Full text of DOI:10.1345/aph.19370

Infectious Diseases
Safety and Tolerability of Bolus Intravenous Colistin in
Acute Respiratory Exacerbations in Adults with Cystic Fibrosis
Steven P Conway, Christine Etherington, James Munday, Martin H Goldman, Joanna J Strong, and
Mandy Wootton
OBJECTIVE: To assess the safety and tolerability of bolus intravenous doses of colistin during acute respiratory exacerbations in
adults with cystic fibrosis and chronic Pseudomonas aeruginosa infection.
METHODS: Twelve patients with acute exacerbations of cystic fibrosis were enrolled in a Phase I open-label study. On day 1, patients
received three doses of colistin 2 mega-units (160 mg), reconstituted in 50 mL of NaCl 0.9%, by infusion over 30 minutes three times
daily. On days 2, 3, and 4, the same dose of colistin was administered by bolus injection three times a day over five minutes after
reconstitution in 20, 15, and 10 mL of NaCl 0.9%, respectively. The injection was given by a nurse or physician using a hand-held
syringe. If the latter dose was tolerated, it was continued for the remaining eight days of the study. If any dose was not tolerated,
treatment reverted to the previously tolerated concentration, which was continued throughout the remainder of the study.
RESULTS: No serious adverse events occurred during the course of the trial. Patients without total indwelling venous access systems
experienced mild to moderate injection pain. There were no clinically significant changes in renal function.
CONCLUSIONS: This study indicates that the administration of bolus intravenous colistin as 2 mega-units (160 mg) in 10 mL of NaCl
0.9% three times a day is safe. It is well-tolerated by patients with total indwelling venous access systems.
KEY WORDS: cystic fibrosis, colistin, intravenous bolus.
Ann Pharmacother 2000;34:1238-42.
ntravenous antibiotics effective against Pseudomonas
aeruginosa are central to treatment regimens in the man-
components and cell death. Intravenous colistin has been
associated with nephrotoxicity (increased serum creatinine
and blood urea, acute renal failure, acute tubular necrosis),
and neurotoxicity (paresthesia, muscle weakness, dizzi-
ness, confusion, respiratory insufficiency secondary to neu-
romuscular blockade).8-11 P. aeruginosa resistance to co-
listin is unusual.12 Therefore, despite long-standing fears of
colistin-induced nephrotoxicity and neurotoxicity, this
agent has been reassessed and was found to be both effica-
cious and safe; it is now increasingly used in the treatment
of acute respiratory exacerbations of cystic fibrosis.13-15
The efficacy of colistin should be maintained by reserving
its use for patients with multiple drug–resistant P. aerugi-
nosa or widespread hypersensitivity reactions to conven-
tionally used intravenous antibiotics.
I
agement of patients with cystic fibrosis.1 As a corollary of
more frequent antibiotic use, bacterial resistance and pa-
tient hypersensitivity reactions have become increasingly
prevalent.2 Colistin is a natural polymixin antibiotic. The
parenteral preparation, colistin sulphomethate, is produced
by treating colistin base with sodium bisulfite in the pres-
ence of formaldehyde.3,4 The serum half-life of colistin af-
ter intravenous administration is between 1.5 and eight
hours.5,6 The US product information states the half-life as
two to three hours7; there is no accurate information about
the half-life of colistin in patients with cystic fibrosis. Co-
listin is primarily excreted through the kidneys. Any resid-
ual drug is probably slowly inactivated in the tissues, al-
though the exact mechanism is unclear.
Colistin is routinely administered three times daily over
30 minutes after reconstitution in 50 mL of NaCl 0.9%.
Self-administered intravenous antibiotic therapy is equiva-
lent to treatment given in the hospital setting for appropri-
ate patients. In cystic fibrosis treatment centers, these regi-
mens are likely to be prescribed as frequently as inpatient
Colistin penetrates between the protein and phospho-
lipid layers of the cell membrane of susceptible gram-neg-
ative bacteria, resulting in a leakage of vital intracellular
Author information provided at the end of the text.
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Research Reports
care.16 Patients treated at home often receive colistin via
preprepared delivery systems such as the Intermate, which
are convenient, and allow easy maintenance of sterility.
However, sterility is easy to maintain, but the infusion re-
quires approximately 30 minutes, and the systems are also
expensive. The delivery of each 6-mega-unit daily dose
(480 mg) costs approximately $145 (currency exchange
rate as of June 2000). Bolus injection offers potential sav-
ings on nursing time and consumables in the hospital, and
patient time and expense for those receiving home therapy.
Serum colistin concentrations were measured using a modified mi-
crobiologic assay.18,19 An aqueous stock solution of 1000 mg/L was
made from colistin sulphomethate sodium powder of known potency.
Stock solution standards ranging from 4 to 64 mg/L were prepared in
pooled normal human serum. Because of this methodology, minimum
and maximum concentrations either <4 or >64 mg/L could not be quan-
tified accurately. The coefficients of variation at low, intermediate, and
high concentrations were 18.8%, 10.6%, and 3.5%, respectively. The
microbiologic assay is the only one available for colistin in biological
fluids, and the present lower level of detection is relatively high. There is
no accurate pharmacokinetic curve for colistin.
The target peak and trough colistin concentrations were 10–15 and
>4 mg/L, respectively.6,20 The target peak value is consistent with data
from a previous study14 and takes into account the 30-minute delay from
the completion of drug administration to blood sampling. High serum
concentrations are obtained 10 minutes after intravenous administration.14
The target trough figure of 4 mg/L is the break point. Using these figures,
we have shown that colistin is effective in the treatment of cystic fibrosis.
Tolerance to colistin was assessed by monitoring and grading the oc-
currence of adverse events. Patients were encouraged daily to report any
new symptoms possibly attributable to colistin. After the second dose
each day, patients were asked standardized questions about whether they
had experienced any new dizziness, numbness, tingling, lack of coordi-
nation, unsteadiness, muscle weakness, pain at the injection site, or chest
wheezing and tightness (Appendix I). Neurotoxicity was defined as a
positive response to any of the first five items.
Methods
PATIENTS
Twelve adults with cystic fibrosis and chronic P. aeruginosa infec-
tion who had tolerated intravenous colistin for treatment of at least one
previous respiratory exacerbation were enrolled in the study at the time
of an acute respiratory exacerbation. Cystic fibrosis had been confirmed
in all patients by sweat electrolyte criteria on two occasions or by identi-
fication of two cystic fibrosis gene mutations. Colistin was chosen be-
cause multiresistant P. aeruginosa had been isolated or because previous
hypersensitivity reactions precluded the use of other antibiotics. An acute
respiratory exacerbation was defined by the presence of four or more of
the following: increased sputum production, change in sputum color
along the scale from clear to yellow to green, increased cough, increased
dyspnea or respiratory rate, decreased exercise tolerance, new crackles
on auscultation, new shadows on the chest X-ray, fever, deterioration in
respiratory function tests, and loss of appetite.
The severity of any reported symptom was graded as mild (not re-
quiring treatment or withdrawal from the study), moderate (marked and
uncomfortable, requiring treatment or prolonged hospitalization, possi-
bly resulting in withdrawal from the study), or severe (severe discomfort,
or severely limited normal function, or hazardous to health and requiring
treatment, resulting in withdrawal from the study). All reported symp-
toms were recorded as adverse events.
Adverse events were defined as possibly, probably, or definitely re-
lated to treatment with colistin. In each case, the event needed to follow a
reasonable temporal sequence from administration of the drug, and a
known or expected response pattern to the drug. Adverse events with a
possible or probable relationship to treatment with colistin were those
that could also have been readily produced by the patient’s clinical state
and/or other therapy or factors. Probable and definitely related adverse
events required further confirmation by observed clinical improvement
on stopping the drug or reducing the dosage. A definite relationship also
required an association with high drug blood concentrations.
All of the most recent sputum culture and sensitivity tests showed
growth of nonmucoid and/or mucoid P. aeruginosa strains sensitive to
colistin. No patient had a history of hypersensitivity to colistin, renal im-
pairment, or signs and symptoms of neurologic toxicity. Pregnant wom-
en were excluded from the trial. All other antibiotic therapy was stopped
at least seven days before entering the study, except for oral flucloxacillin,
which was continued throughout the study period if it was part of routine
therapy; nebulized colistin was stopped on the day of entry. Ten of the
12 patients had a total indwelling venous access system (TIVAS).
All patients were monitored with routine blood tests of renal function
(urea, creatinine) on days 1, 4, and 12; and liver function tests, hematolo-
gy, and urine Multistix testing on days 1 and 12. Nephrotoxicity was de-
fined as a ≥50% increase in urea or creatinine concentrations. Respirato-
ry function tests, forced vital capacity (FVC), and forced expiratory vol-
ume in the first second of FVC (FEV1) were recorded in triplicate using
a hand-held microspirometer at the same time each day. The highest val-
ue of the three measurements was recorded. This was done to evaluate
whether increasing colistin concentrations produced bronchoconstriction.
STUDY DESIGN
Patients received colistin 2 mega-units (160 mg) three times daily for
12 days. The protocol specified a dose of 6 mega-units (480 mg) divided
into three equal daily doses that are usually prescribed for the systemic
treatment of patients >60 kg and is the recommended dosage in the cur-
rent Summary of Products Characteristics sheet.17 When 2 mega-units
(160 mg) of colistin are given as a 50-mL infusion, mean peak serum
concentrations achieved are above the minimum inhibitory concentration
for P. aeruginosa; these concentrations are safe and well tolerated.13-15
Colistin was administered as the sole intravenous antibiotic during the
escalating concentration phase from days 1 to 4 to allow recognition of
any adverse events without the potential confounding factor of a concur-
rently administered intravenous antibiotic, and to facilitate accurate mea-
surement of colistin blood concentrations. On day 1, colistin was recon-
stituted in 50 mL of NaCl 0.9% and infused over 30 minutes. This con-
ventional infusion served as a control for the infusion-related adverse
drug events before patients entered the ascending bolus arm of the study.
On days 2, 3, and 4, colistin was similarly reconstituted but in decreasing
volumes of the diluent: 20 mL on day 2, 15 mL on day 3, and 10 mL on
day 4. The bolus injection was administered over five minutes by a nurse
or physician using a hand-held syringe. If any dose was not tolerated, the
treatment regimen reverted to the previously tolerated concentration and
was continued to day 12. The 10-mL dose was continued when tolerat-
ed. Serum colistin concentrations were measured 30 minutes before and
30 minutes after the second colistin dose on days 1 and 4. The timing of
the peak concentration was chosen to maintain consistency with previ-
ous work.14 A second appropriate antipseudomonal antibiotic was added
from days 5 to 12.
ANALYSIS
As this was a Phase I study of tolerability, it was not controlled, and
the patient cohort was small. It was therefore not reasonable to perform a
full statistical analysis. Descriptive statistics were produced using MS
Excel 97. All patients were included in the data summary. The mean,
standard deviation, median, minimum, and maximum were used to sum-
marize quantitative variables. Counts were used to summarize qualitative
variables. Data from the previous analysis were used to compensate for
missing information. This method was used where the value of the vari-
able concerned was missing at a key time point. Evaluation of efficacy
was not performed.
The study was approved by the hospital ethics committee, and written
informed consent was obtained from all patients.
Results
All 12 patients (8 women) completed the treatment
course. Patient age (mean ± SD) was 20.3 ± 2.2 years, and
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mean weight was 54.5 ± 11.5 kg. Mean values for body
mass index, FEV1, and FVC were 20.2 ± 2.09 kg/m2, 1.81
± 0.9 L, and 2.2 ± 0.97 L, respectively.
Thirteen (46%) adverse events were believed to be prob-
ably, and 11 (39%) possibly related to colistin use (Table
3). The highest number of adverse events were related to
pain and inflammation at the injection site and occurred
only in the two patients without a TIVAS. None of the ad-
verse events resulted in patients withdrawing from the
study. Eleven patients tolerated the maximum bolus con-
centration. One patient returned to the 50-mL diluent regi-
men on day 2 after reporting symptoms of dizziness and
lack of coordination. These symptoms resolved rapidly,
and the patient was able to return to normal activities later
the same day. This patient was not rechallenged with a fur-
ther bolus dose of the increased concentration.
Data points were unavailable for seven measurements:
FEV and FVC values before and after the dose for patient
1
5 from day 11 to day 12, FEV and FVC values after the
1
dose for patient 11 from day 1 to day 2, and ward urine
analysis for patient 6 at exit from the study. The most re-
cent data for these tests were carried forward.
There was an overall trend of improvement in mean
pulmonary function readings both before and after each
dose over the duration of the study. There was no evidence
of bronchoconstriction associated with the administration
of the increased concentration of colistin. Mean FEV read-
Cost savings in consumables for inpatients using bolus
administration of colistin were approximately $65 per day.
Cost savings for patients receiving home intravenous ther-
apy where bolus colistin would replace the Intermate de-
vice would be approximately $128 per day.
1
ings on days 1 and 12 before and after the dose were 1.8
and 1.9 (p = 0.12), and 1.94 and 1.95 (p = 0.93), respec-
tively; FVC readings showed similar changes. The addi-
tional intravenous antibiotics used were ceftazidime (n = 5
pts.), piperacillin (4), meropenem (2), and aztreonam (1).
There were no significant changes in mean blood values
for sodium, potassium, urea, or creatinine over the period
of increasing colistin bolus dose concentrations from day 0
to day 4. Similarly, there were no significant changes in
mean renal function parameters or liver function tests from
day 0 to day 13, except for a rise in mean potassium value
from 4.0 to 4.4 mEq/L (p < 0.05) and a decrease in mean
albumin concentrations from 3.9 to 3.7 g/dL (p < 0.05).
Neither of these changes was clinically significant. In two
patients, blood urea concentrations showed a >50% increase
from baseline and rose above the upper limit of normal
(46.2 mg/dL), from 26.4 to 47.4 mg/dL and 25.2 to 53.4
mg/dL. In one other patient, serum creatinine rose from
0.92 to 1.74 mg/dL (normal 0.8–1.2). No other patient
showed a >50% rise in serum creatinine concentration.
Three other patients developed an increase in serum urea
of 64%, 57%, and 54%, but values determined on day 12
remained within the normal range (Table 1). Ward urinalysis
showed no significant changes. The mean peripheral white
blood cell count fell from 9.9 to 7.0 × 103/mm3 (p = 0.013).
Because of the complex nature of colistin, a simple
chromatographic assay is not yet available; therefore, a mi-
crobiologic assay is used to quantify colistin concentra-
tions in biological fluids. The present lower level of detec-
tion is relatively high. Mean trough and peak serum col-
istin concentrations were slightly lower for conventional
versus bolus dosing, probably reflecting the
Discussion
Bolus doses of colistin 2 mega-units (160 mg) three
times daily reconstituted in NaCl 0.9% given as an ascend-
ing concentration regimen was well tolerated in the treat-
ment of acute respiratory exacerbations in adults with cys-
Table 1. Pre- and Posttreatment Blood Urea and
Creatinine Concentrationsa
Blood Urea (mg/dL)
Serum Creatinine (mg/dL)
Patient
Day 1
Day 12
Day 1
Day 12
1
2
30.6
32.4
16.2
36.6
26.4
25.2
16.8
32.4
17.4
30.0
15.6
25.2
39.6
30.6
10.5
26.4
47.4
53.4
27.6
30.0
25.8
25.2
24.0
39.6
0.62
0.72
0.59
0.99
1.06
0.60
0.66
0.92
0.60
0.52
0.87
0.70
0.44
0.93
0.60
0.91
0.84
0.55
0.67
1.74
0.72
0.51
0.82
0.78
3
4
5
6
7
8
9
10
11
12
aColistin dosage was 2 mega-units (160 mg) three times daily.
fact that the day 1 values determined near ad-
ministration of the second dose do not repre-
sent a steady-state concentration (Table 2). All
Table 2. Mean Serum Colistin Concentrationsa
peak concentrations were above the minimum
target range value of 10 mg/L.
Range
Min Max
Patients Serum Concentration
Day
Time
(n)
(mg/L)
Twenty-eight adverse events were reported
during the study; 21 of these were defined as
1
predose
12
10
5.9
<4.0 9.4
(50-mL infusion) postdose
predose
15.3
10.6 20.8
mild and seven as moderate. Nine samples of
the peak concentration exceeded the upper tar-
get concentration of 15 mg/L; higher colistin
concentrations were not related to increased
incidence of adverse events.
4
12
11
6.9
4.0 11.2
(10-mL bolus)
postdose
15.7
11.4 28.4
Max = maximum; Min = minimum.
aColistin dosage was 2 mega-units (160 mg) three times daily.
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Research Reports
tic fibrosis. Only 1 of 12 patients reverted to the conven-
tional 50-mL diluent. The pattern and frequency of ad-
verse events was similar to those seen with conventional
colistin dosing.14 No serious adverse events were reported
by the patients, and no adverse events were associated with
peak colistin concentrations above the therapeutic range.
Twelve of 13 events thought to be probably related to ther-
apy were defined as mild. The most frequent adverse event
was pain or inflammation at the injection site, which oc-
curred in the two patients who did not have a TIVAS. One
of these patients had local phlebitis. Bolus doses of colistin
were administered to these two patients via a Hydrocath
midline 22G 20-cm catheter. These findings of few ad-
verse events should be interpreted with some caution. Only
12 patients took part in this trial, and one patient (8%) did
not tolerate the bolus dosing schedule. Careful monitoring
in routine clinical practice is recommended before the use
of bolus doses becomes common in the general cystic fi-
brosis population.
There was no significant change in mean blood urea or
serum creatinine concentrations. Blood urea concentra-
tions rose above the normal range in two patients and in-
creased by 50% over baseline values, and serum creatinine
concentrations increased significantly in one patient. Re-
peat measurements at subsequent clinic visits showed all
three values within the normal laboratory range at three
weeks, eight weeks, and one week, respectively. The pa-
tient showing a significant rise in serum creatinine has
maintained a mean value of 1.15 mg/dL (range 0.98–1.3)
over 13 subsequent measurements during a 12-month fol-
low-up period; therefore, no persistent nephrotoxicity was
found within the study protocol. Further definition of po-
tential renal toxicity effects would require a comparison of
creatinine or inulin clearance. There was a significant rise
in mean blood potassium concentrations with treatment,
although mean concentrations did not rise above the nor-
mal range. We do not believe that the change in potassium
concentrations reflected a deterioration in renal function,
as such a hypothesis is not supported by other measure-
ments of renal function. The rise in potassium values may,
in part, be explained by slight hemolysis of samples stored
over the weekends prior to analysis.
The efficacy and safety of colistin as treatment for acute
respiratory exacerbations in patients with cystic fibrosis
and chronic P. aeruginosa infection have been established
in prospective and retrospective studies.13-15 The primarily
physiochemical mechanism of action of colistin may allow
an enhanced effect when used with antibiotics that have a
different mechanism of action. In the treatment of acute
pulmonary exacerbations in our unit, colistin alone result-
ed in an increase in respiratory function similar to that
achieved in combination therapy with two conventional
antipseudomonal antibiotics. When colistin was used con-
currently with a second antibiotic, an even greater im-
provement in lung function was achieved.14
Bolus administration of colistin will have a significant
clinical impact. Colistin is traditionally infused three times
a day for a total of 90 minutes, resulting in physical restric-
tion of the patients. Bolus dosing will reduce the adminis-
tration time to 15 minutes per day. A great amount of nurs-
ing time will be gained in units where patients self-admin-
ister bolus doses of intravenous antibiotics. The time saved
as a result of bolus administration will allow a more nor-
mal lifestyle for patients receiving home intravenous thera-
py. This will be especially appreciated in the mornings,
when it will be easier to complete treatment before leaving
for school or work, as well as over meal times.
Summary
This study extends the safety profile of colistin and should
increase physicians’ confidence in prescribing this antibi-
otic. It is very valuable in the treatment of multiple drug–
resistant P. aeruginosa, and we recommend that it is used
only in such cases. Colistin is usually administered over 30
minutes after reconstitution in 50 mL of NaCl 0.9%. We
found bolus doses of colistin administered three times dai-
ly as 2 mega-units (160 mg) in 10 mL of NaCl 0.9% over
five minutes to be safe and well tolerated in patients with a
TIVAS. Two patients with peripheral midline catheters ex-
perienced pain or inflammation at the injection site. We be-
lieve that it is reasonable to continue to evaluate the use of
bolus administration of colistin in patients with cystic fibro-
sis and recommend that bolus doses should be given only
through a TIVAS. As with conventional dosing regimens,
renal function and neurologic status should be monitored.
Table 3. Frequency Distribution of Adverse Eventsa
50 mL
20 mL
15 mL
10 mL
Description
Chest tightness and wheezing 0
in 30 min in 5 min in 5 min in 5 min
0
1
1
1
0
2
0
2
0
0
0
0
0
0
0
0
0
2
0
0
2
1
5
0
1
1
4
0
0
4
Dizziness
0
0
0
0
0
1
0
0
0
Inflammation at injection site
Lack of coordination
Muscle weakness
Numbness
Pain at injection site
Tingling
Unsteadiness
Other
Total number of events
Total number of doses
AE rate per dose
1
7
2
18
Steven P Conway MB BS FRCP FRCPCH, Director of CF Ser-
vices, St. James’s and Seacroft University Hospitals, Leeds, Eng-
land
67
34
33
296
0.02
0.2
0.06
0.06
Christine Etherington MB BS, Physician, Adult CF Unit, Seacroft
AE = adverse event.
Hospital
aAccording to volume of NaCl 0.9% in which 2 mega-units (160 mg)
of colistin was administered and duration of infusion.
James Munday BSc [Hons], Clinical Research Associate, Phar-
max Ltd., Bexley, England
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Martin H Goldman BSc MB BS MRCP Dip Pharm Med [RCP UK]
FFPM, Senior Medical Advisor, Pharmax Ltd.
Appendix I. Symptom Questionnaire
Joanna J Strong BSc [Hons], Clinical Research Associate, Phar-
max Ltd.
Please read the following script to all patients every time a “symp-
tom checklist” is required to be completed.
Mandy Wootton BSc [Hons], Senior Research Scientist, South-
mead Hospital, Bristol, England
We need you to tell us whether you have experienced any usual or
unusual symptoms today, even ones that were very mild.
Reprints: Steven P Conway MB BS FRCP FRCPCH, Seacroft Hos-
pital, York Rd., Leeds LS14 6UH, England, FAX 44-113-2063738,
E-mail steven.conway@gw.sjsuh.northy.nhs.uk
This checklist is a way for us to remind you of any of these.
I am going to read out a list of symptoms. After each one, state
whether or not you have experienced it during the day by answer-
ing either yes or no.
References
You can take as long as you like to think about each answer. If you
answer yes to any of the questions, your doctor may need to ask
some more detailed questions about the way you have been feeling.
1. Regelmann WE, Elliott GR, Warwick WJ, Clawson CC. Reduction of
sputum Pseudomonas aeruginosa density by antibiotics improves lung
function in cystic fibrosis more than do bronchodilators and chest physi-
otherapy alone. Am Rev Respir Dis 1990;141:914-21.
2. Cheng K, Smyth RL, Govan JRW, Doherty C, Winstanley C, Denning
N, et al. Spread of β-lactam–resistant Pseudomonas aeruginosa in a cys-
tic fibrosis clinic. Lancet 1996;348:639-42.
3. Goodwin NJ. Colistin and sodium colistimethate. Med Clin North Am
1970;54:1267-76.
4. Bergan T, Fuglesang J. Polymyxin antibiotics. Chemical and pharma-
cokinetic properties. Antibiot Chemother 1982;31:119-44.
5. Froman J, Gross L, Curatola S. Serum and urine levels following par-
enteral administration of sodium colistimethate to normal individuals. J
Urol 1970;103:210-4.
MÉTODOS: Doce pacientes con exacerbaciónes respiratorias agudas
fueron incluidos en la fase I del estudio que era de diseño abierto. En el
primer día del estudio, los pacientes recibieron tres dosis de colitina de
dos mega unidades (160 mg). Éstas dosis fueron reconstituidas en 50
mL de 0.9% de cloruro de sodio y fueron adminstradas por medio de
una infusión sobre 30 minutos. Durante los días 2, 3, y 4, las dosis de
colistina fueron administradas tres veces al día por medio de una
infusión de cinco minutos después de ser reconstituidas en 20, 15, y 10
mL de cloruro de sodio, respectivamente. Las injecciónes fueron
adminstradas por medio de una enfermera o un doctor usando una
jeringa de mano. Si se toleró la ultima dosis, las injecciónes fueron
continuadas por el resto de los ochos días de estudio. Si no se toleró una
dosis, se revertió el tratamiento a la dosis previamente tolerada y ésta fue
continuada hasta que se terminó el estudio.
6. Kunin CM. A guide to the use of antibiotics in patients with renal dis-
ease. Ann Intern Med 1967;67:151-8.
7. Data on file. Parke-Davis, 1996.
8. Koch-Weser J, Sidel VW, Federman EB, Kanarek P, Finer DC, Eaton
AE. Adverse effects of sodium colistimethate. Manifestations and specif-
ic reaction rates during 317 courses of therapy. Ann Intern Med 1970;
72:857-68.
9. Walinsky E, Heins JD. Neurotoxic and nephrotoxic effects of colistin in
patients with renal disease. N Engl J Med 1962;266:759-62.
10. Price DJE, Graham DI. Effects of large doses of colistin sulphomethate
sodium on renal function. Br Med J 1970;4:525-7.
11. Cox CE, Harrison LH. Intravenous sodium colistimethate therapy of uri-
nary tract infections; pharmacological and bacteriological studies. Anti-
microb Agents Chemother 1970;10:296-302.
12. Goldman M, Alcorn M. Prevention of chronic Pseudomonas aeruginosa
colonisation in cystic fibrosis by colistin. European Cystic Fibrosis Con-
ference, Madrid, May 21–26, 1993. Poster presentation, Program Ab-
stracts Book, PD45.
RESULTADOS: No hubo eventos adversos serios. Pacientes sin sistemas de
implante de acceso venoso total experienciaron dolor leve o moderado
en el sitio de la injección. No hubo cambios clínicos significativos en la
función renal de estos pacientes.
CONCLUSIONES: Este estudio indica que la colistina es eficaz cuando se
administra en dosis de dos mega unidades (160 mg) en 10 mL de 0.9%
cloruro de sodio por la vía intravenosa sobre cinco minutos. Colistina es
bien tolerada en pacientes con sistemas de implante de acceso venoso
total.
Carlos C da Camara
RÉSUMÉ
13. Bosso JA, Liptak CA, Seilheimer DK, Harrison GM. Toxicity of colistin
in cystic fibrosis patients. DICP 1991;25:1168-70.
OBJECTIF: Évaluer l’inocuité et la tolérance d’un bolus intraveineux de
colistin durant des épisodes respiratoires aigus chez des sujets adultes
atteints de fibrose kystique et d’infection chronique à Pseudomonas
aeruginosa.
14. Conway SP, Pond MN, Watson A, Etherington C, Robey H, Goldman
MH. Intravenous colistin sulphomethate in acute respiratory exacerba-
tions in adult patients with cystic fibrosis. Thorax 1997;52:987-93.
15. Ledson MJ, Gallagher MJ, Calperthwaite C, Convery RP, Walshaw MJ.
Four years’ experience of intravenous colomycin in an adult cystic fibro-
sis unit. Eur Respir J 1998;12:592-4.
16. Pond MN, Newport M, Joanes D, Conway SP. Home v. hospital intra-
venous antibiotic therapy in the treatment of young adults with cystic fi-
brosis. Eur Respir J 1994;7:1640-4.
MÉTHODES: Douze patients ayant manifesté des épisodes aigus ont été
inscrits dans une étude ouverte de phase 1. Au jour 1, les patients ont
reçu trois doses de colistin, chacunes de deux mégaunités 160 mg,
administrées dans 50 mL de chlorure de sodium 0.9% en perfusion
intermittente de 30 minutes. Au jours 2, 3, et 4, le colistin a été injecté
en bolus intraveineux sur cinq minutes trois fois par jour après
reconstitution dans 20, 15, et 10 mL, respectivement. L’injection a été
donnée par une infirmière ou un médecin. Si la dernière dose était bien
tolérée, le traitement était poursuivi durant les huit jours restants de
l’étude. Si une dose n’était pas bien tolérée, le traitement se poursuivait
avec la dernière concentration tolérée jusqu’à la fin de l’étude.
17. Data on file. Pharmax Ltd., 2000.
18. Grove DC, Randall WA. Assay methods in antibiotics: a laboratory
manual. New York: Medical Encyclopedia Incorporated, 1955.
19. Sullman SF. Polymixins. In: Reeves DS, Phillips I, Williams JD, Wise
R, eds. Laboratory methods in antimicrobial chemotherapy. Edinburgh:
Churchill Livingstone, 1978:232-4.
RESULTATS: Il n’y pas eu d’effets secondaires importants. Les patients
n’ayant pas d’accès veineux centraux ont manifesté une douleur à
l’injection légère à modérée. Aucun changement cliniquement
significatif n’a été noté au niveau de la fonction rénale.
20. Catchpole CR, Andrews JM, Brenwald N, Wise R. A reassessment of
the invitro activity of colistin sulphomethate sodium. J Antimicrob
Chemother 1997;39:225-60.
CONCLUSIONS: Cette étude démontre que l’administration d’un bolus
intraveineux en cinq minutes de colistin 160 mg dans 10 mL de chlorure
de sodium 0.9% trois fois par jour est sécuritaire. Il est bien toléré par les
patients ayant un accès veineux central.
EXTRACTO
OBJETIVO: Estudio fue una evaluación de la eficacia y tolerancia de la
colistina administrada por la vía intravenosa durante exacerbaciónes
respiratorias agudas en pacientes adultos con fibrosis cística e
infecciónes de Pseudomonas aeruginosa crónicas.
Louise Gagnon
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The Annals of Pharmacotherapy
2000 November, Volume 34
www.theannals.com