CHEMOTHERAPY

142

RENAL

CLEARANCEMETHANESULFONATE

for theTAKESHI

doseSHIRAI,

RENAL

schedule

Department

MINODAKyushuandUniversity,

HAJIME

Medicine,
Fukuoka,(Received January
A recent increase in the incidence of infection due
to gram-negative
bacteria has drawn concern to theclinician as therapeutic problems.
Accordingly,
anumber of antibiotics
effective to gram-negative
bacteria has been developed.
Sodium colistin methanesulfonate (MCM) is the sodium salt of the methane sulfonate derivative of colistin, which is effective to gram-negative
bacteria, and is also known
to be cffective to the bacteria which have been insensitive to commonly used antibiotics. Some physicians,
however,tend to avoid administration
ofMCM to the patients with chronic urinary tract infection accompanied by chronic renal functional impairment or gram-negative
infectious diseases complicated by renal disease even when causative bacteria of the infection are sensitive to the MCM andrelatively resistant to commonly used other antibiotics.
This is because they feel that MCM might
have strong nephrotoxic potency since polymyxin B
is known to cause impairmentof renal function(MCM belongs to polymyxin group,and is polymyxin E). Actually, MCM itself has little nephrotoxic potency as compared with polymyxin B, buthigh serum levels of MCM is likely to occur inpatients with renal insufficiency,
because MCM iseliminated mainly by renal excretion.
This very
high serum levels of MCM may give rise to unpleasant side effects. Therefore, toavoid over administration of MCM in patients with renal functional
impairment,
the dose schecule should be adjusted
according to their renal function. Thus renal clearance of MCM and other renal function tests including creatinine
clearance and PSP excretion test
have been measured in the normal subjects andpatients with renal diseases with or without renal
functional impairment,
and adequate administration

with

TAKASUGI,of Internal

1971

COUSTIN
AND

PATIENTSDISEASESin patients

MASAYUKIHIROAKI
Third

OF SODIUM
IN NORMALS

WITH"A guideMAR.

impaired

AKIHIKO

renalfunction"

KITAMURA,

YAMAGA
Facultyof Medicine,Japan9, 1970)

plan for the patientrs withrenal functional impairment have been established.
MATERIALS
AND METHODSTwenty cases of chronic renal diseases of varying
etiology (including chronic glomerulonephritis
andchronic pyelonephritis),and 10 cases of healthy
volunteers were used in this study. The age rangeof the group of renal diseases was 15 to 66 years old,
and those of normal subjects was 23 to 39 years old.
A dose of 66. 8 mg base potency (2,000,000 units)of MCM was injected intramuscularly
and blood
samples and urine specimens were collected according to the clearance schedule, i.e. before injectionof MCM and 30. 60 and 90 minutes after the injection.
At the same time paraaminohippuricacid(PAH) clearance was measured by single intravenous
injection of PAH. The load of PAH was adjusted
according to the result of previously performed PSP
excretion test. Also 24 hours endogenous creatinine
clearance was determined on the next day.
The concentrationof MCM was determined by
the method of bioassay using NIH J strain of E.
coli.
RESULTSI) Serum and urine concentrationof MCM following single intramuscular
injection of 66. 8 mg
base potency (2,000,000 units) of MCM.
i) Serum levels of MCM (Fig. 1).
As shown in Fig. 1, the average serum levels of
MCM in normal subjects rose slowly to 2. 5 pg/ml
after 30 minutes, 2.7 ,t2g/ml after 60 minutes,
and2.9 pg/ml
after 90 minutes of injection.
In thegroup of the patients with chronic
without renal functional impairment% of PSP excretion
serum level reachedrenal diseases(more than 25in 15 minutes),
the average
to 4.6 pg/m1 after 30 minutes,

VOL.

19NO.

2143

CHEMOTHERAPYFIG.;. I SERUMLEVELS
OFP101 AFTER
663 PIG
OFMCMI.M. INJECTION.

FIG.2 TOTALURINARY
EXCRETIONCF MCMand thereafter

the serum levels of MCM maintained

about the same levels. In the group of the patientswith renal functional impairment (less than 24% ofPSP excretion in 15 minutes),
the average serum
level of MCM rose to 4. 9 pg/ml after 30 minutes,
5.1 pg/ml after 60 minutes, and 6. 3 pg/ml after 90minutes.
ii) Urine excretion of MCM (Fig. 2)
In the group of the normal subjects, the average
total excretion of MCM was 4.5 mg at the period of
the first 30 to 60 minutes, and 3.7 mg at the period

fis.3 SERUMLEVELSAND
URINARY
EXCRETION
OFMCM
INA PATIENTOR;47mL/MIN)FoLLOWIN6INTRAMUSCULARINJECTION
oF6iteM4,AND
133.6MGOFMCMINTWOSEPARATE OCCASIOPISTable 1

CMC,Ccreat., CPAH and PSP excretion in15 minutes in the normal subjects andPatients with renal diseases.

of 60 to 90 minutes.
In the group of the renal.
diseases without renal functional impairment,
theaverage total excretion of MCM was 4. 1 mg in thefirst 30 minutes collection period and 4. 5 mg in thenext 30 minutes collection period. The urine MCM
in the group of renal diseases with renal functionalimpairment was 1.8 mg in the first 30 minutes and1.5 mg in the second 30 minutes collection period.
A patient with moderate renal functional impairment (GFR: 47 ml/min.) was injected two doses of66.8 mg base potency (2,000,000 units) and 133. 6 mg
base potency (4, 000, 000 units) of MCM into the muscle on the separate days, and the serum levels ofMCM and urine concentration of MCM were determined.
As shown in Fig. 3, the larger dose gave-CHEMOTHERAPY

144

higher serum levels and excreted more in the urine.
However, the values of clearance of MCM werealmost the same at those two different serum levels(CMC: 12. 6 ml/min., and 16. 6 ml/min.).
II) Clearance of MCM (CMC), endogenous creatinine clearance (Coreat.), PAH clearance (CPAH),and PSP excretion test.
The average and the range of each clearance
value were shown in Table 1.
III)
Relationship between CCM and other renal
functions.
The CCMand Corea,. (Fig.4): There was a goodcorrelation between CCMand Coreat , in the normal
subjects and patients with renaldi seases, and theircorrelation coefficient "r" was 0.82.
The CMCandCPAH (Fig. 5): There was a good correlation between CMCand CpAH, although their correlation coefficient was not good as the former one. PSP excretion in 15 minutes and CMC(Fig. 6): There wasa very good correlation between those two in thepatientswith renal diseases,

the "r"being 0.91.

F/ G. 4 RELATIONSHIPBETWEEN
CmcANDCCREAT.

○NORMAL● PATI ENTS

MAR.

1971

DISCUSSIONAs mentioned at the introduction of this article,
the incidence of systemic infection due to gramnegative bacteria has been increasing, and the therapy of those infection has become serious problem,
because many of those gram-negative
bacteria are
relatively insensitive to commonly used antibiotics.
Thus, antibiotics with a high degree of activity
against these gram-negative
bacteria have grown
to great importance.
Sodium colistin methanesulfonate
is a basic polypeptide antibiotics found by KOYAMA1), and is aneffective bacteriocidal
agent for the gram-negative
bacteria which have been resistant to commonly used
antibiotics,
and the clinical effectivenessof thisdrug has been well established2, 3,4). There is,however, some problems for the use of this effective
drug to the patients with renal diseases with renal
functional impairment;(i) this drug is eliminatedmainly by renal excretion,and administration
ofMCM in excess of renal disposal capacity may leadto high serum concentration of MCM and may cause
F1G.6 RELATIoNSHIPBETWEEN
CMC
ANDPSPEXCRETION
RATE
INTHE
PATIENTWITHRENALDISEASESSUSJECTS
WITH

ENAL

PfSEASES

FIG.5 RELATIONSHIPBETWEEN
Cm,ANDCPAH○NORMAL

SUBJECTS●PAIENTS

WiIH

RENAL

DISEASES

FIG.7 ADMINISTRATINGPLANOF MCM
ACCORDINGTO CCREAT.

VOL.

19NO.

2

CHEMOTHERAPY

many unpleasant side effects such as neurophychic
disturbances,paresthesias and further deteriorationof pre-existing
renal disease, (ii) all the polymyxins are potentially nephrotoxic to the epitheliumof convouluted tubules, although MCM (polymyxinE) has not so strong nephrotoxicity
as polymyxin B.
Concerning to nephrotoxicity
to the human kidney,
FEKETY et al.3) studied nephrotoxicity of this drugby means of renal biopsy and concluded that they
could not find any histological evidence of the ne-145

tion tests, although accurate mechanism of elimination of this drug from the kidney is not clear.
From our data MCM is mostly eliminated throughthe kidney and their clearance is about 50 to 60%
of creatinine clearance (GFR). Thu sestimation of
the critical administratingdose can be made depending upon the result of the creatinine clearance of
GFR. Following formula can be used for the estimation of adequate dose in patientswith renalfailure.

phrotoxicityof colistin.
Also TALLGERN et al.5)
reported their experience of colistin treatment for aCreatinine

total 25 patients with impaired renal function ofvarying etiology, and stated that the histologicalfinding did not differ from the expected underlying
renal diseases, although transient deterioration
ofrenal function occurred in some cases of their 25

mended daily dose (66. 8 to 133. 6 mg) =adequate daily
dose for the patient with renal failure (%) (Fig. 7).

patients with renal diseases with chronic renal failure. On the other hand, ELWOOD and his co-workers6) observed that BUN were rised and acute ologuric fata renal failure developed in an advanced
aged subject in the colistin treatment.
But this
may be resulted from abnormal serum concentrationof MCM and this high serum levels of MCM might
have caused further deterioration of the pre-existent
minimal degree of renal changes.
Thus, to avoid high serum concentration of MCM
seems to be the most important point of using of
this drug, namely dosage should be reduced in proportion to the extent of the impairmentof renalfunction.
Concerning to this dosage reduction inpatients with renal failure,GOODWINet al.7) studied 39 subjects with varying degree of renal function and decided recommended dosage plan according to the endogenous creatinine clearance.
Thatis, i) when endogenous creatinine
clearance exceeds 20 ml/min., 75 to 100% of the recommended
daily dose divided into doses every 22 hr, (ii) whenendogenous creatinine clearance is between 5 and
20 ml/min., 50% of the usual daily dose divided
into doses every 12 hr., (iii) when endogenous creatinine clearance is lses than 5 ml/min., 30 to 35%of the normally recommended dose divided into doses
every 12 to 18 hr. And this dosage plan seems to
be excellent one, however, dosage plan appears to
be relatively rough.
From our observation,
there is a positive correlation between serum concentration of MCM andtotal urine excretion of MCM, and also there is agood correlation

between CMCand other renal func-clearance

or GFR of thepatient/×reco‑

100

For example, when creatinine clearance or GFR is
100 ml/min., daily adequate dose to this patient is100% of recommended dose divided in two doses
every 12 hours, aud when creatinine
clearance is75 ml/min., daily adequate dose of this patient is
75% of recommended dose divided in two doses every
12 hours and when the creatinine
clearance is 50
ml/min., daily adequate dose is 50% of recommended dose divided in two doses every 12 hours.
When creatinine clearance is 25 ml/min., the adequate dose is 25% of recommended dose. Whenthe creatinine clearance is less than 25 ml/min., thedose should be adjusted by the period of the administrationof this drug.
It is important to notethat minimum dose of MCM is necessary to maintain the effective body fluid concentrationof MCM
in patients with severe renal functional impairment.
When creatinine clearance and other glomerular
filtration studies are not possible to perform,
administratingdose may be adjusted by 15 minutes
PSP excretion rate instead of creatinine clearance,
as shown in Fig. 8. For example, when the resultsfiG.8ADMINISTRATINGPLANOF MCM ACCORDING TO
RSTPEXCRETloNIN 15 MINUTES

146

MAR.

CHEMOTHERAPYof PSP excretion in 15 minutes is more than 25%,
100% of the recommended dose should be given
divided into two a day, when PSP is 15%, 75% ofrecommended dose is adequate dose of the patientand so on.
These admininstratingplan from our data essentially concurs with GOODWIN's claim, but our administration
plan is more critical,
and also more
universal than their plan.
When using this methodin the sodium colistin methanesulfonate
treatment
to the patients with gram-negative
infection complicated by renal disorder, unpleasantside effectsof this drug will be avoided and successfultreatment will be achieved.
CONCLUSION
To establish
adequate administratingdose ofsodium colistin methanesulfonate(MCM) in patientswith impaired renal function, MCM clearance wasmeasured with other renal function tests in healthy
volunteers and patients with renal diseases.
MCM
clearance was about 50 to 60% of creatinine
clearance and there was a good correlation between
MCM clearance and PSP excretion rate of 15 minutes. Thus, adequate administratingdose may beadjusted by PSP test, and a dosage schedule according to creatinine clearance or PSP excretion test
was introduced.

1)

2)3)

4)

5)

6)

7)

1971

REFERENCES
KOYAMA,Y., KUROSAWA,A., TSUCHIYA, A.
& TAKAKUTA, K.: A new antibiotic, colistin
produced by spore-forming
soil bacteria. J.
Antibiotics 3, 457, 1950
HUGHES, P. D.: Colimycin in the treatmentof urinary infection.
Brit. J. Urol. 35, 109,
1963
FEKETY, F.R., Jr., NORMAN,P. S. & CLUFF,L. E.: The treatment of gram-negative
bacillary infection with colistin.
Ann. Int. Med.
57, 214, 1962
TAYLOR, G. & ALLISON,H.: "Colimycin" laboratory and clinical investigation.
Brit. Med.
J. 2, 161, 1962
TALLGREN, L. G., LIEWENDAHL,K. & KUHLBACK, B.: The therapeutic
success and nephrotoxicity of colistin in acute and chronic
nephropathies with impaired renal function.
Acta Med. Scand. 177, 717, 1965
ELWOOD,C.M., LUCAS, G.D. & MUEHRCHE,R. M.: Acute renal failure associatedwithsodium colistinethate
treatment.
Arch. Int.
Med. 118, 326, 1966
GOODWIN,N.J. & FRIEDMAN,E.A. :The effectsof renal impairment
peritoneal dialysis andhemodialysis on serum sodium colistimethatelevels.
Ann. Int. Med. 68, 984, 1968