colistin nephrotoxicity increases with age
TRANSCRIPT
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Colistin Nephrotoxicity Increases with Age 2
1. Ilker Inanc Balkan, MD, Istanbul University Cerrahpasa School of Medicine, 3
Department of Infectious Diseases and Clinical Microbiology, Istanbul, Turkey. 4
2. Mustafa Dogan, MD, Ass Prof, Namık Kemal University Medical Faculty, 5
Department of Infectious Diseases and Clinical Microbiology, Tekirdag, Turkey. E-6
mail: [email protected] 7
3. Bulent Durdu, MD, Bakirkoy Sadi Konuk Research and Training Hospital, 8
Department of Infectious Diseases and Clinical Microbiology, Istanbul, Turkey. E-9
mail:[email protected] 10
4. Ayse Batirel, MD, Dr Lutfi Kirdar Kartal Research and Training Hospital, 11
Department of Infectious Diseases and Clinical Microbiology, Istanbul, Turkey. E-12
mail: [email protected] 13
5. Ismail N. Hakyemez, MD, Ass Prof, Bezmialem University Medical Faculty, 14
Department of Infectious Diseases and Clinical Microbiology, Istanbul, Turkey. 15
E-mail: [email protected] 16
6. Birsen Cetin, MD, Prof, Koc University Medical Faculty, Department of Infectious 17
Diseases and Clinical Microbiology, Istanbul, Turkey. E-mail: 18
7. Oguz Karabay, MD, Prof, Sakarya University Medical Faculty, Department of 20
Infectious Diseases and Clinical Microbiology, Sakarya, Turkey. E-mail: 21
8. Ibak Gonen, MD, Ass Prof, Suleyman Demirel University Medical Faculty, 23
Department of Infectious Diseases and Clinical Microbiology, Isparta, Turkey. E-mail: 24
9. Ahmet Selim Ozkan, MD, Ass Prof, Inonu University Turgut Ozal Medical Faculty, 26
Department of Anesthesiology, Division of Intensive Care Unit, Malatya, Turkey. E-27
mail: [email protected] 28
10. Muhammed Emin Demirkol, MD, Istanbul University Cerrahpasa School of 29
Medicine, Department of Internal Medicine, Istanbul, Turkey. E-mail: 30
11. Sedat Akbas, MD, Istanbul University Cerrahpasa School of Medicine, Department 32
of Anesthesiology and Reanimation, Istanbul, Turkey. Present Address: Kiziltepe State 33
Hospital, Division of Intensive Care Unit, Mardin, Turkey. E-mail: 34
12. Asiye Bahar Kacmaz, MD, Istanbul University Cerrahpasa School of Medicine, 36
Department of Infectious Diseases and Clinical Microbiology, Istanbul, Turkey. E-37
mail: [email protected] 38
13. Sami Uzun, MD, Haseki Training and Research Hospital, Internal Medicine 39
Department, Division of Nephrology, Istanbul, Turkey. E-mail: 40
14. Sukru Aras, MD, Phd, Istanbul Ahenk Diagnostics, Biochemistry, Bioistatistics, 42
Istanbul, Turkey. E-mail: [email protected] 43
15. Ali Mert, MD, Prof, Istanbul University Cerrahpasa School of Medicine, 44
Department of Infectious Diseases and Clinical Microbiology, Istanbul, Turkey. 45
Present Address: Medipol University Medical Faculty, Department of Internal 46
Medicine & Division of Infectious Diseases, Istanbul, Turkey. E-mail: 47
16. Fehmi Tabak, MD, Prof, Istanbul University Cerrahpasa School of Medicine, 49
Department of Infectious Diseases and Clinical Microbiology, Istanbul, Turkey. E-50
mail: [email protected] 51
Key Words: Colistin, nephrotoxicity, age, ACE inhibitors 52
Running headline: Colistin Induced Nephrotoxicity 53
Corresponding author: Ilker Inanc Balkan, MD, Istanbul University Cerrahpasa School of 54
Medicine, Department of Infectious Diseases and Clinical Microbiology, Istanbul 34098, 55
Turkey. 56
Phone: +90-212-4143000-23066 Fax: +90-212-4143001 E-mail: 57
Conflict of Interest: None to declare 59
ABSTRACT 60
Background: Colistin (COL) has become the backbone in treatment of infections due to 61
extremely-drug resistant(XDR) gram negative bacteria. The most common restriction to its 62
use is acute kidney injury (AKI). 63
Methods: We conducted a retrospective cohort study to evaluate risk factors for new-onset 64
AKI in patients receiving COL. The cohort consisted of 198 adults admitted to 9 referral 65
hospitals between January 2010 and October 2012 and treated with intravenous COL for ≥72 66
hours. Patients with no preexisting kidney dysfunction were compared in terms of risk factors 67
and outcomes of AKI graded according to RIFLE criteria. Logistic regression analysis was 68
used to identify associated risk factors. 69
Results: A total of 198 patients met the inclusion criteria, of whom 167 had no preexisting 70
kidney dysfunction with a mean age of 58.7 (±18.9) years. Blood stream infections (34.8%) 71
and ventilatory associated pneumonia (32.3%) were the two most common indications for 72
COL use. New-onset AKI developed in 46.1% of the patients, graded as Risk (10%), Injury 73
(15%) and Failure (21%). Older age (p=0.001, OR=5.199, CI=2.684-10.072), high Charlson 74
comorbidity index (CCI) (p=0,001), comparatively low initial glomerular filtration rate (GFR) 75
estimations and concomitant use of Angiotensin Converting Enzyme (ACE) inhibitors 76
(p=0,003) were major predictors of AKI. In-hospital recovery of AKI was 58.1%, with a 77
median of 7 days. 78
Conclusions: COL induced nephrotoxicity occured significantly more common in patients 79
older than 60 years and was related to low initial glomerular filtration rate (GFR) estimations 80
and high CCI scores which were basically determined by age. Concomitant use of ACEIs was 81
the other major predictor for AKI. 82
83
84
INTRODUCTION 85
Colistin (COL) has become the backbone in treatment of infections due to multi drug resistant 86
(MDR) gram negative bacteria, particularly extremely-drug resistant (XDR) and COL-only 87
susceptible strains. Given the recent rates of carbapenem resistance among Acinetobacter spp. 88
(67.6 to 70.4%) and Pseudomonas spp. (26.3 to 35.8%) in the training and university hospitals 89
throughout Turkey, COL is likely to be used increasingly more often (1). The most common 90
restriction to its use is nephrotoxicity due to tubular damage in most clinical settings (2). 91
Early experience with COL revealed a high incidence of toxicity and was widely abandoned 92
in the 1970s because of adverse effects. In the late 1990s, with the stepwise trend towards 93
multiple drug resistance in gram negative bacteria and severe infections with high mortality 94
rates due to these organisms, clinicians were forced to resort to salvage therapy COL. The 95
high rates of AKI in early cases were probably due to the lack of true 96
pharmacokinetic/pharmadynamic data, use of high doses and inadequate facilities for kidney 97
replacement therapy. However, recent data from published reports does not corroborate this 98
finding (3). Explanations for the lower overall toxicity today include fewer chemical 99
impurities in colistimethate sodium, better ICU monitoring, and avoidance of co-100
administration of other nephrotoxic drugs (4). 101
Although there are many studies reporting COL nephrotoxicity at various rates, studies that 102
specifically focus on the features and risk factors for COL induced AKI are scarce. In this 103
study we aimed to investigate the outcomes of COL use, to establish the risk factors 104
contributing to COL related nephrotoxicity and provide evidence for more beneficial use of 105
COL to avoid renal dysfunction. 106
PATIENTS AND METHODS 107
1. Study Design 108
A multicenter retrospective cohort study of adults receiving intravenous COL was conducted 109
at 9 referral hospitals between January 2010 and October 2012. Pharmacy-generated reports 110
and medical records were used to identify patients who had received intravenous COL during 111
the study period. 112
1 a. Exlusion criteria 113
Patiens were excluded 114
if they received COL <72 hours, or 115
if they received only inhaled COL, or 116
if they were lacking at least three (initial, highest, end of treatment) consecutive 117
measurements of serum creatinine (SCR), or 118
if they were below 18 years or pregnant. 119
120
1 b. Analysis 121
If a patient received multiple courses of COL, only the first one was considered in the 122
analysis. The whole cohort was divided into three groups: 123
1) Patients with normal baseline SCR with no increase in SCR during COL 124
treatment or a small rise lower than 1.5 fold 125
1) Patients with normal baseline SCR and at least 1.5 fold increase during 126
COL treatment 127
3) Patients with preexisting kidney dysfunction defined with a baseline SCR 128
>1.3 mg/dl for females or SCR >1.5 mg/dl for males. 129
Pateints with and without AKI due to COL use were compared in terms of risk factors and 130
outcomes. AKI was graded according to RIFLE (risk, injury, failure, loss, and end-stage 131
kidney disease) criteria (5). Chronic Kidney Disease Epidemiology Collaboration (CKD-132
EPI) equation formula was used to estimate the initial glomerular filtration rates (GFRs) of 133
the patients (6). Estimated initial GFR values were not used for the classification of the 134
patients in order not to cause a deviation from the daily clinical practice based on initial SCR 135
levels. Patients with previously defined underlying kidney injury with either chronic renal 136
failure (CRF) or acute renal failure (ARF) were not included in the analyses for the primary 137
and secondary outcomes. They were evaluated only in the total descriptive analysis and 138
subgroup analysis in terms of other outcomes. 139
2. Data collection 140
A standardized case form was used to record patient characteristics, including age, gender, 141
weight, underlying comorbidities [evaluated by Charlson comorbidity index (CCI)], acute 142
physical condition [evaluated by Acute Physiology and Chronic Health Evaluation II 143
(APACHE 2) score], site and type of infection, causative bacteria and in vitro susceptibility, 144
daily doses and duration of COL therapy, cumulative dose of COL (mg/kg; daily dose per kg 145
of body weight × duration of treatment), coadministered antibiotics, concomitant (at the time 146
of data collection and at least since the last week for drugs and once in the last week for 147
radiocontrast agent) nephrotoxic agents (aminoglycosides, vancomycin, acyclovir, 148
amphotericin-B nonsteroidal anti-inflammatory drugs(NSAIDs), methotrexate, angiotensin 149
converting enzyme inhibitors (ACEIs) and angiotensin II blockers (ATBs), intravenous 150
radiocontrast agents), serum albumin levels, serial serum creatinine levels and clinical and 151
microbiological responses to therapy (7,8). The primary outcome was the developement of 152
AKI during COL treatment. Secondary outcomes were the risk factors for AKI, features of 153
AKI and outcomes of COL use including mortality. 154
3. Definitions 155
RIFLE Criteria are defined as follows; Risk (R): Increased creatinine level × 1.5 or GFR 156
decrease >25%, Injury (I): Increased creatinine level × 2 or GFR decrease >50%, Failure (F): 157
Increased creatinine level x 3, glomerular filtration rate (GFR) decrease >75%, or SCR level >4 158
mg/dL, Loss (L): Persistent acute renal failure or complete loss of function for >4 weeks, 159
End-Stage Kidney Disease (ESKD) (E): ESKD for >3 months. Renal recovery was defined as 160
the return of decreased kidney function to pre-AKI baseline levels and was assessed during 161
the subject's hospitalization. Hospital infections were defined according to the definitions of 162
Centers for Disease Control and Prevention (CDC). Multi-drug resistance (MDR) was 163
defined as non-susceptibility to at least one agent in three or more antimicrobial categories. 164
Extreme-drug resistance (XDR) was defined as non-susceptibility to at least one agent in all 165
but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only 166
COL and tigecycline) (9). 167
4. Colistin Administration 168
COL used in this study was Colimycin Parenteral (Kocak farma, Istanbul, Turkey). It 169
contains 150 mg of ‘COL base activity’, equivalent to 360 mg (or 4.5×106 IU) of 170
colistimethate sodium per vial. It was dissolved in 100-mL sterile saline and was given over 171
30 minutes. Administration of COL was based on the results of in vitro antimicrobial 172
susceptibility tests (targeted) or high clinical suspicion of infections due to COL only 173
susceptible pathogens (empirical), with the approval of infectious diseases consultant, 174
according to the national regulations. The dosage of i.v. COL recommended by the 175
manufacturer is 2.5–5.0 mg/kg/day for patients with normal renal function. In patients with 176
moderate-to-severe renal impairment (creatinine clearance rate <50 mL/min), dosing 177
adjustments were made according to the manufacturer instructions. None of the patients 178
received a loading dose of COL. Administration of a loading dose as suggested by recent 179
studies had not been implemented during the study period (10). Treatment duration was 180
determined on the basis of the clinical response during follow-up. 181
182
5. Statistical analyses 183
SPSS 17.0 Software (Chicago, IL.,USA) programme was used for statistical analyses. In 184
general comparison, categorical variables were compared by x2 or Fisher’s Exact Test, 185
continuous variables were tested with Student’s t test or One-way ANOVA test as 186
appropriate. Significant variables in the univariate analysis were tested by Spearman's 187
Logistic regression in order to determine the independent risk factors for COL induced AKI. 188
ROC curve was drawn to determine the threshold value of the variable that most likely 189
contributes to AKI. For all analyses, a two-sided P value < 0.05 was considered to be 190
statistically significant. 191
RESULTS 192
1. Demographic Data 193
A total of 198 patients from 9 referral centers were included in the study. 194
1.1. Exclusion 195
Four patients were excluded; 3 because of receiving only inhaled COL and 1 because of age 196
below 18 years. 197
1.2. Gender and Age 198
Onehundred and twentyone (61.1%) were male, and mean age was 58.77 (±18.98) years. 199
1.3. Patient Characteristics 200
A hundred and thirty eight patients (69.7%) were hospitalized in ICUs, 34 (17.2%) in internal 201
medicine units and 26 (13.1%) in surgical units. Thirty-one patients had pre-existing kidney 202
dysfunction; 27 had CRF and 4 had ARF. At least one comorbidity was present in 75.4% of 203
patients; 44 (22.2%) had cardiovascular diseases, 26 had hypertension (HT), 37 (18.7%) had 204
diabetes mellitus (DM), 33 (16.7%) had neurological diseases, 29 (10.1%) had solid tumors, 205
23 (11.6%) had pulmonary diseases, 21(10.6%) had hematologic malignancies, 20 (10.1%) 206
were immunosupressed, and 17 (8.6%) had major trauma or burns. 207
1.4. Sites of Infections and Pathogens 208
The majority of patients had blood stream infections (BSIs) (34.8%), (primary bacteremia 209
n=50, secondary bacteremia n=12, central line-associated BSI n=7), ventilator-associated 210
pneumonia (VAP) (32.3%), nosocomial pneumonia (14.6%), complicated surgical site 211
infection (8.5%), intraabdominal infection (2.5%), nosocomial meningitis (1%), nosocomial 212
urinary tract infection (UTI) (0.5%) and mediastinitis (0.5%). The causative bacteria were 213
Acinetobacter baumannii (74.2%), Pseudomonas aeruginosa (10.1%), Klebsiella pneumoniae 214
(6.1%), E. coli (1.0%) and gram negative bacilli (3.5%). Ten cases (5.1%) were treated 215
empirically. 216
1.5. Treatment Modalities 217
Thirteen patients (6.5%) received COL monotherapy, and 185(93,5%) received combination 218
therapy with other antibiotics such as carbapenems (45%), aminoglycosides (5.5%), 219
tygecyclin (8%), sulbactam (19.7%), cefoperazone-sulbactam (15.5%), piperacillin-220
tazobactam (4.1%), quinolones (6%), ceftazidime (2.4%), cefepime (1.8%). Thirty four 221
patients received triple combinations where COL was most commonly combined with 222
carbapenem plus sulbactam (35.3%). Glycopeptides were the most common accompanying 223
antibiotics used in 37 (18.7%) of the cases while 132 (66.2%) did not receive additional 224
antimicrobial drugs. 225
Inhaled COL was used in 29 (45.3%) patients with VAP, in 3 (10.3%) patients with 226
nosocomial pneumonia, and in 32 (34.4%) patients with respiratory infections due to XDR 227
Gram negative rods. 228
Initial daily COL dose was 300 mg/d in 140 (70.7%), 200 mg/d in 12 (6.1%), 450 mg/d in 7 229
(3.5%), 240 mg/d in 5 (2.5%), 400 mg/d in 3 (1.5%), 150 mg/d in 23 (11.6%), 150 mg/q48h 230
in 4 (2%), 150 mg/q36h in 3 (1.5%) and 100 mg/d in 1 (0.5%) of the cases (n=198). The latter 231
four doses were preferred in patients with chronic kidney dysfunction (n=31). Initial COL 232
doses were not modified during treatment in 163 (82.3%) of patients. Dose modification was 233
performed in 35 (27.7%) patients due to AKI. The most common dose modification was 234
switching to a once-daily dose of 150 mg IV. None of the patients had bacteria that developed 235
resistance to COL during treatment and none received excessive doses of COL. Reasons for 236
COL cessation are shown on Table II. 237
2. Toxicities 238
2.1.Nephrotoxicity 239
A total of 77 (46.1%) patients with normal baseline kidney functions developed AKI during 240
COL use and met the RIFLE criteria at the time of their peak serum creatinine (SCR) level. 241
AKI was graded as Risk in 10%, Injury in 15% and Failure in 21% consequently. Risk 242
factors for AKI are shown together with the basic demographic characteristics of the patients 243
in Table 1. In the univariate analysis; mean age (p=0.001), mean Charlson comorbidity index 244
(CCI) (p=0.001), and concomitant use of ACE inhibitors (p=0.003) were significantly higher 245
while mean initial GFR estimations were significantly lower in those who developed AKI. In 246
the logistic regression analysis, old age was the significant risk factor for AKI during COL 247
treatment. ROC curve analysis showed that patients over 60 years of age had a significantly 248
higher risk of AKI (70.1%) when compared to those under age 60 (31.1%) (p=0.001, 249
OR=5.199 CI=2.684-10.072). AKI of any grade resolved within the in-hospital period in 250
58.1% of patients, mostly within 7 days (median 6.5 days) (range 3-105 days) (Table III). 251
2.2. Neurotoxicity
Neurotoxicity was observed in 1 patient (0.5%) as facial numbness, which resolved 5 days
after discontinuation.
3. Mortality 252
Overall mortality was 36.3%. There was no significant difference between the two groups 253
with and without AKI (41.6% vs. 28.9%, p=0.086) in terms of 28-day mortality. The 254
proportion of patients who died due to severe disease before COL cessation was higher in 255
those who developed AKI (33.3% vs. 20%, p=0.052). The 28-day mortality rate was 45% in 256
patients with pre-existing kidney dysfunction (Table IV). 257
DISCUSSION 258
COL-related nephrotoxicity remains a significant problem. This retrospective cohort study 259
shows a high AKI rate of 46% in patients with no preexisting kidney dysfunction who 260
received intravenous COL. Higher CCIs, lower initial estimated GFR levels [despite similar 261
initial SCR levels] and use of concomitant ACEIs were found as risk factors in the univariate 262
analysis. The first two factors were basically determined by higher age, which is the only 263
significant risk factor in the logistic regression, particularly when over 60 years. 264
A number of studies, designed to assess nephtotoxicity have recently been published in which 265
the rate has ranged from 6% to 60% (11-20). Differences in the characteristics and risk 266
factors of the subjects and the burden of COL exposure account in part for this variation. 267
However, it is basically related to the lack of common criteria to define kidney injury (21). 268
Introduction of RIFLE criteria provided a definition standard for studies assesing this 269
outcome. A comparison of the present study with some recent reports adopting the same 270
criteria (Table 5) reveals a higher proportion of patients with “failure” (21%). Despite higher 271
rates of “failure”, only four (2.4%) patients required renal replacement therapy (RRT) in our 272
cohort and 15 (7.7%) patients discontinued COL. AKI was reversible, was not severe, did not 273
cause discontinuation of COL in most cases, mostly subsided rapidly and no case required 274
long-term dialysis in our study, in concordance with some previous reports (14). 275
Underlying kidney dysfunction is the major determinant of drug induced AKI. Based on the 276
data revealing high frequencies (>60%) of COL induced nephrotoxicity in patients with 277
previous renal dysfunction, outcomes in this subset of our cohort are shown separately (Table 278
4). 279
The dose-related nature of COL induced toxicity is well defined in the literature (16,17, 20, 280
22). Sorli et al. have recently shown that COL induced AKI is significantly correlated with the 281
plasma Cmin of COL on day 7 of treatment (23). In our study we could not establish the 282
correlation between daily or cumulative doses of COL and renal damage. Mean body mass 283
indexes (BMIs), as a recently defined risk factor for over-dosing of COL, were also similar in 284
the two groups (24). 285
Several other risk factors are defined for developement of AKI during COL use in different 286
studies (Table V). Age has been documented as a risk factor in some earlier and recent studies 287
(17, 20, 26). The effect of age probably derives from its major contribution to the estimation 288
of baseline kidney functions and comorbidity scores. This hypothesis is supported by a 289
prospective cohort study where COL use showed no adverse effect on kidney functions in 55 290
patients treated for Pseudomonas or Acinetobacter infections with relatively low mean age of 291
40±16 years (28). 292
Among patients who developed AKI, 7 (9.1%) had records of concomitant ACEI use while no 293
patient without AKI had concomitant ACEI or ATB. When ACEI receivers and non-receivers 294
were compared, mean baseline GFR rates according to the CKD-EPI equation 2009 were 295
similar (80.42 vs 78.76 mL/min p=0.98). Although not significant in the further analysis, this 296
effect should be noted for concomitant users of COL and ACEI. ACEI and ATBs are 297
preferred for their nephroprotective and cardioprotective effects in treatment of hypertension. 298
However, apart from the decrease in the systemic blood pressure, as a consequence of their 299
relatively more potent vasodilatory effect on the efferent arterioles compared to the afferents, 300
they possibly interfere with the kidneys' ability to autoregulate glomerular pressure and 301
decrease GFR by reducing the intraglomerular pressure (29). This causes a predisposition to 302
renal toxicity with a similar mechanism that is observed in patients with dehydration or 303
hypotension for any reason. Adequate hydration is one of the most important components of 304
patient follow up to maintain renal perfusion and avoid drug-induced renal impairment. 305
Concomitant use of other nephrotoxic agents including aminoglycosides and vancomycin did 306
not correlate to increased risk of AKI in our cohort. 307
COL was discontinued due to rise in SCR in 15 (7.7%) cases at a median 9 days (range, 4–17) 308
in our study cohort (n=198). Some previous studies report similar rates (12,13,30). The 309
median time to nephrotoxicity was 7 days in our cohort in contrast to the study by Collins et 310
al. which reported a median time of 12 days in a cohort of 57 critically ill patients receiving 311
COL with concomitant nephrotoxic antibiotics. Early-onset (<7 days) AKI has been 312
associated with increased mortality during COL use (26). 313
In our study, AKI of any grade was recovered in 58.1% of patients mostly within 7 days 314
(median 6.5 days, (range 3-105 days). Given the mild and reversible features of 315
nephrotoxicity if data regarding those who recovered after discharge was available, the rate of 316
recovery from AKI would be even higher. Along with being major risk factors for AKI old 317
age did not change the rate or the duration of recovery in our cases. Recovery rates were not 318
significantly different neither in those below or above 60 years of age (30/62 and 16/24 319
respectively, p=0.153) nor in non-users or users of ACEIs (52.5% of non-users and 66.6% of 320
users recovered, p=0.681). Time to recovery was not significantly different (p>0.05). 321
The main limitation is the retrospective design of our study, in which analysis of 322
nephrotoxicity is limited even with use of a standardized definition. Although HT and DM 323
rates were not significantly different in the two groups, other causes of nephropathy (ie. 324
hydration status) could not be thoroughly ruled out. Pharmacokinetic and pharmacodynamic 325
parameters were not available for assessment and COL doses were not standardized. Despite 326
these limitations, our study offers insight in a variety of patients with a wide range of 327
underlying diseases who received intravenous COL for severe infections, from nine different 328
centers scattered in the most crowded region of the country. 329
In conclusion; nephrotoxicity during COL use occurs significantly more frequently after 60 330
years of age and is related to low initial GFR estimations and high CCI scores which are 331
basically determined by age. 332
Acknowledgements 333
We would like to express our heartfelt thanks to Prof Resat Ozaras for his invaluable 334
contributions to the analysis of the data. Sincere thanks to all medical staff involved in the 335
treatment and follow up of the patients at the participating hospitals. 336
337
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