cerebrospinal fluid pharmacokinetics of colistin
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CEREBROSPINAL FLUID PHARMACOKINETICS OF COLISTIN 2
AFTER INTRAVENTRICULAR ADMINISTRATION OF COLISTIN 3
METHANESULFONATE 4
5
Roberto Imberti,#a Maria Cusato,b Giovanni Accetta,c Valeria Marinò,d 6
Francesco Procaccio,e Alfredo Del Gaudio,f Giorgio A. Iotti,c 7
Mario Regazzib 8
9 aDirezione Scientifica, bUnit of Clinical Pharmacokinetics in Transplantation and 10
Autoimmune Diseases, cDepartment of Anesthesiology and Critical Care Medicine, 11
Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy; dAnesthesia and Neuro 12
Intensive Care Unit, IRCCS Neuromed, Pozzilli, Italy; eNeuro Intensive Care Unit, 13
Azienda Ospedaliera Universitaria Integrata, Verona, Italy; fII Department of 14
Anesthesiology and Critical Care Medicine, IRCCS Ospedale Casa Sollievo della 15
Sofferenza, S. Giovanni Rotondo, Italy 16
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Running title: PK of Intraventricular Colistin 20
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Correspondence with: 24 Roberto Imberti, M.D. 25 Direzione Scientifica 26 Fondazione IRCCS Policlinco S. Matteo 27 27100 Pavia, Italy 28 e-mail: [email protected] 29 30
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Copyright © 2012, American Society for Microbiology. All Rights Reserved.Antimicrob. Agents Chemother. doi:10.1128/AAC.00231-12 AAC Accepts, published online ahead of print on 11 June 2012
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ABSTRACT 32
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Background. Intraventricular colistin, administered as colistin methanesulfonate 34
(CMS), is the last resource for the treatment of central nervous system infections 35
caused by pan-resistant Gram-negative bacteria. The doses and daily regimens 36
vary considerably and are empirically chosen; the cerebrospinal fluid (CSF) 37
pharmacokinetics of colistin after intraventricular administration of CMS has never 38
been characterized. 39
Methods. Nine patients (aged 18-73 years) were treated with intraventricular CMS 40
(daily doses: 2.61-10.44 mg). Colistin concentrations were measured using a 41
selective HPLC assay. The population pharmacokinetic analysis was performed with 42
P-Pharm program. 43
Results. The pharmacokinetics of colistin could be best described by the one-44
compartment model. Estimated values (means±SD) of apparent CSF total clearance 45
(CL/Fm, where Fm is the unknown fraction of CMS converted to colistin) and 46
terminal half-life (t1/2λ) were 0.033±0.014 L/h and 7.8±3.2 hours, respectively, and 47
the average time to the peak concentration was 3.7±0.9 hours. A positive correlation 48
between CL/Fm and the CSF drained (range 40-300 ml) was observed. When CMS 49
was administered at doses of ≥ 5.22 mg/day, measured CSF concentrations of 50
colistin were continuously above the MIC of 2 mcg/ml, and measured values of 51
Ctrough ranged between 2.0 and 9.7 mcg/ml. Microbiological cure was observed in 52
8/9 patients. 53
Conclusions: Intraventricular administration of CMS at doses ≥ 5.22 mg per day 54
was appropriate in our patients, but since external CSF efflux is variable and can 55
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influence the clearance of colistin and its concentrations in CSF, the daily dose of 10 56
mg suggested by the Infectious Diseases Society of America may be more prudent. 57
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Key words: colistin, colistin methanesulfonate, pharmacokinetics, cerebrospinal 61
fluid, intraventricular 62
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INTRODUCTION 65
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Central nervous system infections (meningitis, ventriculitis, abscesses) caused by 67
Gram-negative bacteria are a therapeutic challenge. These infections generally 68
occur in patients during their hospital stay and are secondary to neurosurgical or 69
otorhinologic procedures, head trauma, and, rarely, to metastatic infections from 70
bacteremia (28). Their treatment has been further complicated by the emergence of 71
Gram-negative bacteria, generally Acinetobacter baumannii, Pseudomonas 72
aeruginosa and Klebsiella pneumoniae, which are resistant to third- and fourth-73
generation cephalosporins, aminoglycosides and carbapenems (19). Under these 74
conditions, the treatment relies on polymyxins, such as colistin. Colistin is a 75
bactericidal, concentration-dependent antimicrobial agent with a modest post-76
antibiotic effect (20). Although the pharmacodynamic parameters best predicting the 77
efficacy of colistin have not yet been established in humans, in vitro and in vivo 78
animal studies have suggested that the AUC/MIC ratio of total and unbound colistin 79
is the index best predicting the antibacterial activity against P. aeruginosa (3,7,8). 80
Colistin is usually administered as colistin methanesulfonate (CMS). CMS, which is 81
inactive, is converted to colistin (the active form with antimicrobial activity) both in 82
vitro and in vivo by hydrolysis of methanesulfonate radicals (2,4). Data available 83
from the literature indicate that in humans the penetration of CMS and colistin into 84
cerebrospinal fluid (CSF) is poor, both in patients with uninflamed and inflamed 85
meninges (1,11,21,30). Reported CSF-to-serum concentration ratios are 0.051 to 86
0.057 (21) and 0.16 (estimated from Fig. 1, ref. (11)). CMS is, therefore, generally 87
administered via the intraventricular (IVT) or intrathecal route alone or in association 88
with the systemic route (for a comprehensive review, see ref. (9)). The dosages of 89
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IVT/intrathecal colistin are empirically chosen and range between 1.6 – 40 mg, as a 90
single dose or in divided doses (9,13). Guidelines published by the Infectious 91
Diseases Society of America (IDSA) in 2004 suggest that the IVT dosage of colistin 92
(presumably CMS) should be 10 mg (27), but the optimal IVT/intrathecal dosing 93
regimen for CMS remains unknown. 94
To our knowledge, the pharmacokinetics of colistin after IVT administration of CMS 95
has never been characterized. Moreover, it is not known whether colistin 96
accumulates in CSF following repeated IVT doses (as used clinically). 97
Since CNS infections caused by pan-resistant Gram-negative bacteria occur 98
relatively infrequently, a detailed description of the pharmacokinetics of colistin after 99
IVT administration of CMS will require many centers and a considerable period of 100
time. We, therefore, deemed it appropriate to present these preliminary results. 101
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PATIENTS and METHODS 103
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Study population 105
The pharmacokinetics of colistin was evaluated in 9 adult patients (aged 18 – 73 106
years; 6 males, 3 females) who, during their hospital stay, developed central 107
nervous system infection by pan-resistant Klebsiella pneumoniae (6 patients), 108
Acinetobacter baumannii (2 patients) or Pseudomonas aeruginosa (1 patient). A 109
bacteriological diagnosis of CSF infection was available for all patients. The 110
patients’ simplified acute physiology II (SAPS II) score (16) at admission ranged 111
from 21 to 65 (Table 1) and the sequential organ failure assessment (SOFA) score 112
(29) on the day of sampling ranged from 3 to 11. 113
The study protocol was approved by the Local Ethics Committee at each 114
participating center which waived the patients’ consent since no changes were 115
made to usual treatment; all patients had an external ventricular drainage, and the 116
concentrations of colistin were evaluated in CSF spontaneously draining outside 117
and then discarded. Consent to data use was obtained from patients surviving in 118
conscious conditions, in accordance with the ethical requirements of the institutional 119
ethical committees. 120
121
Treatment schedule 122
Patients were treated with IVT CMS 2.61 mg/24 hours (1 patient), 2.61 mg/12 hours 123
(3 patients), 5.22 mg/24 hours (2 patients), and 5.22 mg/12 hours (3 patients). The 124
CMS dosing regimens were selected by physicians on the basis of their experience. 125
In the summary of product characteristics of Colimicina®, the CMS content is 126
reported in international units and not in milligrams, but the manufacturer provided 127
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us this information for the conversion in writing (1 mg CMS = 11494 IU). The 128
selected dose of CMS was diluted in 3 ml saline solution and administered as a 129
bolus in 1-2 minutes. Solutions were prepared just before administration. 130
Prior to CMS administration, 5 ml of CSF were aspirated and discarded (to avoid the 131
increase of intracranial pressure induced by the bolus of CMS). After CMS 132
administration the ventricular drainage was flushed immediately with 2 ml of saline 133
solution to minimize the dose remaining in the drainage. The CMS was injected and 134
the CSF samples collected under sterile conditions via a needleless connector in the 135
ventricular drainage system which was disinfected with chlorhexidine. The external 136
ventricular drainage was kept closed for at least 60 minutes in the absence of an 137
increase of intracranial pressure greater than 20 mm Hg. Otherwise, the drainage 138
was opened. The amount of CSF drained during the period of sample collection for 139
the pharmacokinetic studies (12 or 24 hours) and the time of closure of the external 140
ventricular drainage after CMS administration were reported in the case report form. 141
The ventricular catheters inserted were not impregnated with antibiotics. Five 142
patients were also treated with intravenous CMS (174 mg/8 hours) dissolved in 50 143
ml of saline solution and administered over a period of 30 minutes by a volumetric 144
pump. 145
Potential nephrotoxicity was assessed by daily measurements of creatinine 146
clearance. 147
148
Chemicals and reagents 149
Colistin sulfate salt, trifluoroacetic acid (TFAA) and 9-fluorenylmethyl chloroformate 150
(FMOC-CL) were purchased from Sigma-Aldrich (St. Louis, MO, USA), Sep-Pak 151
SPE cartridges were obtained from Waters (Waters, Milford, MA, USA). 152
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Polypropylene tubes were purchased from Eppendorf (Milano, Italy). HPLC grade 153
methanol, acetonitrile, tetrahydrofuran and acetone were purchased from Carlo 154
Erba Reagents (Milano, Italy). Water was purified by a Milli Q System (Millipore, 155
Bedford, MA, USA). CMS (Colimicina®) was purchased from UCB Pharma, 156
Pianezza, Italy. 157
158
Conversion of CMS to colistin in vitro in human CSF 159
Concentration-dependent hydrolysis of CMS was studied by storing CMS solutions 160
at different concentrations. Blank human CSF (250 µl) was spiked with CMS at 161
concentrations of 10, 20, 50, 100 and 200 mcg/ml and kept at 37°C. Assuming that 162
the total volume of CSF in adult humans is 150 ml (5,23), the daily dose of CMS 163
administered IVT to our patients was within this range. At 0.5, 1, 2, 4, 8 and 16 164
hours, samples (250 µl) were removed and analyzed immediately. The levels of 165
colistin formed by hydrolysis of CMS were assayed by high performance liquid 166
chromatography (HPLC) as described below. 167
The percentage of colistin formed by hydrolysis of CMS was calculated on a molar 168
basis. In the present study the molecular weight of colistin A and colistin B was set 169
at 1170 and 1156 respectively. The molecular weight of CMS was set at 1743. 170
171
Pharmacokinetic procedures 172
Colistin concentrations in CSF were evaluated after at least 2 days of treatment with 173
CMS. CSF samples were obtained immediately before and at 10 minutes, 1, 2, 4, 8 174
and 12 hours after the bolus in patients receiving CMS every 12 hours, and 175
immediately before and at 10 minutes, 1, 2, 4, 8, 12, 16 and 24 hours after the bolus 176
in patients receiving CMS every 24 hours. Concentrations of colistin in CSF were 177
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also evaluated just before CMS administration in the 3 days following the day of the 178
pharmacokinetic studies to evaluate the possibility of colistin accumulation. CSF 179
samples were collected and stored in polypropylene tubes at –80 °C until analysis. 180
The maximum time that CSF was stored at -80 °C was 3 months. 181
182
Colistin assay 183
Colistin in CSF was measured using the method described by Li et al. (18) with 184
minor modifications (10). This is a sensitive method which discriminates colistin from 185
CMS. The concentration of colistin was determined by HPLC with fluorescence 186
detector. An aliquot (250μl) of CSF was vortex-mixed in a polypropylene tube with 187
internal standard (10 μl of 10 mg/L netilmicin sulfate), 50 μl TFAA (50/50, v/v) 188
solution, and centrifuged (4°C, 1000xg, 10 min). The supernatant was loaded into a 189
Sep-Pak cartridges preconditioned with methanol and equilibrated with carbonate 190
buffer. Colistin was derivatized with FMOC-Cl (60 µl) in SPE C18 cartridges, eluted 191
with acetone and evaporated under a nitrogen stream. Samples were reconstituted 192
(boric acid and mobile phase) and 25 μl injected into HPLC. Separation was 193
performed on a Zorbax SB-C18 column. The mobile phase consisted of acetonitrile, 194
tetrahydrofuran and water delivered isocritically at 1 ml/min. 195
The calibration curve was linear between 0.4 and 10 mcg/ml. Intra-assay and inter-196
assay variability was < 10% and 12%, respectively. The lower limit of quantification 197
(LOQ) was 0.1 mcg/ml. The recovery, calculated by comparing the responses (the 198
slopes of the lines describing the change in derivatized colistin to internal standard 199
as increasing amounts of colistin were added to the samples) from CSF with those 200
from water, was 104.8±1.2%(SD) (n=3). The validation of the method in a CSF 201
matrix was performed according to the Guidance for Industry, “Bioanalytical Method 202
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Validation”, issued by the FDA in May 2001 203
(http://www.fda.gov/cder/guidance/index.htm). 204
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CSF pharmacokinetic analysis 206
The colistin CSF data were used to construct the model and to estimate the 207
pharmacokinetic parameters of colistin intraventricularly administered as CMS. A 208
one-compartment model with input and output from a central IVT compartment was 209
used to analyze the data (Figure 2). The input was characterized by the extent and 210
by the formation rate constant of colistin from CMS. The output consisted of one 211
elimination rate constant, describing both the diffusion of colistin from the CSF to the 212
systemic circulation and its elimination through the external ventricular drainage 213
flow. Pharmacokinetic parameters were: kf (first-order rate constant for CMS 214
conversion to colistin), t1/2,f (formation half-life of colistin from CMS), CL/Fm 215
(apparent total CSF clearance of colistin after IVT administration of CMS corrected 216
by Fm, the unknown fraction of CMS converted to colistin), Vd/Fm (apparent CSF 217
volume of distribution of colistin corrected by Fm), k10 (first-order removal rate 218
constant of colistin from CSF), and t1/2λ (terminal half-life of formed colistin). 219
The maximum steady-state concentration (Cmax) achieved in CSF during a dosage 220
interval (τ) and the corresponding time (Tmax) were derived from the estimated 221
pharmacokinetic parameters (6,26). 222
The area under the CSF concentration-time curve (AUC0-24), which represents CSF 223
exposure to colistin during the 24-hour period, was calculated using the following 224
equation: CMS daily dose / (CL/ Fm). The estimated average concentration (Css,avg) 225
of colistin during 24 hours was calculated using the ratio AUC0-24 /24 h. Ctrough was 226
the concentration of colistin in CSF measured immediately before dosing. Data were 227
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analyzed using a population pharmacokinetic statistical software program (P-Pharm, 228
Version 3, Simed, Creteil, France). The population estimation algorithm used in P-229
PHARM is an EM-type procedure. This algorithm computes the maximum likelihood 230
estimates by an iterative procedure, as follows: (a) an expectation step (E step), in 231
which the individual parameters are estimated for each individual (Bayesian 232
estimate) given the current population parameters and the individual data, and (b) a 233
maximization step (M step), in which the population parameters are estimated by 234
maximum likelihood given the current estimates (E step) of the individual 235
parameters. The E and M steps are iterated up to the convergence of the algorithm. 236
Preliminary analysis revealed that the data were best fitted by a one-compartment 237
model (on the basis of examination of the Akaike criterion, the objective function, 238
and the distribution of residuals), that the probability density function of the random 239
effect parameters was better approximated by a log-normal rather than a normal 240
distribution, and that the distribution of residuals showed that the error variance was 241
better described by a heteroscedastic (proportional to the estimated values of the 242
predictions) model. 243
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RESULTS 245
Conversion of CMS to colistin in vitro in human CSF 246
The conversion of CMS to colistin in human blank CSF was evaluated in vitro by 247
measuring the amount of colistin formed from the hydrolysis of CMS. The 248
percentage of CMS converted to colistin was inversely proportional to the amount of 249
CMS spiked in CSF. At 16 hours, the percentages were 101.1, 96,2, 88,1, 62.8, and 250
35,9 for spiked CMS concentrations of 10, 20, 50, 100, and 200 mcg/ml, 251
respectively. The AUC0-16 of colistin formed from the hydrolysis of CMS showed a 252
markedly nonlinear relationship with the amount of spiked CMS (Figure 1). 253
254
CSF concentrations of colistin and population pharmacokinetic analysis 255
The pharmacokinetics of colistin after IVT administration of CMS could be best 256
described by the one-compartment model (Figure 2).. The values of estimated 257
pharmacokinetic parameters and measured Ctrough for every patient are detailed in 258
Table 2. The following parameters, reported as mean±SD, were found to describe 259
colistin CSF disposition in our patients: kf= 0.45±0.23 h-1, Vd/Fm = 0.32±0.05 L, 260
CL/Fm=0.033±0.014 L/h, k10=0.10±0.04 h-1. Pharmacokinetic parameters were not 261
influenced by the covariates entered in the model: body weight, age, gender or 262
concomitant intravenous administration of CMS. 263
The terminal half-life of formed colistin (t1/2λ) was 7.8±3.2 hours. Steady-state 264
concentrations (Css,avg) ranged between 3.0 and 12.2 mcg/ml. The average time to 265
Cmax (Tmax) was 3.7±0.9 hours. 266
Figure 3 shows the concentration-time profiles of colistin in CSF at steady-267
state after IVT administration of CMS at different dose regimens. 268
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CSF Ctrough was 0.99 mcg/ml when CMS was administered at the dose of 2.6 269
mg/day, whereas when CMS was administered at doses ≥ 5.2 mg/day, Ctrough values 270
were continuously above 2 mcg/ml (the accepted MIC value for A. Baumannii, P. 271
aeruginosa and K. pneumoniae), ranging between 2.0 and 9.7 mcg/ml (Table 2). 272
Values of CSF Cmax and AUC0-24 increased when the daily dose of CMS was 273
doubled from 2.61 mg to 5.22 mg, but unexpectedly no further increment was 274
observed when the daily dose of CMS was 10.44 mg. 275
During the pharmacokinetic sampling period the amount of CSF drained ranged 276
between 40 and 300 ml (Table 2), and the time of external ventricular drainage 277
closure after CMS administration ranged between 60 and 240 min. A significant 278
(p=0.0475) correlation was found between the amount of drained CSF and the 279
clearance of formed colistin (CL/Fm) (Figure 4). 280
The measured pre-dose concentrations of colistin in CSF at baseline, 24, 48 and 72 281
hours after the day of sampling for pharmacokinetic studies were similar and did not 282
show any statistically significant differences (5.77±2.95, 6.67±4.45, 7.42±4.43 and 283
5.41±5.13 mcg/ml, respectively), indicating that colistin did not accumulate in the 284
CSF in the 3 days which followed sampling for the pharmacokinetic studies. 285
Assuming a MIC breakpoint of 2 mcg/ml, Cmax/MIC ratio and AUC0-24/MIC 286
ratio after a daily dose of CMS of 2.61 mg were 3.1 and 36.2, respectively. After the 287
administration of a daily dose of 5.22 mg/Kg, Cmax/MIC ranged between 3.5 and 288
11.1, and AUC0-24/MIC ranged between 55.5 and 146.6. After the administration of a 289
daily dose of CMS of 10.44 mg, Cmax/MIC ranged between 4.5 and 7.2, and 290
AUC0-24/MIC ranged between 74.6 and 141.5. 291
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Clinical results 293
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The duration of IVT treatment with CMS ranged between 11 and 36 days (Table 1). 294
Cure of infection (improvement of biochemical parameters and subsequent 295
sterilization of CSF) was observed in 8 out of the 9 patients. Four patients died in an 296
Intensive Care Unit; in one patient death was related to the central nervous system 297
infection. The measured mean creatinine clearance was 114.4±18.6 ml/min (range 298
80.2-143) before CMS administration, and 109.1±15.9 ml/min (range 86.3-134) at 299
the end of treatment. None of the patients developed aseptic meningitis or seizures. 300
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DISCUSSION 303
To our knowledge, this is the first report describing the pharmacokinetics of colistin 304
after IVT administration of CMS. We believed that it was useful to evaluate the 305
pharmacokinetics of colistin for two reasons: 1) the doses and daily regimens of IVT 306
CMS reported in literature are empirically chosen and very varied (9,13); 2) 307
inflammation of meninges can cause profound alterations in CSF turn-over, and the 308
efflux of CSF through the external ventricular drainage can vary substantially among 309
patients, which could result in too high (potentially toxic) or too low (subtherapeutic) 310
concentrations of colistin. 311
Our results show that IVT administration of CMS gives concentrations of colistin that 312
could never be achieved with systemic delivery, and confirm that IVT administration 313
of CMS is effective and safe in the treatment of central nervous system infections 314
caused by Gram-negative bacteria susceptible only to colistin. 315
Assuming a susceptibility breakpoint of 2 mcg/ml, the MIC value for A. baumannii, 316
P. aeruginosa and K. pneumoniae according to the European Committee on 317
Antimicrobial Susceptibility Testing and the US Clinical and Laboratory Standards 318
Institution, when patients were treated with CMS ≥ 5.22 mg/day, the CSF 319
concentrations of colistin were continuously above 2 mcg/ml, the Cmax/MIC ratio was 320
≥ 3.5, and the AUC/MIC ratio was ≥ 55.5. Contrariwise, a daily dose of CMS of 2.61 321
mg resulted in colistin concentrations which were frequently below 2 mcg/ml. 322
The disappearance of colistin from the CSF was dose-independent and 323
monoexponential, with 10% removed every hour. The colistin terminal half-life, 324
which is generally longer for drugs in CSF, was comparable to that reported in 325
plasma (10,17,22). 326
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The apparent total CSF clearance of formed colistin (CL/Fm) ranged between 0.018 327
and 0.058 L/h/kg (Table 2), showing a large interpatient variability (CV%= 42%). 328
Several factors could have contributed to this variability. In fact CL/Fm results from 329
the unknown fraction of CMS metabolized to colistin (Fm), the diffusion from the 330
CSF to the systemic circulation and the cerebral tissue, and the elimination through 331
the external efflux of CSF. The process of colistin formation from CMS could have 332
been different among patients, but since we only measured colistin (the active 333
antimicrobial agent) and not CMS (the inactive prodrug), we could not evaluate the 334
fraction of CMS converted to colistin and, therefore, its contribution to the variability 335
observed. Secondly, if we consider that the volume of CSF within the cranial and 336
spinal spaces in an adult is about 150 ml and that the bulk flow is 20-30 ml/h (5,23), 337
another factor which probably played an important role in the disposition and 338
clearance of colistin was the amount of CSF spontaneously drained, which was 339
influenced by the fluctuation of intracranial pressure and ranged between 40 and 340
300 ml. The correlation between the amount of CSF spontaneously drained and the 341
clearance of colistin (Figure 4) supports this hypothesis. A better understanding of 342
this factor could have been gained from the measurement of colistin in the CSF 343
collected in the reservoir during the period of sampling (12 or 24 hours); but this 344
would have required more frequent sampling to avoid the spontaneous hydrolysis of 345
CMS to colistin, thus increasing the risk of superimposed infections. Another 346
element which is peculiar to patients with a ventriculostomy is the non-uniform time 347
of closure of the external ventricular drainage, both after a drug administration and 348
during the day. This considerable variability (in our patients the range was 60 – 240 349
min after CMS administration) likely influenced both the clearance of colistin and the 350
amount of formed colistin. Finally, the correlation between the dose of CMS 351
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administered intraventricularly and that of CMS converted to colistin by hydrolysis 352
might have been nonlinear also in the infected CSF of our patients (Figure 1). 353
For the reasons reported above, the dose-concentration correlation, which in a 354
closed compartment such as CSF should be strong, was in fact weak, and no 355
further increment in values of Cmax and AUC was observed when the dose of CMS 356
was increased to 10.44 mg/day (Figure 3). 357
358
Five out of our 9 patients were also treated with intravenous CMS. In these 359
patients the contribution of intravenous CMS to the concentration of colistin in the 360
CSF is unknown. However, it has been reported that the plasma concentration of 361
colistin is 2-3 mcg/ml (7,17,22,25), and on the basis of currently available data in 362
humans (1,11,21,30) it is reasonably to expect that diffusion or active transport 363
(active transport has been excluded in an animal model (12)) of colistin across the 364
blood-CSF barrier made a very small contribution to the levels of colistin in the CSF. 365
366
Clinical efficacy and toxicity 367
The IVT administration of CMS was effective in the treatment of the central nervous 368
system infections in our patients. Microbiological cure was obtained in 8 out of 9 369
patients. In one patient colistin failed to sterilize the CSF, although the 370
concentrations of the biochemical parameters suggested an improvement of the 371
infection. In one patient the concomitant administration of fosfomycin could have 372
contributed to CSF sterilization. 373
Microbiological cure was also obtained in the patient treated with CMS 2.61 mg/day 374
even though the concentration of colistin in this patient was often below 2 mcg/ml. 375
We believe that it would be unwise to treat patients with central nervous system 376
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infections with this dose regimen, given also the marked intra- and inter-patient 377
variability. 378
Neurotoxicity (e.g., seizures, aseptic meningitis, hypotonia, diaphragmatic paralysis, 379
cauda equina) has been described after systemic or IVT/intrathecal administration of 380
colistin (9,14,15,24). At the doses used in our patients, we did not observe signs or 381
symptoms of central nervous system toxicity, but our patients were mechanically 382
ventilated and sedated and we might, therefore, have underestimated this aspect. 383
384
Conclusions 385
IVT administration of CMS gives concentrations of colistin in CSF that could never 386
be achieved with systemic delivery. IVT administration of CMS at doses ≥ 5.22 387
mg/day was appropriate for the treatment of central nervous system infections 388
caused by pan-resistant Gram-negative bacteria in our patients, but since several 389
factors can influence the clearance of colistin and its concentrations in CSF (in 390
particular the external drainage of CSF), the daily dose of 10 mg suggested by the 391
Infectious Diseases Society of America may be more prudent. 392
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ACKNOWLEDGEMENTS 394
The study was supported by the Gruppo di Studio in Neuroanestesia e 395
Neurorianimazione, SIAARTI, Italy. We thank Dr. Rachel Stenner for her linguistic 396
revision of this manuscript. 397
398
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540
FIGURES 541
542
543
544
Figure 1. Relationship between the dose of spiked CMS and AUC0-16 values of 545
colistin formed from the conversion of CMS in vitro. Different doses of colistin 546
methanesulfonate (CMS) were spiked in blank human cerebrospinal fluid (CSF) and 547
colistin concentrations formed from hydrolysis of CMS were measured as described 548
in the Patients and Methods section. AUC = area under the CSF concentration-time 549
curve. 550
551
552
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553
554
555
556
CMSmetabolism
kf ColistinCMS, DIVT
k10
Removal (clearance) by convection, diffusion, and elimination through the EVD
V
557
558
Figure 2. Diagram of the one-compartment model for intraventricular administration 559
of CMS. The essential features are represented by the rate constants kf and k10 560
(see Patients and Methods section). CMS = colistin methanesulfonate; DIVT = 561
intraventricular dose CMS; EVD = external ventricular drainage; V = intraventricular 562
compartment. 563
564
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565
566
567
568
569
570
571
0,1
1
10
100
0 4 8 12 16 20 24
Time
Co
listi
n (
mc
g/m
l)
2.61 mg X 1 2.61 mg x 2 5.22 mg x 1 5.22 mg x 2
572 573
Figure 3. Concentration-time profiles of colistin at steady-state after intraventricular 574
administration of colistin methanesulfonate (CMS) at different dosage regimens. 575
CMS was diluted in 3 ml saline solution and administered as a bolus in 1-2 minutes. 576
Symbols represent the mean concentrations (±SD) of colistin. 577
578
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579
580
581
582
y = 0.0001x + 0.0171
R2 = 0.4513
0
0,01
0,02
0,03
0,04
0,05
0,06
0,07
0 100 200 300
CSF drained (ml)
CL
/Fm
(L
/h)
583
Figure 4. Relationship between the amount (ml) of cerebrospinal fluid (CSF) 584
drained during the period of pharmacokinetic sampling and the total clearance of 585
colistin (CL/Fm, L/h). 586
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Patients Age /Sex
CMS dose
(mg) and schedule
Admission diagnosis
Putative source of infection
SAPS II score(1)
Pathogen Susceptibility MIC for colistin
Antibiotic co-administered
i.v.
Duration of IVT
therapy (days)
Micro-biology
ICU Outcome
1 70/M 2.61/24 h Brain tumor EVD 34 A. baumannii Carbapenem-resistant
< 2 CMS, rifampicin 27 Cure Death unrelated
to infection
2 26/M 2.61/12 h Brain trauma - brain abscess
Oro-pharyngeal contamination
50 K.
pneumoniae Carbapenem-
resistant < 2
CMS, meropenem,
linezolid 36 Cure Survival
3 46/M 2.61/12 h Aneurysmal
SAH and ICH EVD 50
K. pneumoniae
Carbapenem-resistant
< 2 Ceftazidime 18 Cure Survival
4 18/F 2.61/12 h STBI/abscess EVD 47 A. baumannii Carbapenem-resistant
< 2 Meropenem,
ampicillin-sulbactam
17 Cure Survival
5 40/M 5.22/24 h Aneurysmal
SAH and ICH EVD 50
K. pneumoniae
Carbapenem-resistant
< 2 Amikacin,
ceftazidime 31 Cure Survival
6 51/M 5.22/24 h Aneurysmal
SAH and ICH EVD 50
K. pneumoniae
Carbapenem-resistant
< 2 Ceftazidime 24 Cure Survival
7 44/F 5.22/12 h Aneurysmal
SAH EVD 36
P. aeruginosa
Carbapenem-resistant
< 2 CMS, linezolid 15 Cure Death unrelated
to infection
8 58/M 5.22/12 h SAH Wound
infection 65
K. pneumoniae
Carbapenem-resistant
< 2 CMS,
vancomycin 11 Failure
Death caused by infection
9 73/F 5.22/12 h Brain
tumor/abscess Wound
infection 21
K. pneumoniae
Carbapenem-resistant
< 0.5
CMS, meropenem,
linezolid, fosfomycin
34 Cure Death unrelated
to infection
Table 1. Demographic, clinical characteristics and outcome of the patients. SAH = subarachnoid hemorrhage; CMS = colistin methanesulfonate; EVD
= external ventricular drainage; ICH = intracerebral hemorrhage; ICU = intensive care unit; SAPS II = Simplified Acute Physiology score II; STBI =
severe traumatic brain injury.
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Patients
Dose regimen of CMS
(mg)
Daily dose of CMS (mg)
CSF drained
during PK sampling
Measured in CSF Estimated pharmacokinetic parameters of colistin in CSF
Ctrough (mcg/ml)
Cmax (mcg/ml)
Tmax (h)AUC0-24 (mgxh/L)
Css,avg (mcg/ml)
kf (h-1)
t1/2,f (h)
CL/Fm (L/h)
Vd/Fm (L) k10 (h-1) t1/2λ (h)
1 2.61/24
h 2.61 222 0.99 6.2 2.9 72.5 3 0.76 0.91 0.036 0.34 0.11 6.5
2 2.61/12
h 5.22 40 6.8 11.9 3.4 248.6 10.4 0.481 1.44 0.021 0.35 0.06 11.6
3 2.61/12
h 5.22 55 8.1 10.8 3.5 226.9 9.5 0.425 1.63 0.023 0.37 0.06 11.2
4 2.61/12
h 5.22 138 2.0 7 2.4 111.1 4.6 0.705 0.98 0.047 0.3 0.16 4.5
5 5.22/24
h 5.22 148 5.52 22.1 3 261 10.9 0.731 0.95 0.02 0.19 0.11 6.5
6 5.22/24
h 5.22 142 6.1 16.2 5.5 293.3 12.2 0.317 2.19 0.018 0.33 0.05 12.9
7 5.22/12
h 10.44 150 8.4 13.1 4.4 282.9 11.8 0.171 4.05 0.037 0.34 0.11 6.4
8 5.22/12
h 10.44 300 4.6 9 3.9 180 7.5 0.205 3.38 0.058 0.35 0.17 4.1
9 5.22/12
h 10.44 72 9.7 14.4 4 149.1 6.2 0.258 2.69 0.035 0.34 0.1 6.7
591
Table 2. Estimated pharmacokinetic (PK) parameters of colistin in cerebrospinal fluid (CSF) following intraventricular administration of colistin 592
methanesulfonate (CMS) at different dose regimens. The reported Ctrough values were measured.; AUC= area under the CSF concentration-time 593
curve; Cmax= maximum plasma colistin concentration; Ctrough = minimum plasma colistin concentration; Css,avg = average concentration; CL/Fm= 594
total CSF clearance of colistin corrected by the unknown fraction (Fm) of CMS converted to colistin; EVD= external ventricular drainage; kf= 595
elimination rate constant; k10= first-order removal rate constant of colistin from CSF; t1/2,f= elimination half-life; t1/2λ= terminal half-life of formed 596
colistin; Tmax= time to Cmax; Vd/Fm= apparent volume of distribution of colistin corrected by Fm. 597
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