COLISTIN METHANE SULPHONATE IN CHILDHOOD INFECTIONS

740

patients had been treated with a variety of antibiotics and urinary antiseptics without the urine ever being rendered sterile. None had been given polymyxin. Their case-histories

are

summarised in the table.

Laboratory Investigations Immediately before and after the course of colistin full bloodcounts and blood-urea estimations were done in each case. Midstream specimens of urine were examined daily for protein, cells, and casts, and they were cultured. The urine examinations were repeated at intervals after the end of treatment, in some cases for as long as 8 months. In disc-sensitivity tests all ten strains of Ps. pyocyanea were sensitive to colistin and polymyxin; one was sensitive to streptomycin and all were resistant to tetracycline, chloramphenicol, kanamycin, nitrofurantoin, and sulphafurazole. The bacteriostatic and bactericidal levels of colistin were determined for seven of the ten strains. The tests were performed in glucose-indicator broth using doubling dilutions of colistin and an inoculum of 0’02 ml. of a 1 in 10 dilution of a 6-hour nutrient-broth culture. One strain was inhibited by 3.1 jjLg. per ml., five by 6’25 g. per ml., and one by 12-5 g. per ml. In most cases the bactericidal concentration was four times the bacteriostatic concentration. Dosage of Colistin All the patients were in hospital during their treatment with colistin. They were adult males, weighing 60-70 kg., and they were given 1-5 million units (120 mg.) of colistin methane sulphonate by intramuscular injection 8-hourly for 5 days. Two patients were given two courses, and one patient was given four, the fourth course being of twice the normal dosage (3 million units 8-hourly). Thus in all, fifteen courses of colistin were given. Results of Treatment During fourteen of the fifteen courses of colistin Ps. pyocyanea disappeared from the urine by the 2nd or 3rd day, and there was a correspondingly rapid fall in the number of white cells in the urine. During one course only the urine did not become sterile until the 5th day, probably because of an indwelling catheter. After nine of the fifteen courses, there was a relapse between 8 and 28 days later. In two of these nine courses, indwelling catheters were present during and after treatIn none of the relapses have drug-resistant ment.

organisms developed. Five of the ten patients

now have sterile urine, and two of them have been free from infection for 8 months. One of these two (case 1) had pre-existing gross impairment of renal function, and for 2 years he had had frequent exacerbations of his chronic pyelonephritis and epididymo-orchitis, despite Two many courses of antibiotics and urinary antiseptics. patients, both with poor renal function, have remained free from infection for 4 months. In the fifth patient, who had had a urethral stricture and acute exacerbations of chronic pyelonephritis and epididymo-orchitis for 3 years, the urine has remained sterile for 3 months after a final course at double the usual dosage. In a sixth patient the urine remained sterile after treatment until he died from carcinoma of the prostate 3 months later. In four patients the infection still persists, possibly because some organisms were inaccessible to the antibiotic owing to the urinary-tract abnormalities.

Side-effects the injection site.-None of the patients found the of colistin painful. Eight adult volunteers were injections given an intramuscular injection of colistin into the lateral aspect of one thigh, and of polymyxin into the other. The dose of colistin was two-thirds of the recommended therapeutic dose (colistin methane sulphonate 1 million units in 1 ml. of physiological saline) and the dose of polymyxin was half the recommended therapeutic dose (polymyxin B sulphate

Pain

at

125,000 units in 1 ml. of sterile water). Neither preparation contains local anaesthetic, and none of the subjects knew which injection was which. At the site of injection of the polymyxin all experienced appreciable pain, beginning soon after the injection and lasting 10 hours or more, but they had little or no discomfort after the injection of colistin. Nephrotoxicity.-As far as could be assessed there was no evidence of nephrotoxicity. The blood-urea and daily urinary red-cell counts did not increase during or after the courses of treatment. Renal casts were not seen at any time. All patients had proteinuria owing to their urinary infections. -

Neurotoxicity.-Two patients experienced

a

slight tingling

sensation around the mouth 5 to 10 minutes after administration of the drug, and lasting for 4 to 5 minutes. Of these patients one (case 1) noticed the sensation in the first of his two courses, and the second (case 5) in the last of his four courses, when he was given double the usual dosage. Full blood-counts before and after treatment showed no

change.

Summary and Conclusions Our trial of colistin methane sulphonate (’Colomycin’)’) was carried out in patients with obstinate urinary infection caused by Pseudomonas pyocyanea, all of whom had severely damaged urinary tracts. In one case especially, where there was severe impairment of renal function, the result was highly satisfactory. Although relapses occurred, in five of the ten patients treated the urine has remained sterile for periods ranging from 3 to 6 months, and in a sixth patient the urine remained sterile after treatment until he died from carcinoma of the prostate 3 months later. In one patient, whose infection recurred after each of three courses, the urine has remained sterile for 3 months after a course at double the usual dosage. This higher dosage might be advisable, therefore, in some of the more

complicated

cases.

In our selected group of cases, colistin appeared to be a safe and useful drug. It did not cause pain at the site of injection, and it was almost free from side-effects. There was no evidence of nephrotoxicity. We wish

to

thank Mr. R. Cox and Mr. S. 0. Aylett for permission cases; and Messrs. Pharmax, Ltd., for

publish details of their supplies of ’Colomycin’.

to

REFERENCES A. (1959-60) Antibiot. Annu. p. 75. Carroll, G., Malette, W. F. (1961) J. Urol. 85, 86. Clifford, H. E., Stewart, G. T. (1961) Lancet, ii, 177. Cuthbert, M. F. (1962) ibid. i, 383. Hopper, J., Jawetz, E., Hinman, F. (1953) Amer. J. med. Sci. 225, 402. Jawetz, E. (1952) Arch. intern. Med. 89, 90. Kagan, B. M., Krevsky, D., Milzer, A., Locke, M. (1951) J. Lab. clin. Med. 37, 402. Stewart, G. T. (1962) Lancet, i, 326. Swift, P. N., Bushby, J. R. M. (1953) ibid. i, 110. Yow, E. M., Moyer, J. H. (1953) Arch. intern. Med. 92, 248. Tan, E., Shane, L., Schonfield, S., Abu-Nassar, H. (1961) ibid. 108, 664.

Blaustein,

—

COLISTIN METHANE SULPHONATE IN CHILDHOOD INFECTIONS H. B. MARSDEN M.B. Manc., D.C.H., D.Path. CONSULTANT PATHOLOGIST

W. A. HYDE F.I.M.L.T. SENIOR TECHNICIAN

THE ROYAL MANCHESTER

CHILDREN’S HOSPITAL,

PENDLEBURY, LANCS

COLISTIN is an antibiotic which is obtained from culture filtrates of Bacillus colistinus, a microorganism isolated in Japan by Koyama in 1950. Chemically it is a cyclic polypeptide based on acyl aminoacids; and it is prepared as the sulphate for the oral route of administration and as the methane sulphonate for intramuscular

741

from the gastrointestinal tract is thus obtained are insufficient blood-levels the and poor, Colistin is for the treatment of systemic infections. effective against gram-negative bacilli, such as salmonella,

injection. Absorption

shigella, escherichia, klebsiella, pseudomonas, brucella, and hasmophilus. It is relatively ineffective against proteus. Clinical and laboratory studies have been carried out, in Europe and America, with encouraging et al. (1960) found colistin to be most Ross results. in effective Escherichia coli gastroenteritis, rather less so in salmonella enteritis, and disappointing in shigella enteritis. Carroll and Malette (1961) obtained good results with urinary infections caused by pseudomonas, escherichia, and aerobacter. In eighty cases of urinary-tract infections with these organisms seventy-seven showed no growth at the end of treatment. The activity against Pseudomonas pyocyanea was excellent, including three cases of meningitis. In view of these findings a short trial was carried out at the Royal Manchester Children’s Hospital to assess the efficacy and toxicity of colistin methane sulphonate (’Colomycin’) in childhood infections.

principally

STRAINS SENSITIVE TO COLISTIN

against these organisms, and suitable therapy was given simultaneously. But, because the colistin-sensitive organisms in these cases (pseudomonas 2, aerobacter 2) were completely resistant to the other antibiotic given, it seems likely that they were eliminated by colistin alone. Carroll and Malette (1961) have pointed out that a single antibiotic cannot be depended upon for the treatment of recurrent urinary infections, and in fact four of the patients in this series later became infected with colistin-resistant organisms-i.e., the proteus group and Staphylococcus pyogenes. Gastroenteritis Specific Esch. coli infections.-Eight cases were treated in this group, four infected with the 055 strain, and one each with 0128, 0111, 026, and 0119. In four of the patients the pathogenic organism was eliminated after 5 days without recurrence. In another patient, aged 9 months, the organism was still present after 5 days, and the dose of 750,000 units daily was doubled; after having this increased dosage for a further 5 days the child was cured. The organism was temporarily eliminated in two patients, but in one there was no response to treatment even after increased dosage. In the last case of gastroenteritis positive cultures were obtained throughout despite the doubled dosage; neomycin was also ineffective. Shigella sonnei infections.-Nine patients between the ages of 2 months and 10 years were treated, and the infecting organism was eliminated in all except one. In seven of the cases where colistin was successful a course of 5 days was sufficient, but double the dosage was necessary for a further period in one The one failure in this group had negative cultures case. for 10 days, and the possibility of reinfection had to be considered.

Meningitis Two infants with meningoceles and meningitis, one infected with Ps. pyocyanea and the other with Esch. coli were included. Both these patients rapidly responded to intramuscular treatment with elimination of the infecting organism. Gomirato Sandrucci (1956) suggested that the blood-brain barrier is particularly permeable to colistin, and that higher cerebrospinal-fluid levels may be expected than with other antibiotics.

Discussion The Trial LABORATORY STUDIES

The in-vitro sensitivities of sixty-three organisms freshly isolated from clinical material are shown in the table. Because of the blood-levels obtained by Forni and Guidetti (1956) 25 g. per ml. was regarded as the upper limit of sensitivity. But this level was obtained only after the recommended dosage had been increased, and the level found after injection of 2 mg, per kg. (approximate normal dosage) was 14 g. per ml. All the 63 organisms were sensitive to 25 g. per ml., and only 4 of them were in the 14-25 g. per ml. range. CLINICAL STUDIES

Twenty-seven patients between the ages of 1 month and 10 years with urinary infections or gastroenteritis were treated with colistin. In addition two babies, aged 3 weeks, with infected meningoceles and meningitis, were included in the trial. The daily dosage varied according to age between 250,000 and 1,500,000 units by intramuscular injection, or 750,000 and 4,500,000 units by mouth. Urinary Infections Ten cases of urinary infection caused by appropriate organisms (aerobacter 4, pseudomonas 4, escherichia 1, aerobacter and escherichia 1) were treated. In all but one the organisms were eliminated, and the time taken varied between 3 and 9 days. The other case, caused by aerobacter, showed reduction in bacterial content though the organism was sensitive only to 25 g. per ml., and the therapy given was inadequate. Two of the

faecalis and

two

also infected with Streptococcus others with proteus. Colistin was ineffective

cases were

The above laboratory and clinical studies suggest that colistin, with its great efficacy against pseudomonas and klebsiella, is a valuable addition to the antibiotic armoury. It is also useful for infections caused by other gramnegative organisms, such as escherichia and shigella. Our results in gastroenteritis are at variance with those of Ross et al. (1959), who reported a disappointing response in shigella infections and good results in Esch. coli gastroenteritis. Failure might have been avoided in some of our cases of specific Esch. coli gastroenteritis if a larger initial dosage had been given. The fact that there was no toxic effect of any kind in our series suggests that considerably greater amounts of colistin could be administered even to very young patients. The transient oral paraesthesiae and vertigo noted in adults by Yow et al. (1961) would be difficult to exclude in our younger cases. One advantage in using colistin for gastrointestinal infections was the complete absence of candida in the fseces at the end of treatment, whereas with other antibiotics there are often heavy growths.

Summary

Sixty-three strains of gram-negative bacilli, obtained from routine cultures in a children’s hospital, were all shown to be sensitive to colistin methane sulphonate

(’ Colomycin ’). Twenty-nine patients with infections caused by gramnegative bacilli were treated with colistin. The infecting organism was eliminated in twenty-seven, and no toxic

742

effects were encountered. Colistin seems to be a very useful addition to the list of existing antibiotics. A supply of ’Colomycin’ was made available by Dr. M. F. Cuthbert, of Messrs. Pharmax Ltd. REFERENCES

Carroll, G., Malette, W. F. (1961) J. Urol. 85, 86. Forni, P. V., Guidetti, E. M. (1956) Minerva med. 2, suppl. 77, p. 823. Gomirato Sandrucci, M. (1956) ibid. p. 839. Koyama, Y. (1950) J. Antibiot. 3, 457. Ross, S., Puig, J. R., Zaremba, E. A. (1959-60) Antibiot. Annu. p. 89. Yow, E. M., Tan, E., Shane, L., Schonfeld, S., Abu-Nassar, H. (1961) Arch. intern. Med. 108, 664.

RESPIRATORY STIMULANTS IN THE NEWBORN HERBERT BARRIE M.D. Lond., M.R.C.P. SENIOR REGISTRAR

DENNIS COTTOM M.C., B.M. Oxon., M.R.C.P. PHYSICIAN

CHILDREN’S DEPARTMENT,

irritation, depression,

Method monitored Respiration by a method similar to that described by Holland et al. (1960). A continuous record of oesophageal pressure and chest movement was obtained on a two-channel Evershed recorder. (Esophageal pressures were measured with a water-filled polyethylene catheter, 0-5 mm. in internal diameter, passed via the nose to midsternal level and attached to a Statham strain-gauge manometer. The rate and amplitude of the chest movements were registered by means of a mercury strain-gauge pneumograph applied around the chest and upper abdomen (fig. 1). This instrument cannot be calibrated and records non-respiratory as well as respiratory movements. Rhythmic deflections are probably proportional to tidal ventilation, and those obtained during crying (" vital capacity ") are usually eight to ten times greater than those obtained during quiet breathing. However, overall shifts from the baseline may be due to trunk movement and do not necessarily indicate changes in lung volume. was

B. D. R. WILSON Lond., F.R.C.P.

M.B.

PHYSICIAN

ST.

studied on the 18th day. Babies with cerebral difficult births were not tested.

or

THOMAS’S HOSPITAL, LONDON, S.E.1

THE value of respiratory stimulants in neonatal resusciThe current view is, rightly, to tation is uncertain. condemn their use until the air-passages have been cleared and unless adequate ventilation with oxygen can be performed. Nevertheless, these drugs are used widely. Ampoules of nikethamide, lobeline, and various other drugs are to be found in most labour wards, whereas few are adequately equipped for the giving of intermittent positive pressure oxygen. In addition to this conflict between current opinion and actual practice, there is TABLE I-OBSERVATIONS ON TWO SERIES

Series I A sterile catheter was inserted into the umbilical vein as far the inferior vena cava, and 5 % dextrose solution was infused slowly to prevent clotting. Injections were given rapidly in volumes of 2 ml. through a two-way tap between the catheter and the infusion set, and flushed through with a few millilitres of dextrose solution. The test substances were given in random order except that small doses and inert agents were used first in order to avoid undue restlessness. Sufficient time was allowed between injections for the respiratory pattern to return to normal. Nikethamide, caffeine sodium benzoate, lobeline, amiphenazole, vanillic acid diethylamide (’Vandid), and spiractin (’ Karion’) were studied in this way. Intramuscular injections were given into the outer side of the thigh, and the period of observation was extended to thirty minutes. Only nikethamide, vanillic acid diethylamide, and spiractin were studied in this way. as

much confusion on the relative merits of the various drugs, the correct dosage, and the best route of administration. Evidence based on clinical observation may be grossly misleading, as past experience with intragastric oxygen has shown, and even a careful experimental evaluation, such as that on newborn rabbits by Lim and Snyder (1945), may not be strictly applicable to the human infant. The present investigation was undertaken in babies with normal respiration in the hope that the data might provide a rational basis for the use of respiratory stimulants in neonatal asphyxia. Material The data comprise a total of 120 observations on 25 infants and include 25 control observations. The infants belong to two series (table i): Series 1.-5 babies with congenital lumbar meningomyeloceles in whom the responses to intravenous and intramuscular injections were measured. These babies had extensive cord damage with anxsthesia of the lower limbs, into which injections could be given without disturbing the baby. The tests were performed as soon as possible after birth, but some were repeated later. Clinical examination of the heart and lungs was normal and the neurological status relevant to respiration was considered intact at the time of measurement. The prognosis and the nature of the investigation was explained to the parents, from whom permission was obtained. Series 11.-20 normal babies in whom the response to lingual administration was studied. All were term babies less than 24 hours old, except for 1 premature baby who was

Fig. 2- Normal variations of the respiratory pattern.