NEW PENICILLINS

1382 CLIFFORD HENRY COOMER SEARBY, M.B., M.S. Melb., F.R.C.S., F.R.A.C.S. President of the Medical Board, State of Victoria; surgeon,

Royal

Melbourne

Hospital. M.S. Lond., F.R.C.S. University of Bristol.

Conferences NEW PENICILLINS

ROBERT MILNES WALKER, Professor of surgery,

AN international symposium on the New Penicillins held from June 2 to 4 in London, under the chairmanship of Sir CHARLES DODDS, P.R.C.P.

was

M.V.O.

Surgeon-Commander JOHN

(4th class)

MARSDEN

HAUGHTON, M.R.C.S.,

R.N.

Pharmacology

J. T. PARK (Boston) explained that penicillin acted by interO.B.E. (Military) fering with the synthesis of cell-wall mucopeptide-a substance Colonel ALEXANDER GRIEVE, M.B. St. And., late R.A.M.C. which is essential to preserve the integrity of many microbial cells but is completely lacking in other forms of life. MucoO.B.E. (Civil) peptide is believed to be an essential constituent, not only of all bacteria, but also of actinomycetes, rickettsix, and organisms SILVIO CASIMIR BETTENCOURT-GOMES, M.B. Edin. Senior physician, St. Joseph’s Mercy Hospital, British Guiana. of the psittacosis-lymphogranuloma group; thus it is reasonable to CH.M. CLIVE RODNEY BOYCE, hope for new penicillins effective against all these groups Sydney. Medical superintendent, Brisbane Mental Hospital. of organisms. The bactericidal action of penicillin is observed EDGAR SUNDERLAND CLAYTON, M.D. Sheff., F.R.C.S.E. only with growing cells; and a second antibiotic may effectively General practitioner, Whitchurch, Shropshire. stop growth and hence the bactericidal effect. Bactericidal action often involves mass lysis of cells which may release EDGAR COCHRANE, M.D. Glasg. Senior medical officer of health, Barbados. endotoxins from the invading organism, and this could explain sudden toxic reactions at the onset of penicillin therapy. RoY OLIVIER CooKE, M.D. Dalhousie. Senior medical’ officer, Bellevue Hospital, Jamaica. ERIC KNUDSEN said that 75% of penicillin is present in the SIDNEY ELIZABETH CROSKERY, M.D. Edin. body in a therapeutically inactive protein-bound form. It is Medical officer in charge of Aden Port Trust families clinic. not antimicrobial in this bound form, but the remaining 25% which is free and active is sufficient for clinical purposes. M.B. N.Z. ERIC TEWSLEY DAWSON, Lately superintendent, Bay of Plenty Hospital Board, New Interpretation of assay values of penicillin is extremely difficult, Zealand. for protein-binding gives a false impression of therapeutic HENRY ERSKINE DOWNES, M.B. Melb. potential. Likewise tissue concentration may be misleading Assistant director-general, Department of Health, Canberra. because so many factors influence the level. The only worthwhile laboratory investigations are the free serum level and JOHN DOW FiNLAYSON, M.B. Glasg. the minimum inhibitory concentration in broth; and the only Formerly deputy director of medical services, Sarawak. reliable therapeutic yardstick is clinical trial. REGINALD HENRY JAMES HAMLIN, M.B. N.Z., F.R.C.O.G. Obstetrician and gynaecologist, Princess Tsahai Memorial HosJILLIAN BOND has found that people vary in the extent to pital, Addis Ababa. which they bind penicillin to serum-albumin but that each ERIC THEODORE HILLIARD, M.B. Sydney. individual tends to maintain the same pattern. She re-tested Formerly director, State psychiatric service, New South Wales. people after a year and noted the same percentage binding in FENWICK LISHMAN, M.B. Durh. the same individual. General practitioner, Durham. E. L. QUINN (Detroit) observed that the degree of reduction HENRY DAVIES LLEWELLYN, M.R.C.S., J.P. in antimicrobial activity due to serum was directly proportional For social and cultural activities in Llanelly, Carmarthenshire. to the degree of protein-binding of various penicillins. D. R. BROWN studied the effect of protein-binding on JOHN DEREK LLEWELLYN-JONES, M.D. Dubl. M.A.O., F.R.C.O.G. Specialist obstetrician and gynaecologist, General Hospital, urinary excretion in the hen after the renal tubular secretory Kuala Lumpur, Malaysia. mechanism had been blocked; the various penicillins are all IVOR ANDERSON MACDOUGALL, M.B.E., M.R.C.S. filtered by the glomeruli to the same degree, irrespective of the Medical officer of health, Hampshire. large differences in protein-binding. He found that the conALEXANDER JAMES SMITH McFADZEAN, M.D. Glasg., F.R.C.P. centrations of penicillin in inflammatory fluid and in Professor of medicine, University of Hong Kong. turpentine-induced granulomas are similar to that in serum, but that the levels of penicillin in lymph are higher than in serum. Major GERALD CORNELIUS VINCENT O’DRISCOLL, M.B. Dubl. medical

officer, Northern Nigeria. M.B. Cantab., F.R.C.S. Specialist ophthalmologist, Northern Rhodesia.

Principal

CHARLES MALCOLM PHILLIPS,

DENIS ROGERS, E.D., M.B. N.Z. Mayor of Hamilton, New Zealand. NORA ISABEL WATTIE, M.B. Aberd. Principal medical officer for maternity and child welfare,’ City of Glasgow. ALFRED ELLINGTON OLUKOTUN WILLIAMS, F.R.C.S.I. Senior surgeon specialist, Ministry of Health, Sierra Leone.

M.B.E. (Military) Flight-Lieutenant JAMES MICHAEL BROWN, M.B. Cantab., R.A.F. Flight-Lieutenant BERTIE JAMES WILKEN, M.B. Edin., F.R.C.S.,, R.A.F.

retd.

Surgeon Lieut.-Commander FRANK ROGER WILKES, M.B.E.

M.B.

Birm.,

(Civil)

JAMES CRAIG CAMERON, M.B. Belf. For political services in Chigwell. JOHN LEIPER, M.D. Aberd. For medical services to the fishing industry in Aberdeen. LOTTIE SHARFSTEIN, M.B. Sydney. Of Auburn, New South Wales; for services to medicine.

R.N.I.

Treatment of Staphylococcal Infections W. M. M. KIRBY (Seattle) analysed the cure-rates for staphylococcal septicaemia in three succeeding five-year periods. In 1950-55 the cure-rate was 35-40% using. principally erythromycin, chloramphenicol, or novobiocin. It rose to 60-65% in 1955-59 with vancomycin; and to 70-75% in 1960-64 with methicillin or oxacillin. C. A. GREEN (Newcastle upon Tyne) found that four-fifths of postoperative chest infections were due to penicillinresistant staphylococci needing methicillin or cloxacillin. He had noted that penicillin-resistant staphylococci had risen from 57% to 72% in Newcastle in the past decade; about 30% were resistant to streptomycin or tetracycline, 10% to erythromycin, and 1% to chloramphenicol. SUSAN GOLDFARB achieved permanent eradication of staphylococcal cross-infection in a thoracic surgical ward by spraying methicillin 10 g. in 200 ml. fluid daily. She emphasised that this treatment was cheaper than maintaining infected patients in hospital. She also recommended methicillin by inhalation for chronic bronchitic patients with sputa infected with staphylocci. During a three-year trial of methicillinspraying no resistant organisms have emerged, and no hypersensitivity reactions have been detected. ELLARD Yow (Houston) advocated prophylactic methicillin

1383

for patients undergoing cardiovascular surgery, and cephalothin for those who were penicillin-sensitive. These measures have eliminated postoperative staphylococcal sepsis, although occasional gram-negative bacillary infections have been observed. In

a

three-year period, he likewise observed

no

emergence of

methicillin-resistant staphylococci. J. TuRIAF and P. MASSIAS (Paris) have found the penicillinaseresistant penicillins effective in respiratory disease and osteodue to Staphylococcus aureus, 70% of which, in Paris, resistant to benzylpenicillin and 50% to streptomycin. Of 41 patients with staphylococcal osteomyelitis, 26 were cured and 9 improved (85% in all) by 36-40 days’ treatment with methicillin or oxacillin, always in conjunction with surgery.

myelitis are

Methicillin-resistant Staphylococci Methicillin resistance or methicillin tolerance appears to be a laboratory phenomenon rather than of clinical significance, at least at present. M. T. PARKER estimated their incidence at about 0-5%. They belonged to phage-group III, produced large quantities of penicillinase, were resistant to mercury salts, and were also resistant to many other antibiotics. The only way in which they appeared to differ from other " " hospital staphylococci was in their relative insusceptibility to the new as well as the old penicillins. For their detection he used a screening test in which paper discs containing 10 tg. methicillin were placed on inoculated plates. By contrast, PETER FLEMING (Toronto) had not identified methicillin-resistant staphylococci in Canada despite a carefully planned and exhaustive screening programme for their detection. K. R. ERIKSEN (Copenhagen) did not feel that naturally occurring methicillin-resistant strains of Staph. aureus were due to the use of the new penicillins; most of his resistant strains had been isolated in a hospital where these antibiotics had been rarely used. They inactivated 10 jg. per ml. methicillin almost completely within 24 hours; and these strains showed cross-resistance with oxacillin, cloxacillin, and cephalothin.

Urinary-tract Infections attributed urinary-tract infections to many BRUMFITT W. factors including bacterial virulence, organic abnormalities of the tract, alterations in urine flow, vesicoureteric reflux, and instrumentation. Asymptomatic infection with over 100,000 organisms per ml. urine should be treated vigorously to prevent ultimate progress to chronic irreversible pyelonephritis. He had found sulphonamides effective in 75-83% of cases; if these cheap agents failed, then ampicillin should be given by mouth or if necessary by intramuscular injection together with

probenecid. P. NAUMANN (Hamburg) has found ampicillin particularly helpful in urinary-tract infections due to proteus and enterococci. He has given it orally in a dosage of 65 mg. per kg. body-weight daily. In renal insufficiency with blood-urea levels of 90 mg. per 100 ml., 500 mg. intravenous ampicillin was well tolerated, providing blood-levels of 30 g. per ml. compared with 9 g. per ml. one hour after its oral administration in the non-ursmic subject. In urinary-tract infections J. C. GOULD and E. EDMOND (Edinburgh) claimed cures in 32 (70%) of 45 with sulphonamides, compared with 18 (86%) of 21 with ampicillin. They routinely used urine-soaked discs on agar plates to detect antibacterial substances normally present in urine. PRISCILLA KINCAID-SMITH (Melbourne) found asymptomatic bacteriuria with over 100,000 organisms per ml. urine in 6% of pregnant Melbourne women-a prevalence similar to that observed by E. Kass in Boston and by J. C. Gould in Edinburgh. In a double-blind controlled trial, 31% of pregnant

patients receiving placebo developed symptomatic urinary infections, compared with 1-5% receiving antibacterial drugs; but treatment did not prevent the higher incidence of prema-

turity and stillbirth associated with pregnancy pyelitis. Dr. Kincaid-Smith advocated continuous administration of antibacterial drugs throughout pregnancy in an endeavour to She prevent pyelonephritis in women with bacteriuria. claimed splendid initial results with ampicillin in 24 patients with pregnancy pyelitis and 12 with postpartum pyelonephritis.

Salmonella Infections A recent outbreak of paratyphoid B fever in Ediburgh provided A. N. GEDDES with the opportunity of comparing the outcome of treatment with chloramphenicol or ampicillin. By random selection 65 patients received chloramphenicol and 80 ampicillin, the latter in the high dosage of 6 g. daily because of its rapid absorption from the upper small bowel and its rapid renal excretion. Pyrexia subsided in 3 days with chloramphenicol and in, 6 days with ampicillin. Relapses occurred in 50% of patients with chloramphenicol and in 38% with ampicillin. Drug hypersensitivity, comprising rashes and recrudescence of fever, occurred in 20% of patients with ampicillin, necessitating change of therapy to chloramphenicol. A. B. CHRISTIE (Liverpool) succeeded in converting 7 of 8 typhoid carriers to negative for 1 year with a combination of oral and intramuscular ampicillin and probenecid for a week, and thereafter oral ampicillin and probenecid for 3 months. F. DE RITIS (Naples) also found ampicillin effective in salmonella infections. Subacute Bacterial Endocarditis I. R. GRAY (Coventry) successfully treated 13 patients with bacterial endocarditis for 6 weeks with oral propicillin in 10 and ampicillin in 3 instances, always combined with probenecid. A dose of 500 mg. 4-hourly was found satisfactory. Infection was always controlled, but in 2 patients it recurred 2 months later; 2 patients died from cardiac failure and another during cardiac surgical repair of a perforated aortic valve. He felt that infection with Streptococcus viridans could be treated effectively with drugs of the phenoxypenicillin group by mouth, but that ampicillin with its broad antibacterial spectrum should be given initially, particularly with Strep. facalis infection. Most participants agreed that in Strep. fcecalis infections the combination of penicillin and streptomycin had not yet been ousted by penicillin alone. H. infiuenzae Meningitis L. D. THRUPP (Los Angeles) compared chloramphenicol with ampicillin in 70 patients with Hcemophilus influenzae meningitis. Of 26 patients treated with ampicillin, 1 died and 2 had serious neurological sequelae, of 44 patients treated with conventional regimens, 4 died and 1 had serious brain damage. Cerebrospinal-fluid (c.s.F.) cultures were negative after 24 hours in both groups. The initial response in C.S.F. pleocytosis appeared slower in the ampicillin group, although there was no difference by the 3rd day. Bronchitis and influenzce pneumococci are the most important in chronic bronchitis. Since pneumococci can pathogens usually be eradicated easily by any form of penicillin, J. R. MAY felt that management of bronchitis consisted primarily in the control of H. influenzae. He found that, whereas ampicillin in conventional dosage of 2 g. daily was no more effective than tetracycline, doses of the order of 4 g. daily provided sputum concentrations of 1-2 g. ampicillin per ml.-a sputum level sufficient to kill 90% of strains of H. influenzae. He advocated further trials with this larger dose, which he predicted would be superior to tetracycline. H.

Biliary-tract Infections Since ampicillin is excreted in bile at 300 times the serum level, W. ZYLKA (Cologne) used it for mixed infections associated with cholangitis in doses of 2-3 g. by mouth daily. Of 9 patients, 8 showed rapid clinical improvement. It appears to be the drug of choice to sterilise bile when surgery is not

contemplated. A. B. CHRISTIE

(Liverpool)

also advocates at least as

biliary carriers of typhoid bacilli, alternative

to

ampicillin for a preliminary

cholecystectomy. Gonorrhoea

In gonorrhoea R. R. WILLCOX prefers 1.2 mega-units of

procaine penicillin in a single-injection treatment of gonorrhoea, but he and C. D. ALERGANT (Liverpool) have found oral ampicillin 1 g. initially followed by a further 1 g. 4 hours later just as effective.