificity 87%) and 11.9 μg/ml for nephrotoxicity (sensitivity 77%, specificity 82%). Conclusions: These results suggest a relationship of trough vancomycin concentration with clinical efficacy and incidence of nephrotoxicity. We propose a target trough vancomycin concentration of around 11.5 μg/ml for febrile neutropenia in patients with hematological malignancy. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Immediate initiation of empirical antibiotic therapy is the standard of care for patients with febrile neutropenia [1], but no single regimen is ideal. Vancomycin is an option for selected patients such as those with hemodynamic instability, pneumonia, clinically evident catheterrelated infection, skin and soft tissue infections, severe mucositis while on empirical ceftazidime treatment after fluoroquinolone prophylaxis, and known colonization with methicillin-resistant Staphylococcus aureus (MRSA) [1]. In general, therapeutic drug monitoring (TDM) of vancomycin is important to improve clinical outcome and to avoid adverse effects such as nephrotoxicity and development of resistance [2,3]. Recent vancomycin therapeutic monitoring guidelines recommend more aggressive vancomycin dosing regimens and maintaining vancomycin trough concentrations between 15 and 20 μg/ml [2,3], in order to maintain an area under the serum concentration–time curve (AUC)/MIC ratio [4–6] at or ⁎ Corresponding author. Tel.: +81 97 586 6113; fax: +81 97 586 6119. E-mail address: [email protected] (Y. Suzuki).
http://dx.doi.org/10.1016/j.cca.2014.11.027 0009-8981/© 2014 Elsevier B.V. All rights reserved.
above 400 [7,8]. On the other hand, a recent prospective multicenter trial suggests that vancomycin trough concentration higher than 15 μg/ml at steady state is a risk factor for nephrotoxicity [9]. Thus, it is necessary to maintain vancomycin trough concentrations between 15 and 20 μg/ml with careful attention to nephrotoxicity. In febrile neutropenia, however, the target trough concentration of vancomycin has not been reported. Thus, the optimal vancomycin dosage in febrile neutropenic patients remains unclear. In this study, we analyzed the correlation of the first trough concentration with clinical efficacy and safety, and estimate the target trough concentration of vancomycin for febrile neutropenia in patients with hematological malignancy. 2. Patients and methods 2.1. Patients Medical records were reviewed to identify hospitalized patients with hematological malignancy treated with vancomycin for febrile neutropenia due to bacteriologically documented or presumptive
184
Y. Suzuki et al. / Clinica Chimica Acta 440 (2015) 183–187
Gram-positive infections at Oita University Hospital between June 2005 and April 2014. Patients who had received prophylactic antifungal agents such as triazole (fluconazole or itraconazole) and candin (micafungin), and remained febrile after at least 3 days of treatment with anti-Gram-negative antibiotics such as broad spectrum penicillin (tazobactam/piperacillin), fourth generation cephem (cefepime), carbapenem (meropenem or doripenem) and fluoroquinolone (ciprofloxacin or levofloxacin) before initiation of vancomycin therapy were included in the study. Patients who were younger than 12 years of age, patients who were hemodialyzed, patients who co-administered other anti-MRSA agents, and patients with Gram-negative bacteremia were excluded. Febrile neutropenia was defined as an axillary temperature of ≥ 37.5 °C sustained for 1 h, with an absolute neutrophil count of b500 cells/mm3 or b1000 cells/mm3 with an anticipated decline to 500 cells/mm3 in the next 48 h [10]. Axillary body temperatures were measured N 4 times a day. Serum trough concentration of vancomycin was obtained from routine TDM data. The following clinical data recorded during vancomycin therapy were collected: gender; age; body weight; and laboratory data including absolute neutrophil count, hemoglobin, platelet count, serum creatinine and blood urea nitrogen. Creatinine clearance was calculated according to the Cockcroft– Gault equation [11]. This study was approved by the Ethics Committee of Oita University Hospital. Since blood samples were collected as part of the routine patient care for TDM and laboratory testing, written informed consent was not necessary.
2.5. Analysis of factors associated with clinical efficacy and nephrotoxicity For the analysis of factors related to clinical efficacy and nephrotoxicity, univariate and multiple logistic regression analyses were performed using patient background, laboratory data and co-administered drugs as independent variables. Co-administered drugs were analyzed when they were used in more than 10 patients. 2.6. Determination of target range of serum trough vancomycin concentrations To evaluate the diagnostic accuracy of the first trough concentration of vancomycin, receiver operating characteristic (ROC) curve and area under the ROC curve (AUCROC) were analyzed. The first trough concentration of vancomycin showing the highest accuracy and specificity for efficacy or safety was defined as the cut-off value. 2.7. Statistics Data are expressed as mean ± standard deviation (SD). Differences between two groups were analyzed by paired t test, 2-sided Student's t test or Welch's t test. A p b 0.05 was considered statistically significant. Statistical analyses were performed using the R software version 2.15.2 (http://www.r-project.org) and Predictive Analysis Software (PASW) Statistics ver 21 (SPSS Inc.). 3. Results
2.2. Drug concentration monitoring Vancomycin was infused intravenously over 1 to 2 h. Blood sampling for the measurement of the first trough concentration at steady state was performed between 2 and 6 days after the initiation of vancomycin therapy [2]. Venous blood samples were collected within an hour before the next administration of vancomycin. A vancomycin assay was performed as a routine laboratory test at Oita University Hospital. Serum vancomycin concentrations were determined by a particle enhanced turbidimetric inhibition immunoassay based on Dimension® Xpand (Siemens Inc.). With this method, the limit of detection was 0.8 μg/ml and the coefficient of variation was b 5% for routine clinical TDM. Furthermore, the measurement error was less than 10% in serum containing creatinine 30 mg/dl and urea 500 mg/dl. 2.3. Evaluation of clinical efficacy Treatment outcome was classified as cure (defervescence within 72 h after initiation of vancomycin therapy, sustained for at least 48 h, and improvement of signs and symptoms of infection), improvement (defervescence within 72 h after initiation of vancomycin therapy and improvement of signs and symptoms of infection), minor response (defervescence within 144 h after initiation of vancomycin therapy and improvement tendency of signs and symptoms of infection) or failure (no defervescence within 144 h after initiation of vancomycin therapy and persistence or progression of clinical signs and symptoms of infection, or administration of any additional antibacterial agent for persistent fever, lack of improvement, progressive infection, or new bacterial infection). Defervescence was defined as a maximum axillary temperature of ≤37.0 °C. Response to vancomycin treatment was defined as the achievement of cure or improvement, and non-response was defined as minor response or failure. 2.4. Evaluation of nephrotoxicity Occurrence of nephrotoxicity was defined as an increase in serum creatinine level of 0.5 mg/dl or an increase of 50%, whichever was greater, between 2 and 10 days after initiation of vancomycin therapy [12].
A review of patient records identified 76 patients who satisfied the selection criteria, and 13 patients who met exclusion criteria were excluded. Table 1 shows the characteristics of 63 patients on the first day of vancomycin administration. Acute leukemia accounted for a substantial fraction of the underlying disease (acute myeloid leukemia, 44.4%; acute lymphoblastic leukemia, 12.7%). Most (84.1%) patients had absolute neutrophil counts of b 100 cells/mm3 at the first day of vancomycin administration. Fever of unknown origin and oral mucositis related infection were the most common etiologies (46.0% and 30.2%, respectively). A wide variety of anti-Gram-negative antibiotics and antifungal agents were administered. The first trough concentration of vancomycin was 10.7 ± 6.8 μg/ml, showing large variability. Of the 63 patients, 25 were assessed as showing clinical response (response group) and 38 as showing no response (non-response group). As shown in Fig. 1a, a significant difference in the first trough concentration of vancomycin was observed between the response and non-response groups (p = 0.016). Univariate and multiple logistic regression analyses by stepwise selection identified the first trough concentration as the only independent variable associated with efficacy. The odds ratio (95% confidence interval) was 1.10 (1.01–1.20) (p = 0.026). Fig. 2a shows the optimal ROC curve for predicting response to vancomycin using the first trough vancomycin concentration. The AUCROC was 0.72 and the cut-off value of the first trough concentration for clinical efficacy was 11.1 μg/ml (sensitivity 60%, specificity 87%). Nephrotoxicity was observed in 13 patients. The durations of vancomycin treatment were 9.5 ± 4.8 and 8.7 ± 3.5 days in patients with and without nephrotoxicity, respectively, and did not differ significantly between 2 groups (p = NS). Nephrotoxicity occurred 5.8 ± 2.7 days after initiation of vancomycin, and was significantly later than the time of blood sampling for TDM (2.7 ± 0.9 days) (p = 0.0061). As shown in Fig. 1b, a significant difference in the first trough concentration of vancomycin was observed between the nephrotoxicity and non-nephrotoxicity groups (p = 0.0047). In univariate logistic regression analysis for clinical factors associated with nephrotoxicity, the p values for the first trough concentration (p b 0.0001), blood urea nitrogen (p = 0.0011) and use of opioids (p = 0.078) were less than 0.10. Multiple logistic regression analysis by stepwise selection using the first trough concentration, blood urea nitrogen and use of opioids
Y. Suzuki et al. / Clinica Chimica Acta 440 (2015) 183–187 Table 1 Patient characteristics at the first day of vancomycin administration. Characteristic
Value
No. of subjects Males/females Age (y) Body weight (kg) Underlying disease Acute leukemia Acute myeloid leukemia Acute lymphoblastic leukemia Adult T-cell leukemia Diffuse large B-cell lymphoma Multiple myeloma Myelodysplasia Hodgkin lymphoma Other Hematopoietic stem cell transplant Autologous Allogeneic Absolute neutrophil count (cells/mm3) b100 100–500 N500 Duration of neutropenia (day) Hemoglobin (g/dl) Platelet count (/μl) Blood urea nitrogen (mg/dl) Serum creatinine (mg/dl) Creatinine clearancea (ml/min) Infections Fever of uncertain origin Oral mucositis related Bacteremiab Staphylococcus aureus Staphylococcus epidermidis Streptococci Enterococcus faecalis Other Enterococci Corynebacteria Vascular-catheter related Pneumonia Anti-infective treatment started before initiation of vancomycin Broad spectrum penicillins Tazobactam/Piperacillin Cephalosporins Cefepime Carbapenems Meropenem Doripenem Aminoglycosides Amikacin Fluoroquinolones Ciprofloxacin Levofloxacin Antifungal Amphotericin B Fluconazole Itraconazole Voriconazole Micafungin Antiviral Acyclovir Other co-administered drugs during vancomycin therapyd Proton pump inhibitor Granulocyte colony stimulating factor Calcineurin inhibitor Loop diuretic Benzodiazepine Acetaminophen Antihistamine Opioids Non-steroid anti-inflammatory drug Steroid Recombinant thrombomodulin Calcium inhibitor
63 43/20 50.9 ± 14.2 [25–78] 55.6 ± 7.9 [37.8–78.3]
28 8 10 6 4 3 1 3 3 42 53 10 0 7.4 ± 6.6 [1–40] 8.6 ± 1.4 [5.1–12.7] 25,332 ± 18,066 [2900–92,000] 17.6 ± 12.1 [6.3–85.2] 0.65 ± 0.28 [0.30–1.66] 113.1 ± 40.6 [38.0–209.9] 29 19 9 2 5 1 4 1 1 3 3
3 7 47 12 4 1 25 4 10 11 4 39 41
58 47 34 33 29 24 22 21 20 17 16 12
185
Table 1 (continued) Characteristic
Value
Duration of vancomycin therapy (day) Time of blood sampling for first TDMc (day) First trough concentration of vancomycin (μg/ml)
8.9 ± 3.8 [4–25] 2.7 ± 0.9 [2–6] 10.7 ± 6.8 [2.5–34.4]
Data are expressed as numbers or mean ± S.D. [Range]. a Creatinine clearance was calculated according to the Cockcroft–Gault equation. b Some patients were infected with more than 1 pathogen. c TDM: therapeutic drug monitoring. d Drugs administered in N10 patients.
identified the first trough concentration as the only independent variable of vancomycin-related nephrotoxicity. The odds ratio (95% confidence interval) was 1.21 (1.08–1.36) (p = 0.00092). Fig. 2b shows the optimal ROC curve for predicting nephrotoxicity using the first trough concentration of vancomycin. The AUCROC was 0.83 and the cut-off value of the first trough concentration for nephrotoxicity was 11.9 μg/ml (sensitivity 77%, specificity 82%). 4. Discussion In this study, we attempted to set the target trough concentration of vancomycin for febrile neutropenia in patients with hematological malignancy. It is reported that 80% patients with hematologic malignancies develop fever associated with neutropenia during more than 1 chemotherapy cycle [13]. Gram-positive bacteria have become more common in the epidemiologic spectrum of bloodstream isolates from febrile neutropenic patients [14,15] because of increased use of indwelling plastic venous catheters, which may facilitate colonization by and entry of Gram-positive skin flora [15,16]. Thus, vancomycin is needed for febrile neutropenia suspected to be caused by Gram-positive infections, especially MRSA infection. This study enrolled only patients who had received prophylactic anti-fungal agents and who had remained febrile and neutropenic despite treatment with anti-Gram-negative antibiotics for more than 3 days before initiation of vancomycin. Therefore, this study presumably evaluated the clinical efficacy of vancomycin against Gram-positive infections. Some prospective studies suggested that the inclusion of glycopeptides in the initial empiric antibiotic regimen has no benefit because they do not improve the interval to defervescence or mortality rate in febrile neutropenic patients [17,18]. However, Ramphal et al. reported that the addition of vancomycin resulted in defervescence in some febrile neutropenia patients in whom fever persisted after ceftazidime monotherapy [19]. Consistent with their finding, the use of vancomycin achieved defervescence in approximately 40% of our febrile neutropenic patients in whom anti-Gram-negative antibiotics failed to achieve defervescence. This result suggests that vancomycin may be appropriate when fever persists despite treatment with antibiotics for Gramnegative infections. On the other hand, nephrotoxicity was observed in 13 patients (20.6%) in this study. According to a review, nephrotoxicity associated with vancomycin therapy was observed in 2–28% of patients [20]. Patients with hematological malignancy are at high risk of renal failure associated with serious clinical condition and multiple co-administered medications, which may account for the relatively high incidence of nephrotoxicity. First, our study showed significant differences in the first trough concentration of vancomycin between the response and non-response groups and between the nephrotoxicity and non-nephrotoxicity groups. These findings suggest that trough concentration of vancomycin may be associated with clinical efficacy and nephrotoxicity in febrile neutropenic patients with hematological malignancy. Second, multiple logistic regression analysis identified the first trough concentration of vancomycin as the only independent variable associated with both clinical efficacy and nephrotoxicity. This is the first report on the association of trough vancomycin concentration with clinical
Y. Suzuki et al. / Clinica Chimica Acta 440 (2015) 183–187
(a)
(a)
p = 0.016
1
0.8 0.6 0.4 0.2 0
0
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0.4
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0.8
1
0.8
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1-specificity
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efficacy and nephrotoxicity in febrile neutropenic patients with hematological malignancy, although such association has been reported in patients with bacteremia [7], lower respiratory tract infection [8] and pneumonia [21–23]. Finally, the cut-off trough concentrations of vancomycin were estimated to be 11.1 μg/ml for clinical efficacy and 11.9 μg/ml for nephrotoxicity in febrile neutropenic patients with hematological malignancy. Therefore, we propose that the trough concentration should be targeted within a narrow range at approximately 11.5 μg/ml when vancomycin is used for the treatment of febrile neutropenia in patients with hematological malignancy. The cut-off trough level of 11.1 μg/ml for clinical efficacy estimated in this study is lower than those recommended in recent guidelines (15 to 20 μg/ml) [2,3], suggesting that less vancomycin exposure is required to achieve clinical response in patients with febrile neutropenia. One possible reason is a low prevalence of deep infection by MRSA in febrile neutropenic patients [24]. Like clinical efficacy, the cut-off trough level of 11.9 μg/ml for nephrotoxicity is also lower than the recommended levels. Febrile neutropenic patients with hematological malignancy are at high risk of nephrotoxicity associated with serious clinical condition and multiple co-administered medications. Thus, even a normal level of vancomycin exposure may trigger nephrotoxicity in these patients. This is the first report proposing to target trough concentration of vancomycin within a narrow range centering at 11.5 μg/ml, and this finding may
Sensitivity
186
0.6 0.4
40
Trough concentration of vancomycin (μg/mL)
0.2 30 0
0.2
0.4
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20
Figure 2. Receiver operating characteristic curves for predicting clinical efficacy (a) and nephrotoxicity (b) using the first trough concentration of vancomycin.
10
0
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(b)
Non-response
p = 0.0047
40
Trough concentration of vancomycin (μg/mL)
0
30
20
10
0
Nephrotoxicity
Non-nephrotoxicity
Figure 1. Trough concentrations of vancomycin in response and non-response groups (a) and in nephrotoxicity and non-nephrotoxicity groups (b). Bar indicates the mean value.
contribute to proper use of vancomycin for febrile neutropenia in patients with hematological malignancy. Our study has some limitations. First, occurrence of nephrotoxicity was defined as an increase in serum creatinine level only, while other markers of kidney damage such as proteinuria were not considered in this study. More refined study using a combination of useful markers reflecting kidney damage may be useful to evaluate an association of trough concentration of vancomycin with occurrence of nephrotoxicity. Second, there were only 9 patients with bacteremia in this study. Further study of a larger number of patients with bacteremia may be helpful to correlate MIC, trough vancomycin concentration, treatment response, and nephrotoxicity. Finally, this study analyzed only Japanese patients with hematological malignancy in a single center. Further large-scale study including patients in multiple centers and different countries is required to verify whether this target trough concentration of vancomycin is applicable to other patient cohorts. In conclusion, the present study suggests a relationship of trough vancomycin concentration with clinical efficacy and incidence of nephrotoxicity, and proposes a target trough concentration of around 11.5 μg/ml for febrile neutropenic in patients with hematological malignancy.
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