CLINICAL TRIAL OF BRL 1241 (CELBENIN)

By DOUGLAS MONTGOMERY, M.A., M.D., F.R.C.S.I. Meath Hospital, Dublin

B RL 1241, branded " Celbenin " by the Beecham Research Labora- ,tories, where it was characterised by the isolation of the penicillin nucleus (6-amino-penici'llanie acid) and synthesised to sodium 6- -

(2, 6 dimethonybenzamido) penicillanate monohydrate, has become widely known as an antibiotic with outstanding bactericidal properties of dramatic and lasting value.

Briefly, Celbenin is stable to staphylococcal penicillinase and therefore retains activity against penicillinase-producing, penicillin-resistant staphy~lococci. In consequence it is effective when penicillin G and V are not. Being acid-labile it mus~ be injected intramuscularly or intra- venously. This can be done without known risk of toxicity or side-effects, except in cases which are ~lso penicillin-sensitive. Such rare cases are adequately controlled by antihistamines.

For tuna te ly in this country there has been no serious outbreak of infection due to a penicillin-resistant staphylococcus aureus comparable wh'h those experienced by our colleagues in Great Britain. True, two minor incidents have occurred in Dublin hospitals within the past three years. Hence this trial was natura l ly confined to spora,die cases in the Meath Hosplta*l during the preceding twelve months.

In two cases only was it used empirically. These will be mentioned later. All other cases were found infected with penicillin-resistant staphylococcus aureus which had not responded previously to ot,her antibiotics.

In all, twelve eases were t reated and these are well exemplified by the fol'lo~cing :

CASE 1 : A med ica l co l league , in S e p t e m b e r 1960, whi le rescu ing inf i rm p a t i e n t s f rom a fire in a N u r s i n g H o m e , s u s t a i n e d e x t e n s i v e 1st, 2nd a n d 3rd degree b u r n s o f h a n d s , face a n d neck. Ce lben in was n o t t h e n ava i l ab l e in I r e l and , b u t an i m p o r t l icence was u rgen t l y g r a n t e d b y t h e cou r t e sy o f t h e G o v e r n m e n t D e p a r t m e n t conce rned and suppl ies were flown over b y t he he lp of B e e c h a m R esea r ch Labora to r i e s r epresen ta t ives bo th here a n d in Englemd. Cc lben in was a d m i n i s t e r e d i n t r a m u s c u l a r l y and V iacu t an tul le was app l ied local ly by h i s own medica l a t t e n d a n t . No o r g a n i s m s could be demon- s t ra ted as no in fec t ion occurred. H e a l i n g w i t h o u t a n y d i s f i gu remen t was comple t e wi th in seven days . B o t h p a t i e n t a n d doc to r descr ibed t he resu l t as m i r a c u l o u s and due to Celbenin as a p rophy lac t i c .

CASE 2 : A w o m a n aged 45, suf fer ing f rom nephro t i c s y n d r o m e c o m p l a i n e d o f pa in in bo th h ips on J a n u a r y 16th, 1961. E x a m i n a t i o n revea led b i la te ra l abscesses . P y r e x i a 101°F. Lef t s ide was opened trader local a n a e s t h e s i a on J a n u a r y 17th, 1961. Bacter io- logical e x a m i n a t i o n o f swabs revea led t he in fec t ing o r g a n i s m to be s t aphy lococcus auretm sens i t ive to C h l o r o m y c e t i n only . T h i s was a d m i n i s t e r e d for 6 days , (250 m g m s . g-hourly). Th i s was c h a n g e d to S u l p h a t r i a d 0.5 gm. 4 -hour ly and c o n t i n u e d for 7 days . I ~ r F u r a d a n t i n 50 m g m s . 4 -hour ly was s u b s t i t u t e d a n d c o n t i n u e d un t i l F e b r u a r y 10th. Meanwhile , t he abscesses c o n t i n u e d to d i scharge freely and t he infec t ion spread to a lmos t the whole o f t he an t e r io r a b d o m i n a l wall . A t t h i s s t age he r life was despaired of. ~ x i a h a d been p e r s i s t a n t b e t w e e n 99 and 100.2°F. A swab t a k e n on F e b r u a r y 8 th

pen ic i l l in - res i s tan t s t aphy l ococcus au reus sens i t ive to Celbenin. Celbenin 1 gm. ~ h o u r l y i n t r a m u s c u l a r l y was s t a r t ed on F e b r u a r y 10th. Swabs t a k e n on F e b r u a r y 1 l t h

ve ry s c a n t y g r o w t h o f s t aph , a u r e u s - - t o o few colonies to t es t for sens i t iv i ty . { ~ l ~ i , dosage was c h a n g e d to 6 -hour ly on F e b r u a r y 14th. On F e b r u a r y 18th the l ~ i ~ t ' s t e m p e r a t u r e d ropped to n o r m a l a n d the rea f t e r r e m a i n e d so. The infect ion o f t h e alNlominal wal l a n d b u t t o c k s r ap i d l y cleared a n d t he d i scharge changed f rom pus to ~ fluid before f inal ly hea l ing . Ce lben in was s t opped on Feb rua ry 15th. The

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c o m m e n t of the physic ian , under whose care she was, was terse, t rue and hear tening : " Other ant ib iot ics were no t suitable. Celbenin saved her life."

CASE 3: A womar~ aged 68, admi t ted J a n u a r y 17th, 1961 for appendicec tomy following drainage of append ix abscess six m on t hs previously, developed pos topera t ive b roncho-pneumonia . Pyrex ia 100--101.6F. cont inued in spite of adminis t ra t ion of the fol lowing : J a n u a r y 19th-26th Penicillin ½ mega b.d. J a n u a r y 26th-30th Achromycin 250 mgms . 6 hour ly . J a n u a r y 30th-February 8th Chloromycet in 250 mgms . 6 hourly. S p u t u m was repea tedly sent for culture. Repor t on Februa ry 25th was : " Gram-posi t ive cocci seen in film. Staphylococcus aureus grew on culture. Res i s tan t to penicillin and s t r ep tomyc in ". Celbenin was s tar ted on February 28th, 1 gm. 4-hourly to March 3rd, then 1 gm. 6-hourly. Tempera tu re had become normal at this stage and remained so. She was discharged as cured on April 2nd.

CASE 4 : A w o m a n medical s tudent , aged 21, wi th hyper t rophic bleeding g u m s admi t t ed on Apri l 4th, 1961 was confirmed as a case of Vincent 's angina. Ini t ia l t reat- m e n t was 600,000 I .U. procaine penicillin daily for seven days and local applicat ion of 3~o chromic acid. The condi t ion appeared to have resolved, bu t bleeding recommenced after the elapse of a few days. Meanwhile local t rea tment continued. On April 20th the s t reng th of chromic acid was increased to 10~), applied every second day and immedi- a te ly followed by I-I~O 2. I n addit ion, the mou th was rinsed wi th H.zO~ t.i.d. Aseorbie acid 600 m g m . dai ly and Ferraplex B one cap t.i.d, were given by mouth . After several days on th is regime, her m o u t h became very sore, and contained numerous small ulcers due to peeling off of a pseudofibrinous membrane . Const i tut ional s y m p t o m s were s l ight bu t ea t ing was painful. I t then t ranspired tha t she had previously received penicill in for p n e u m o n i a and sinusitis. Swabs now taken revealed a penici l l in-resistant s taphylococcus aureus which was Celbenin-se~xsitive. Accordingly, on April 29th Celbenin inject ions were commenced and all local t r ea tment stopped. Dosage was 1 gin. 4-hour ly for 4 days and 1 gin. 6-hourly for 3 days. I m p r o v e m e n t was apparen t af ter 3 days , and on the 5th day her m o u t h appeared normal .

CASE 5 : A w o m a n aged 31 was admit ted on September 28th, 1961 wi th an acute mas t i t i s and breas t abscess wi th discharging sinus, which had been treated in a ma te rn i ty hospi ta l . Confined on Augus t 10th, she developed signs of th is impending trouble 4 weeks later. E x a m i n a t i o n revealed a penicill in-resistant s taphylococcus aureus which was sensi t ive to Celbenin. T r e a t m e n t was inst i tuted wi th the accustomed dosage. Operat ion on October 2nd for adequa te drainage was followed by rapid healing. Discharged h o m e on October 19th, she had no fur ther trouble.

CASE 6 : A female child, aged 7½ years, with acute osteomyeli t is of r ight femur, on admiss ion was very ill, toxic and pyrexic up to 99--103.4°F. Pulse 120. W i thou t isolat ion of the infective organism, Celbenin was immediate ly commenced in t ravenously 0.5 gin. di luted to 5 ml. for 2 days. Her condi t ion improved dramatical ly , bu t did no t set t le comple te ly unt i l af ter surgical drainage performed on September 23rd. Swabs taken at opera t ion were sterile on culture. She was discharged home on December 12th, when the wound was comple te ly healed. X-rays on September 23rd showed erosion below greater t rochanter . N o v e m b e r 13th, defect filling in with no evidence of seques t rmn format ion .

CASE 7 : A male , aged 17 years, admit ted on November 8th, 1961 wi th left basal effusion and some p u l m o n a r y consolidation. Sputum culture on Nove mbe r 10th showed no th ing of interest . Repea ted on November 20th, examina t ion revealed a penicillin- res i s tan t s taphylococcus aureus which was sensitive to Celbenin. T rea tmen t wi th th is for 7 days b rough t h is t empera tu re down to normal and it thereaf ter remained so. Fo r his first 10 days in hosp i ta l he had been on the usual dosage of Tetracycline, which had no apparen t effect.

CAS~. 8 : A male , aged 63 years, following part ial gas t ree tomy for chronic duodenal ulcer, developed an uncont ro l lable diarrhoea. No infective organisms were isolated f rom the mot ions . I n the bel ief t ha t it migh t be a staphylococcal enteri t is , his surgeon empir ica l ly prescribed Celbenin, I gm. adminis tered with in t ravenous saline drip 8- hourly. No i m p r o v e m e n t occurred and other ant ibiot ics were also t r ied wi thou t effect. The condi t ion la ter resolved when he was not on ant ibiot ic t r ea tmen t and the pa t ien t recovered. This case trarrspired as one in which the admin is t ra t ion of ant ibiot ics was no t necessary, bu t was cer ta in ly justified by the fact that. had it been t ru ly the suspected infection, a fatal issue would have been avoided.

Conclusion Cel~benin has proved its wort~h in other cases in the Meath Hospital

as we],l, but enough has been exemplified to show its major preeminence

(NANICAL TRIAL OF BRL 1241 (CELBENIN) 223

in eases where other drugs would fail. Most impor tant of all, Celbenin may be regarded as unlikely to produce resistant strains of staphy- lococcus aureus and therefore will continue as a permanent weapon against a foe that demands respect.

My sincere thanks are due to Professor F. S. Stewart, M.D., F.R.C.P.L. Professor of Bacteriology, T.C.D., for performing all of the tests and to the Medical, Surgical and Nursing Staff of the Meath Hospital for their helpful and generous co-operation and for their permission to use these cases for publication. I wish to record also m y grateful thanks to the Beecham Research Laboratories for providing the Celbenin.

References.

Knudsen, E. T. and Rolinson, G. ,N. (1960). Brit . Med. J . , i i , 700. Rolinson, Stevens. et al. (1960). Lancet , i i , 564. Brown, I). M. and Acred, P. (1960). Ibid. , i i , 568. Branch, Rodger et al. 0960). Canad., ~/I. A . J . , 83, 991. Editorial, (1961). Brit . Med. J . , i, 886. Douthwaite, A. H. (1961). Prazti t ioner, I86, 511. Lowbury, Lilly et al. (1961). Lancet, i, 1318. Douthwaite, Trafford et al. (1961). Brit . Med. J . , ii, 6. Harding, J. W. and Thompson, R. E. M. (1961). Postgrad. Med. J . , 196], 5/ , 4~5. Clinical Staff Conference (1961). Antibiot ics and Chemotherapy. i i , No. 9~ 537-554.

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