- Email: [email protected]
Risk factors for colistin-associated nephrotoxicity
Letters to the Editor
187
7. Chang CM, Lauderdale TL, Lee HC, Lee NY, Wu CJ, Chen PL, et al. Colonisation of fluoroquinolone-resistant Haemophilus influenzae among nursing home residents in southern Taiwan. J Hosp Infect 2010;75:304e8.
Kuei-Pin Chung Yu-Tsung Huang Li-Na Lee Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan Chong-Jen Yu Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan Chih-Cheng Lai Department of Intensive Care Medicine, Chi-Mei Medical Center, Liouying Tainan, Taiwan Po-Ren Hsueh* Department of Laboratory Medicine, National Taiwan University Hospital, No. 7, Chung-Shan, South Rd, Taipei 100, Taiwan Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan, South Rd, Taipei 100, Taiwan * Corresponding author. Tel.: þ886 2 23123456x65355. E-mail address: [email protected] Accepted 6 December 2010 Available online 8 December 2010 ª 2010 The British Infection Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2010.12.001
Risk factors for colistin-associated nephrotoxicity
Dear Editor, We read with interest the article by Yau et al. on colistin hetero-resistance in multidrug-resistant Acinetobacter baumannii clinical isolates from the western Pacific region.1 Less than a decade after intravenous colistin had been re-introduced to clinical practice, resistance to colistin in clinical isolates has become a global problem.1e5 Some hypothesized that development of colistin resistance is the result of suboptimal dosage of colistin therapy.6 Intravenous colistin had been abandoned over 20 years because of its nephrotoxicity. Increasing dosage of colistin
to prevent the emergence of resistance may lead to this adverse drug reaction. Lack of knowledge on risk factors for nephrotoxicity is an obstacle to prevent this unpleasant event. Given these considerations, we conducted a retrospective case-control study to identify risk factors for nephrotoxicity in patients who received intravenous colistin. This study was conducted at Siriraj Hospital, a 2300-bed tertiary care university hospital in Bangkok, Thailand, from January 1, 2007 through December 31, 2007. The study was approved by the Siriraj ethical committee. All hospitalized patients who received intravenous colistin for at least 24 h were identified through the Siriraj pharmacy database. We enrolled only the patients in whom serum creatinine (SCr) levels before and after the initiations of intravenous colistin were available. Patients were excluded if they had been on renal replacement therapy prior to the initiation of intravenous colistin. Cases were those who developed at least one event of nephrotoxicity during the entire course or within 7 days after the discontinuation of intravenous colistin. Controls were those who had never developed nephrotoxicity during the same monitoring period. Nephrotoxicity was defined as an increased SCr by 50% when comparing to a baseline SCr level and/or renal replacement therapy was required.7 For each admission, we included only the first course of intravenous colistin therapy for a given patient. Inpatient medical records of all eligible subjects were reviewed to obtain the data on baseline characteristics, comorbidities, suspected site(s) of infection, causative pathogens, hospital course and detail of all antimicrobial therapy. Serum creatinine (SCr) levels were directly retrieved from the Central Laboratory Database. During the study period, there were 139 eligible courses of intravenous colistin in 134 unique subjects. Of these 139 eligible courses of intravenous colistin, we enrolled 73 cases and 66 controls. The cumulative incidence of nephrotoxicity was 52.5% (73/139), and only 1.4% (2/139) of all study patients required renal replacement therapy. Of these 73 cases, 33 (58.9%) and 22 (30.1%) of them developed nephrotoxicity during the first week and the second week of receiving intravenous colistin, respectively. Median duration and cumulative dose of intravenous colistin at the onset of nephrotoxicity was 7 days (1e25 days) and 1200 mg (75e5000 mg), respectively. Patients’ characteristics, comorbidities and detail of antimicrobial therapy among cases and controls are presented in Table 1. Cases had a significantly lower baseline SCr level (0.8 mg/dl vs. 1.7 mg/dl, p < 0.001) and were exposed to longer duration (14.0 vs. 6.5 days, p < 0.001) and higher dose of intravenous colistin (3.6 vs. 3.0 mg of colistin base/kg/d, p < 0.001). Nebulized colistin therapy was given to 6.9% of cases and 3.0% of controls (p Z 0.45). Concomitant vancomycin therapy was more prevalent among cases when compared to controls (42.1% vs. 23.9%, p Z 0.02). The variables that remained independent risk factors for nephrotoxicity after multivariable analysis are shown in Table 2. Independent risk factors included old age, long duration of intravenous colistin, high dose of intravenous colistin and concomitant vancomycin therapy. Although old age has been previously documented as a risk factor for colistin-associated nephrotoxicity,8 the present study was, to our knowledge, the first to
188 Table 1
Letters to the Editor Patients’ characteristics and detail of antimicrobial among cases and controls.
Variables
Cases (n Z 73)
Controls (n Z 66)
p-value
Median age, years (range) Median weight, kilograms (range) Median baseline Cr level, mg/d (range) Male gender Medicine service ICU admission on the first day of receiving colistin Comorbidities Chronic kidney diseases Chronic liver diseases Coronary artery diseases Diabetes mellitus Hypertension Malignancy Neurological diseases Receiving immunosuppressive therapy Site (s) of infection Respiratory tract infection Urinary tract infection Soft tissue infection Catheter-related infection Bacteremia Causative pathogen Acinetobacter baumannii Multidrug-resistant pathogens Intravenous colistin therapy Median duration, days Median length of stay prior to therapy, days Median dose (mg of colistin base/d) Median dose (mg of colistin base/kg/d) Dose by categories Low (<3 mg of colistin base/kg/d) Moderate (3e5 mg of colistin base/kg/d) High (>5 mg of colistin base/kg/d) Nebulized colistin therapy Concomitant antibiotics Beta-lactam antibiotics Fluoroquinolones Aminoglycosides Vancomycin Clindamycin Metronidazole Amphotericin B Others
72.0 50.0 0.8 39 60 16 71 7 5 24 23 33 20 29 11
66.5 50.0 1.7 33 50 13 64 13 4 20 24 35 11 17 8
(12.0e96.0) (36.0e80.0) (0.3e7.5) (50.0) (75.8) (19.7) (97.0) (19.7) (6.1) (30.3) (364) (53.0) (16.7) (25.8) (12.1)
0.25 0.25 <0.001 0.69 0.35 0.75 >0.99 0.09 >0.99 0.75 0.55 0.36 0.13 0.08 0.61
(80.3) (12.1) (10.6) (1.5) (12.1)
0.62 0.29 0.43 >0.99 0.45
56 (84.9) 56 (84.9)
0.23 0.17
61 5 5 2 6
(19.0e99.0) (35.0e89.0) (0.1e5.4) (53.4) (82.2) (21.9) (97.3) (9.6) (6.9) (32.9) (31.5) (45.2) (27.4) (39.7) (15.1) (83.6) (6.9) (6.9) (2.7) (8.2)
56 (76.7) 55 (75.3) 14.0 22.0 200 3.6
(2.0e44.0) (1.0e347) (75-320) (1.1e8.6)
26 (35.6) 29(39.7) 18 (24.7) 5 (6.9) 62 (84.9) 38 (52.1) 10 (13.7) 3 (4.1) 31 (42.5) 3 (4.1) 10 (13.7) 3 (4.1) 12 (16.4)
53 8 7 1 8
6.5 16.0 150 3.0 40 20 6 2 49 37 5 5 16 2 4 7 11
(2.0e74.0) (0.0e174.0) (50-450) (1.0e7.5) (60.6) (30.3) (9.1) (3.0) (74.2) (56.1) (7.6) (7.6) (22.2) (3.0) (6.1) (10.6) (16.7)
<0.001 0.21 <0.001 <0.001 0.006
0.45 0.12 0.64 0.25 0.48 0.02 >0.99 0.14 0.19 0.97
Note: Chi-square or Fisher’s exact test was used to compare the categorical variables while ManneWhitney U-test was used to compared the continuous variables.
demonstrate this association after adjusting for other risk factors. Similar to previous studies,8e10 we found that nephrotoxicity of colistin was associated with dose and duration. Furthermore, the moderate dose of intravenous colistin (which was comparable to the generally recommended dosage) appeared to be an independent risk factor. Unfortunately, we did not have enough information to explore if those given dosages were appropriately adjusted for patients’ renal function. According to inpatient-antimicrobial therapy, only concomitant vancomycin therapy appeared to be an independent risk
factor for nephrotoxicity. Although it was commonly believed that vancomycin given with other nephrotoxic antibiotics would increase risk of nephrotoxicity, its synergistic effect on colistin nephrotoxicity has never been confirmed before. Previous study noted that renal impairment at baseline had a protective effect against nephrotoxicity associated with colistin therapy.11 In our univariate analyses, patients in the control group had a significantly higher baseline SCr level and a slightly higher prevalence of chronic kidney diseases. A possible explanation was patients with renal impairment may be closely monitored for nephrotoxicity
Letters to the Editor Table 2
189
Independent risk factors for nephrotoxicity (multivariable analysis).
Variables
Unadjusted OR [95% CI]
Adjusted OR [95% CI]
Old age (years) Colistin duration (days) Colistin dose Low dose (<3 mg/kg/d) Moderate dose (3e5 mg/kg/d) High dose (>5 mg/kg/d) Concomitant vancomycin therapy
1.01 [1.00e1.03] 1.12 [1.04e1.19]
1.04 [1.01e1.06] 1.10 [1.03e1.19]
0.004 0.007
Ref 2.20 [1.05e4.74] 4.61 [1.62e13.16] 2.32 [1.06e5.14]
Ref 3.05 [1.25e7.45] 15.3 [3.87e60.6] 2.84 [1.21e6.69]
<0.001
and perhaps they were treated with shorter duration and lower dose of intravenous colistin. This assumption was supported by the results from our multivariable analysis. The protective effect of a higher baseline SCr level and having chronic kidney diseases were disappeared when we adjusted for the dose and duration of intravenous colistin in the multivariable model. Our study had several potential limitations. The lack of data on other nephrotoxic agents such as non-steroidal antiinflammatory drugs (NSAIDs) may result in information bias; nevertheless NSAIDs are rarely used in critically-ill patients at our institution. Although we did not have data on severity of illness and hypotensive episodes but comorbidities were comparable between cases and controls. Therefore, we did not have a reason to believe this would introduce differential bias. Additionally, our study was conducted at the largest university hospital in Thailand. Thus, the results may be inapplicable to smaller settings such as community hospitals. Intravenous colistin therapy has been considered the last resort for treatment of multidrug-resistant gram-negative infections.12e14 Hence, prescribing this highly nephrotoxic antibiotic may be unavoidable. Our study results have important implication with regard to possible interventions to prevent nephrotoxicity events. Drug monitoring program to shorten duration and closely adjust dose of intravenous colistin as appropriate should be endeavored. Finally, renal function should be carefully monitored in the high risk group especially elderly patients and patients who received concomitant vancomycin.
4.
5.
6. 7.
8.
9.
10.
11.
12.
Acknowledgment Funding: Faculty of Medicine Siriraj hospital, Mahidol University, Bangkok, Thailand. Transparency declarations: none to declare.
References 1. Yau W, Owen RJ, Poudyal A, Bell JM, Turnidge JD, Yu HH, et al. Colistin hetero-resistance in multidrug-resistant Acinetobacter baumannii clinical isolates from the Western Pacific region in the SENTRY antimicrobial surveillance programme. J Infect 2009 Feb;58(2):138e44. 2. Li J, Rayner CR, Nation RL, Owen RJ, Spelman D, Tan KE, et al. Heteroresistance to colistin in multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother 2006 Sep;50(9):2946e50. 3. Beno P, Krcmery V, Demitrovicova A. Bacteraemia in cancer patients caused by colistin-resistant gram-negative bacilli
13.
14.
p-value
0.02
after previous exposure to ciprofloxacin and/or colistin. Clin Microbiol Infect 2006 May;12(5):497e8. Hawley JS, Murray CK, Jorgensen JH. Colistin heteroresistance in acinetobacter and its association with previous colistin therapy. Antimicrob Agents Chemother 2008 Jan;52(1):351e2. Rodriguez CH, Bombicino K, Granados G, Nastro M, Vay C, Famiglietti A. Selection of colistin-resistant Acinetobacter baumannii isolates in postneurosurgical meningitis in an intensive care unit with high presence of heteroresistance to colistin. Diagn Microbiol Infect Dis 2009 Oct;65(2):188e91. Li J, Nation RL. Old polymyxins are back: is resistance close? Clin Infect Dis 2006 Sep 1;43(5):663e4. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004 Aug;8(4):R204e12. Koch-Weser J, Sidel VW, Federman EB, Kanarek P, Finer DC, Eaton AE. Adverse effects of sodium colistimethate. Manifestations and specific reaction rates during 317 courses of therapy. Ann Intern Med 1970 Jun;72(6):857e68. Falagas ME, Fragoulis KN, Kasiakou SK, Sermaidis GJ, Michalopoulos A. Nephrotoxicity of intravenous colistin: a prospective evaluation. Int J Antimicrob Agents 2005 Dec;26(6):504e7. Deryke CA, Crawford AJ, Uddin N, Wallace MR. Colistin dosing and nephrotoxicity in a large community teaching hospital. Antimicrob Agents Chemother 2010 Jul 26;54(10):4503e5. Hartzell JD, Neff R, Ake J, Howard R, Olson S, Paolino K, et al. Nephrotoxicity associated with intravenous colistin (colistimethate sodium) treatment at a tertiary care medical center. Clin Infect Dis 2009 Jun 15;48(12):1724e8. Koomanachai P, Tiengrim S, Kiratisin P, Thamlikitkul V. Efficacy and safety of colistin (colistimethate sodium) for therapy of infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii in Siriraj Hospital, Bangkok, Thailand. Int J Infect Dis 2007 Sep;11(5):402e6. Michalopoulos AS, Tsiodras S, Rellos K, Mentzelopoulos S, Falagas ME. Colistin treatment in patients with ICU-acquired infections caused by multiresistant gram-negative bacteria: the renaissance of an old antibiotic. Clin Microbiol Infect 2005 Feb;11(2):115e21. Falagas ME, Rafailidis PI, Ioannidou E, Alexiou VG, Matthaiou DK, Karageorgopoulos DE, et al. Colistin therapy for microbiologically documented multidrug-resistant Gramnegative bacterial infections: a retrospective cohort study of 258 patients. Int J Antimicrob Agents 2010 Feb;35(2):194e9.
Pinyo Rattanaumpawan Division of Infectious Diseases and Tropical Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
190
Letters to the Editor Puangpaka Ungprasert Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
Visanu Thamlikitkul* Division of Infectious Diseases and Tropical Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand * Corresponding author. Division of Infectious Diseases and Tropical Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand. Tel./fax: +66 2 412 5994. E-mail address: [email protected] Accepted 24 November 2010 Available online 1 December 2010 ª 2010 The British Infection Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2010.11.013
Time to blood culture positivity as a predictor of methicillin resistance in Staphylococcus aureus bacteremia
Dear Editor, Recently, Kim et al. described the association between time to blood culture positivity (TTP) and clinical outcome in 684 patients with Staphylococcus aureus bacteremia in a retrospective study.1 Results from their multivariate logistic regression analysis revealed that the 30-day mortality rate was associated with age, nosocomial acquisition of infection, focus of infection, liver disease, methicillin-resistant S. aureus (MRSA), and TTP 12 and TTP > 48 h.1 In addition, the median TTP was shorter for methicillin-susceptible S. aureus (MSSA) isolates (15; IQR, 12e20 h) than for MRSA isolates (17; IQR, 13e22 h, P Z 0.015). Thus, we wonder whether the longer TTP of S. aureus isolates could help clinicians predict resistance to methicillin before formal drug susceptibility tests. S. aureus is responsible for 10%e18% of all communityacquired and about 20% of all nosocomial bacteremia.2,3 In addition, the emergence of MRSA is a growing clinical challenge in hospital-associated settings and, more recently, in community settings in both the United States and worldwide.4 In Taiwan, MRSA infection accounts for about 60% of nosocomial S. aureus infections5 and it is also an emerging community-acquired pathogen.6 Furthermore, the impact of the increasing frequency of MRSA bacteremia is magnified by the poor prognosis associated with this serious infection.6,7 Therefore, early detection of MRSA isolates followed by the administration of appropriate antibiotic therapy is necessary to improve the outcome of patients with S. aureus bacteremia.
In this study we evaluated the ability of TTP to differentiate between MRSA and MSSA bacteremia. This study was prospectively conducted at the National Taiwan University Hospital, a 2500-bed tertiary care medical center in northern Taiwan. Patients with S. aureus bacteremia were identified by central laboratory personnel from July to October, 2010. TTP for each patient was retrieved from the hospital automated blood culture instrument. Each patient was included only once at the time of detection of the first bloodstream infection. Patients younger than 18 years and patients with polymicrobial bacteremia were excluded. At least two sets of blood samples, 10 ml each, were taken from separate locations and inoculated into aerobic and anaerobic culture bottles (Bactec 9240, Becton Dickinson, Sparks, MA, USA). Susceptibility to antimicrobial agents was determined by the standard disk diffusion method.8 TTP, defined as the time from the start of incubation to the start of the alert signal (as documented by the monitoring system), was recorded for each bottle of positive blood culture. For a patient with multiple sets of positive blood cultures at approximately the same time, the shortest TTP was used. Means and standard deviations were calculated for continuous variables. ManneWhitney test was used for comparison of continuous variables. Receiver operating characteristic (ROC) curves were plotted for TTP to identify MRSA bacteremia and the area under the curve (AUC) was calculated. A P-value < 0.05 was considered to represent statistical significance. Data were analyzed with the statistical package SPSS for Windows (Version 10.0; SPSS, Chicago, IL, USA). During the study period, a total of 90 patients with S. aureus bacteremia were recruited. Most of the patients were men (63.3%) and the mean age was 56.2 21.9 years. A total of 36 (40%) S. aureus isolates were MRSA. The mean TTP for all S. aureus isolates was 19.9 19.4 h. The median TTP was shorter for MSSA isolates (14.1 9.8 h) than for MRSA isolates (28.6 26.1 h; P Z 0.003). Fig. 1 shows the receiver operating characteristic (ROC) curves, which were plotted to evaluate the ability of TTP to identify MRSA isolates in patients with S. aureus bloodstream infections. The area under the ROC curve (AUC) was 0.778 (95% CI 0.678e0.859). Overall, the diagnostic sensitivity was 91.7% (95% CI 0.775e0.982), the specificity was 57.4% (95% CI 0.432e0.708), the positive predictive value was 58.9%, and the negative predictive value of TTP for MRSA bacteremia in patients with S. aureus bacteremia was 91.2%, with a TTP cutoff value of 11.46 h. In this study, there are two significant findings about the relationship between TTP and S. aureus bacteremia. First, the TTP was significantly shorter in patients with MSSA bacteremia than in patients with MRSA bacteremia. This is consistent with findings from Kim et al.1 and Khatih et al.9 Second, we found that the overall sensitivity and specificity of TTP for identifying MRSA bacteremia in patients with S. aureus bacteremia were 91.7% and 57.4%, respectively, with a TTP cutoff of 11.46 h. In addition, the high negative predictive value of 91% may be helpful for physicians to exclude the presence of methicillin resistance among S. aureus isolates. Although the drug susceptibility test is still the gold standard to identify MRSA, TTP may provide earlier detection of methicillin-resistant
187
7. Chang CM, Lauderdale TL, Lee HC, Lee NY, Wu CJ, Chen PL, et al. Colonisation of fluoroquinolone-resistant Haemophilus influenzae among nursing home residents in southern Taiwan. J Hosp Infect 2010;75:304e8.
Kuei-Pin Chung Yu-Tsung Huang Li-Na Lee Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan Chong-Jen Yu Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan Chih-Cheng Lai Department of Intensive Care Medicine, Chi-Mei Medical Center, Liouying Tainan, Taiwan Po-Ren Hsueh* Department of Laboratory Medicine, National Taiwan University Hospital, No. 7, Chung-Shan, South Rd, Taipei 100, Taiwan Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan, South Rd, Taipei 100, Taiwan * Corresponding author. Tel.: þ886 2 23123456x65355. E-mail address: [email protected] Accepted 6 December 2010 Available online 8 December 2010 ª 2010 The British Infection Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2010.12.001
Risk factors for colistin-associated nephrotoxicity
Dear Editor, We read with interest the article by Yau et al. on colistin hetero-resistance in multidrug-resistant Acinetobacter baumannii clinical isolates from the western Pacific region.1 Less than a decade after intravenous colistin had been re-introduced to clinical practice, resistance to colistin in clinical isolates has become a global problem.1e5 Some hypothesized that development of colistin resistance is the result of suboptimal dosage of colistin therapy.6 Intravenous colistin had been abandoned over 20 years because of its nephrotoxicity. Increasing dosage of colistin
to prevent the emergence of resistance may lead to this adverse drug reaction. Lack of knowledge on risk factors for nephrotoxicity is an obstacle to prevent this unpleasant event. Given these considerations, we conducted a retrospective case-control study to identify risk factors for nephrotoxicity in patients who received intravenous colistin. This study was conducted at Siriraj Hospital, a 2300-bed tertiary care university hospital in Bangkok, Thailand, from January 1, 2007 through December 31, 2007. The study was approved by the Siriraj ethical committee. All hospitalized patients who received intravenous colistin for at least 24 h were identified through the Siriraj pharmacy database. We enrolled only the patients in whom serum creatinine (SCr) levels before and after the initiations of intravenous colistin were available. Patients were excluded if they had been on renal replacement therapy prior to the initiation of intravenous colistin. Cases were those who developed at least one event of nephrotoxicity during the entire course or within 7 days after the discontinuation of intravenous colistin. Controls were those who had never developed nephrotoxicity during the same monitoring period. Nephrotoxicity was defined as an increased SCr by 50% when comparing to a baseline SCr level and/or renal replacement therapy was required.7 For each admission, we included only the first course of intravenous colistin therapy for a given patient. Inpatient medical records of all eligible subjects were reviewed to obtain the data on baseline characteristics, comorbidities, suspected site(s) of infection, causative pathogens, hospital course and detail of all antimicrobial therapy. Serum creatinine (SCr) levels were directly retrieved from the Central Laboratory Database. During the study period, there were 139 eligible courses of intravenous colistin in 134 unique subjects. Of these 139 eligible courses of intravenous colistin, we enrolled 73 cases and 66 controls. The cumulative incidence of nephrotoxicity was 52.5% (73/139), and only 1.4% (2/139) of all study patients required renal replacement therapy. Of these 73 cases, 33 (58.9%) and 22 (30.1%) of them developed nephrotoxicity during the first week and the second week of receiving intravenous colistin, respectively. Median duration and cumulative dose of intravenous colistin at the onset of nephrotoxicity was 7 days (1e25 days) and 1200 mg (75e5000 mg), respectively. Patients’ characteristics, comorbidities and detail of antimicrobial therapy among cases and controls are presented in Table 1. Cases had a significantly lower baseline SCr level (0.8 mg/dl vs. 1.7 mg/dl, p < 0.001) and were exposed to longer duration (14.0 vs. 6.5 days, p < 0.001) and higher dose of intravenous colistin (3.6 vs. 3.0 mg of colistin base/kg/d, p < 0.001). Nebulized colistin therapy was given to 6.9% of cases and 3.0% of controls (p Z 0.45). Concomitant vancomycin therapy was more prevalent among cases when compared to controls (42.1% vs. 23.9%, p Z 0.02). The variables that remained independent risk factors for nephrotoxicity after multivariable analysis are shown in Table 2. Independent risk factors included old age, long duration of intravenous colistin, high dose of intravenous colistin and concomitant vancomycin therapy. Although old age has been previously documented as a risk factor for colistin-associated nephrotoxicity,8 the present study was, to our knowledge, the first to
188 Table 1
Letters to the Editor Patients’ characteristics and detail of antimicrobial among cases and controls.
Variables
Cases (n Z 73)
Controls (n Z 66)
p-value
Median age, years (range) Median weight, kilograms (range) Median baseline Cr level, mg/d (range) Male gender Medicine service ICU admission on the first day of receiving colistin Comorbidities Chronic kidney diseases Chronic liver diseases Coronary artery diseases Diabetes mellitus Hypertension Malignancy Neurological diseases Receiving immunosuppressive therapy Site (s) of infection Respiratory tract infection Urinary tract infection Soft tissue infection Catheter-related infection Bacteremia Causative pathogen Acinetobacter baumannii Multidrug-resistant pathogens Intravenous colistin therapy Median duration, days Median length of stay prior to therapy, days Median dose (mg of colistin base/d) Median dose (mg of colistin base/kg/d) Dose by categories Low (<3 mg of colistin base/kg/d) Moderate (3e5 mg of colistin base/kg/d) High (>5 mg of colistin base/kg/d) Nebulized colistin therapy Concomitant antibiotics Beta-lactam antibiotics Fluoroquinolones Aminoglycosides Vancomycin Clindamycin Metronidazole Amphotericin B Others
72.0 50.0 0.8 39 60 16 71 7 5 24 23 33 20 29 11
66.5 50.0 1.7 33 50 13 64 13 4 20 24 35 11 17 8
(12.0e96.0) (36.0e80.0) (0.3e7.5) (50.0) (75.8) (19.7) (97.0) (19.7) (6.1) (30.3) (364) (53.0) (16.7) (25.8) (12.1)
0.25 0.25 <0.001 0.69 0.35 0.75 >0.99 0.09 >0.99 0.75 0.55 0.36 0.13 0.08 0.61
(80.3) (12.1) (10.6) (1.5) (12.1)
0.62 0.29 0.43 >0.99 0.45
56 (84.9) 56 (84.9)
0.23 0.17
61 5 5 2 6
(19.0e99.0) (35.0e89.0) (0.1e5.4) (53.4) (82.2) (21.9) (97.3) (9.6) (6.9) (32.9) (31.5) (45.2) (27.4) (39.7) (15.1) (83.6) (6.9) (6.9) (2.7) (8.2)
56 (76.7) 55 (75.3) 14.0 22.0 200 3.6
(2.0e44.0) (1.0e347) (75-320) (1.1e8.6)
26 (35.6) 29(39.7) 18 (24.7) 5 (6.9) 62 (84.9) 38 (52.1) 10 (13.7) 3 (4.1) 31 (42.5) 3 (4.1) 10 (13.7) 3 (4.1) 12 (16.4)
53 8 7 1 8
6.5 16.0 150 3.0 40 20 6 2 49 37 5 5 16 2 4 7 11
(2.0e74.0) (0.0e174.0) (50-450) (1.0e7.5) (60.6) (30.3) (9.1) (3.0) (74.2) (56.1) (7.6) (7.6) (22.2) (3.0) (6.1) (10.6) (16.7)
<0.001 0.21 <0.001 <0.001 0.006
0.45 0.12 0.64 0.25 0.48 0.02 >0.99 0.14 0.19 0.97
Note: Chi-square or Fisher’s exact test was used to compare the categorical variables while ManneWhitney U-test was used to compared the continuous variables.
demonstrate this association after adjusting for other risk factors. Similar to previous studies,8e10 we found that nephrotoxicity of colistin was associated with dose and duration. Furthermore, the moderate dose of intravenous colistin (which was comparable to the generally recommended dosage) appeared to be an independent risk factor. Unfortunately, we did not have enough information to explore if those given dosages were appropriately adjusted for patients’ renal function. According to inpatient-antimicrobial therapy, only concomitant vancomycin therapy appeared to be an independent risk
factor for nephrotoxicity. Although it was commonly believed that vancomycin given with other nephrotoxic antibiotics would increase risk of nephrotoxicity, its synergistic effect on colistin nephrotoxicity has never been confirmed before. Previous study noted that renal impairment at baseline had a protective effect against nephrotoxicity associated with colistin therapy.11 In our univariate analyses, patients in the control group had a significantly higher baseline SCr level and a slightly higher prevalence of chronic kidney diseases. A possible explanation was patients with renal impairment may be closely monitored for nephrotoxicity
Letters to the Editor Table 2
189
Independent risk factors for nephrotoxicity (multivariable analysis).
Variables
Unadjusted OR [95% CI]
Adjusted OR [95% CI]
Old age (years) Colistin duration (days) Colistin dose Low dose (<3 mg/kg/d) Moderate dose (3e5 mg/kg/d) High dose (>5 mg/kg/d) Concomitant vancomycin therapy
1.01 [1.00e1.03] 1.12 [1.04e1.19]
1.04 [1.01e1.06] 1.10 [1.03e1.19]
0.004 0.007
Ref 2.20 [1.05e4.74] 4.61 [1.62e13.16] 2.32 [1.06e5.14]
Ref 3.05 [1.25e7.45] 15.3 [3.87e60.6] 2.84 [1.21e6.69]
<0.001
and perhaps they were treated with shorter duration and lower dose of intravenous colistin. This assumption was supported by the results from our multivariable analysis. The protective effect of a higher baseline SCr level and having chronic kidney diseases were disappeared when we adjusted for the dose and duration of intravenous colistin in the multivariable model. Our study had several potential limitations. The lack of data on other nephrotoxic agents such as non-steroidal antiinflammatory drugs (NSAIDs) may result in information bias; nevertheless NSAIDs are rarely used in critically-ill patients at our institution. Although we did not have data on severity of illness and hypotensive episodes but comorbidities were comparable between cases and controls. Therefore, we did not have a reason to believe this would introduce differential bias. Additionally, our study was conducted at the largest university hospital in Thailand. Thus, the results may be inapplicable to smaller settings such as community hospitals. Intravenous colistin therapy has been considered the last resort for treatment of multidrug-resistant gram-negative infections.12e14 Hence, prescribing this highly nephrotoxic antibiotic may be unavoidable. Our study results have important implication with regard to possible interventions to prevent nephrotoxicity events. Drug monitoring program to shorten duration and closely adjust dose of intravenous colistin as appropriate should be endeavored. Finally, renal function should be carefully monitored in the high risk group especially elderly patients and patients who received concomitant vancomycin.
4.
5.
6. 7.
8.
9.
10.
11.
12.
Acknowledgment Funding: Faculty of Medicine Siriraj hospital, Mahidol University, Bangkok, Thailand. Transparency declarations: none to declare.
References 1. Yau W, Owen RJ, Poudyal A, Bell JM, Turnidge JD, Yu HH, et al. Colistin hetero-resistance in multidrug-resistant Acinetobacter baumannii clinical isolates from the Western Pacific region in the SENTRY antimicrobial surveillance programme. J Infect 2009 Feb;58(2):138e44. 2. Li J, Rayner CR, Nation RL, Owen RJ, Spelman D, Tan KE, et al. Heteroresistance to colistin in multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother 2006 Sep;50(9):2946e50. 3. Beno P, Krcmery V, Demitrovicova A. Bacteraemia in cancer patients caused by colistin-resistant gram-negative bacilli
13.
14.
p-value
0.02
after previous exposure to ciprofloxacin and/or colistin. Clin Microbiol Infect 2006 May;12(5):497e8. Hawley JS, Murray CK, Jorgensen JH. Colistin heteroresistance in acinetobacter and its association with previous colistin therapy. Antimicrob Agents Chemother 2008 Jan;52(1):351e2. Rodriguez CH, Bombicino K, Granados G, Nastro M, Vay C, Famiglietti A. Selection of colistin-resistant Acinetobacter baumannii isolates in postneurosurgical meningitis in an intensive care unit with high presence of heteroresistance to colistin. Diagn Microbiol Infect Dis 2009 Oct;65(2):188e91. Li J, Nation RL. Old polymyxins are back: is resistance close? Clin Infect Dis 2006 Sep 1;43(5):663e4. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004 Aug;8(4):R204e12. Koch-Weser J, Sidel VW, Federman EB, Kanarek P, Finer DC, Eaton AE. Adverse effects of sodium colistimethate. Manifestations and specific reaction rates during 317 courses of therapy. Ann Intern Med 1970 Jun;72(6):857e68. Falagas ME, Fragoulis KN, Kasiakou SK, Sermaidis GJ, Michalopoulos A. Nephrotoxicity of intravenous colistin: a prospective evaluation. Int J Antimicrob Agents 2005 Dec;26(6):504e7. Deryke CA, Crawford AJ, Uddin N, Wallace MR. Colistin dosing and nephrotoxicity in a large community teaching hospital. Antimicrob Agents Chemother 2010 Jul 26;54(10):4503e5. Hartzell JD, Neff R, Ake J, Howard R, Olson S, Paolino K, et al. Nephrotoxicity associated with intravenous colistin (colistimethate sodium) treatment at a tertiary care medical center. Clin Infect Dis 2009 Jun 15;48(12):1724e8. Koomanachai P, Tiengrim S, Kiratisin P, Thamlikitkul V. Efficacy and safety of colistin (colistimethate sodium) for therapy of infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii in Siriraj Hospital, Bangkok, Thailand. Int J Infect Dis 2007 Sep;11(5):402e6. Michalopoulos AS, Tsiodras S, Rellos K, Mentzelopoulos S, Falagas ME. Colistin treatment in patients with ICU-acquired infections caused by multiresistant gram-negative bacteria: the renaissance of an old antibiotic. Clin Microbiol Infect 2005 Feb;11(2):115e21. Falagas ME, Rafailidis PI, Ioannidou E, Alexiou VG, Matthaiou DK, Karageorgopoulos DE, et al. Colistin therapy for microbiologically documented multidrug-resistant Gramnegative bacterial infections: a retrospective cohort study of 258 patients. Int J Antimicrob Agents 2010 Feb;35(2):194e9.
Pinyo Rattanaumpawan Division of Infectious Diseases and Tropical Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
190
Letters to the Editor Puangpaka Ungprasert Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
Visanu Thamlikitkul* Division of Infectious Diseases and Tropical Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand * Corresponding author. Division of Infectious Diseases and Tropical Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand. Tel./fax: +66 2 412 5994. E-mail address: [email protected] Accepted 24 November 2010 Available online 1 December 2010 ª 2010 The British Infection Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2010.11.013
Time to blood culture positivity as a predictor of methicillin resistance in Staphylococcus aureus bacteremia
Dear Editor, Recently, Kim et al. described the association between time to blood culture positivity (TTP) and clinical outcome in 684 patients with Staphylococcus aureus bacteremia in a retrospective study.1 Results from their multivariate logistic regression analysis revealed that the 30-day mortality rate was associated with age, nosocomial acquisition of infection, focus of infection, liver disease, methicillin-resistant S. aureus (MRSA), and TTP 12 and TTP > 48 h.1 In addition, the median TTP was shorter for methicillin-susceptible S. aureus (MSSA) isolates (15; IQR, 12e20 h) than for MRSA isolates (17; IQR, 13e22 h, P Z 0.015). Thus, we wonder whether the longer TTP of S. aureus isolates could help clinicians predict resistance to methicillin before formal drug susceptibility tests. S. aureus is responsible for 10%e18% of all communityacquired and about 20% of all nosocomial bacteremia.2,3 In addition, the emergence of MRSA is a growing clinical challenge in hospital-associated settings and, more recently, in community settings in both the United States and worldwide.4 In Taiwan, MRSA infection accounts for about 60% of nosocomial S. aureus infections5 and it is also an emerging community-acquired pathogen.6 Furthermore, the impact of the increasing frequency of MRSA bacteremia is magnified by the poor prognosis associated with this serious infection.6,7 Therefore, early detection of MRSA isolates followed by the administration of appropriate antibiotic therapy is necessary to improve the outcome of patients with S. aureus bacteremia.
In this study we evaluated the ability of TTP to differentiate between MRSA and MSSA bacteremia. This study was prospectively conducted at the National Taiwan University Hospital, a 2500-bed tertiary care medical center in northern Taiwan. Patients with S. aureus bacteremia were identified by central laboratory personnel from July to October, 2010. TTP for each patient was retrieved from the hospital automated blood culture instrument. Each patient was included only once at the time of detection of the first bloodstream infection. Patients younger than 18 years and patients with polymicrobial bacteremia were excluded. At least two sets of blood samples, 10 ml each, were taken from separate locations and inoculated into aerobic and anaerobic culture bottles (Bactec 9240, Becton Dickinson, Sparks, MA, USA). Susceptibility to antimicrobial agents was determined by the standard disk diffusion method.8 TTP, defined as the time from the start of incubation to the start of the alert signal (as documented by the monitoring system), was recorded for each bottle of positive blood culture. For a patient with multiple sets of positive blood cultures at approximately the same time, the shortest TTP was used. Means and standard deviations were calculated for continuous variables. ManneWhitney test was used for comparison of continuous variables. Receiver operating characteristic (ROC) curves were plotted for TTP to identify MRSA bacteremia and the area under the curve (AUC) was calculated. A P-value < 0.05 was considered to represent statistical significance. Data were analyzed with the statistical package SPSS for Windows (Version 10.0; SPSS, Chicago, IL, USA). During the study period, a total of 90 patients with S. aureus bacteremia were recruited. Most of the patients were men (63.3%) and the mean age was 56.2 21.9 years. A total of 36 (40%) S. aureus isolates were MRSA. The mean TTP for all S. aureus isolates was 19.9 19.4 h. The median TTP was shorter for MSSA isolates (14.1 9.8 h) than for MRSA isolates (28.6 26.1 h; P Z 0.003). Fig. 1 shows the receiver operating characteristic (ROC) curves, which were plotted to evaluate the ability of TTP to identify MRSA isolates in patients with S. aureus bloodstream infections. The area under the ROC curve (AUC) was 0.778 (95% CI 0.678e0.859). Overall, the diagnostic sensitivity was 91.7% (95% CI 0.775e0.982), the specificity was 57.4% (95% CI 0.432e0.708), the positive predictive value was 58.9%, and the negative predictive value of TTP for MRSA bacteremia in patients with S. aureus bacteremia was 91.2%, with a TTP cutoff value of 11.46 h. In this study, there are two significant findings about the relationship between TTP and S. aureus bacteremia. First, the TTP was significantly shorter in patients with MSSA bacteremia than in patients with MRSA bacteremia. This is consistent with findings from Kim et al.1 and Khatih et al.9 Second, we found that the overall sensitivity and specificity of TTP for identifying MRSA bacteremia in patients with S. aureus bacteremia were 91.7% and 57.4%, respectively, with a TTP cutoff of 11.46 h. In addition, the high negative predictive value of 91% may be helpful for physicians to exclude the presence of methicillin resistance among S. aureus isolates. Although the drug susceptibility test is still the gold standard to identify MRSA, TTP may provide earlier detection of methicillin-resistant