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ANTIBIOTICS IN SURGICAL TREATMENT OF SEPTIC LESIONS
1077 counts tend to be higher in the presence of considerable splenomegaly. If these indicate proliferation, then the distribution of this activity shows an asymmetry when related to the extent of splenic enlargement. Furthermore the lower packed-cell volumes found in those patients with considerable splenomegaly did not result from a tendency to a lowered cell mass but more directly from an increase in plasma-volume which has been observed in other conditions associated with severe splenomegaly. Requests for reprints should be addressed to T. A. J. P., Department of Clinical Hxmatology, University College Hospital,
platelet
London W.C.I. REFERENCES
3. 4. 5. 6. 7. 8.
Dacie, J. V., Lewis, S. M. Practical Hæmatology. London, 1968. Joske, R. A., McAlister, J. M., Prankerd, T. A. J. Clin. Sci. 1956, 15, 511. Scholar, H. Am. Heart J. 1965, 69, 701. Laurence, J. H., Berlin, N. Y. Yale J. Biol. Med. 1952, 24, 498. Harman, J. B., Ledlie, E. M. Br. med. J. 1967, ii, 146. Modan, B., Lilienfield, A. M. Medicine, Baltimore. 1965, 44, 305. Szur, L., Lewis, S. M. Br. J. Radiol. 1966, 39, 122. Perkins, J., Israels, M. C. G., Wilkinson, J. F. Q. Jl Med. 1964,
9. 10. 11.
132, 499. McFadzean, A. J. S., Todd, D., Tsang, K. C. Blood, 1958, 13, 524. Prankerd, T. A. J. Br. med. J. 1963, ii, 517. Bowdler, A. J. Proc. R. Soc. Med. 1967, 60, 44.
1. 2.
ANTIBIOTICS IN SURGICAL TREATMENT OF SEPTIC LESIONS W. H. RUTHERFORD D. HART
J. W. CALDERWOOD J. D. MERRETT
Accident and Emergency Service, Royal Victoria Hospital, Belfast, and Department of Medical Statistics, Queen’s University, Belfast
controlled clinical trial of the of three types of septic lesions it was found that the penicillin-resistance rate of staphylococci was 73% and that the average healingtime of a group of patients who had been given cloxacillin was about half a day less than that of similar patients who had not been given any antibiotic; this difference was not significant at the 5% level. An analysis of the results by the preference technique showed that the excess of preferences for cloxacillin was not significant at the 5% level. There is, therefore, no evidence to suggest that antibiotic cover with cloxacillin reduced the healing-time of these septic lesions by an amount likely to be of clinical value.
Summary
In
a
treatment
Introduction
WE describe here
trial of
.
penicillinase-resistant penicillin (cloxacillin) as an adjunct to surgery in the septic conditions treated on an outpatient basis. a
a
Antibiotic resistance of the causative was tested at the same time.
staphylococci
Method
Type of Lesion The trial
done on the three most common types of for which outpatient surgery is done in the accident and emergency service of the Royal Victoria Hospital, Belfast-hand infections, excluding cases of suppurative tenosynovitis, deep palmar abscesses, and cases complicated by vascular diseases; boils and subwas
pyogenic abscesses; and infected sebaceous cysts. Within each of these " clinical groups," patients were allotted to one of four subgroups according to their age ( < 50 years and > 50 years) and by whether or not they had had antibiotic treatment before coming to hospital. Age was considered in this way in case the lesions of older patients took longer to heal because of poorer circulation. cutaneous
Choice of Drug Previous experience suggested that over 80% of lesions under consideration would be caused by staphylococci, many of which would be resistant to penicillin. To test the efficacy of antibiotics without getting involved in the question of antibiotic resistance, we chose cloxacillin as a drug likely to be efficaceous, and to which few organisms would be likely to be resistant. Treatment Regimen Within each subgroup of each clinical group, patients were allotted at random to one of the following treatment
regimens: Treatment A.-For lesions operated on under a local an oral dose of 500 mg. of cloxacillin and an intramuscular dose of 250 mg. were given half an hour before operation. When a general anxsthetic was given, the whole 750 mg. of cloxacillin was given by injection half an hour before operation. In both cases postoperatively 500 mg. was given orally at approximately 6-hourly intervals during the day for the next 5 days. Treatment B.-Surgery only; placebos were not given. Only the nursing sister who gave the patients their treatment according to the random treatment plan had access to this plan during the trial.
anaesthetic,
Dressings Simple dry dressings were used for the vast majority of lesions. However, if a wet dressing seemed to be required, a normal saline dressing was used. Patients were asked to attend for dressings every 48 hours. Healing-time This was assessed as the interval, in days, between the day of operation and the day on which absolutely no discharge was found on the dressing. Consequently the lesion had been healed for 48 hours before this end-point was reached. However, this overstatement of healing-time applies equally to treatment A and treatment B. Statistical Design of Trial Within each of the four subgroups of each clinical group, patients were considered in pairs by taking the first patient given treatment A with the first patient given treatment B, the second patient given treatment A with the second patient given treatment B, and so on. The difference in healing-time between members of a pair (treatment B minus treatment A) was calculated for each pair so that positive differences suggested that the antibiotic was effective and negative differences that it was not. These differences were analysed in two ways, namely: By a sequential t test.-We decided that an average difference (IL) in healing-time of 3 days would be clinically important. However, we knew nothing about the likely variability of these differences (i.e., the standard deviation, a). An analysis of the first forty pairs suggested that an estimate of 6 days for a would be reasonable. The design adopted has a 95 % chance ( 1- (i) of detecting an average difference of at least 3 days as being significant at the 5% level (2cx). In Armitage’s1 notation this design has the following specification:
septic lesion
By preference.-A preference was defined as a difference which was numerically 3 days or more; the sign of the difference determining whether the preference was for treatment A or for treatment B. The design used is such
1078 TABLE I-BACTERIOLOGICAL REPORTS
TABLE II-ANALYSIS OF 379 POSITIVE BACTERIOLOGICAL REPORTS ACCORDING TO CAUSATIVE ORGANISMS
Fig. 1-Sequential
that if the probability (61) of a preference for treatment A is as high as 0-75, there is a 95 % chance (1- p) of detecting it as a significant at the 5% level (2or). Again in Armitage’s notation1 : This alternative method of analysis was used because analysis of the first forty differences suggested that these were not normally distributed (a prerequisite for a valid
analysis by sequentialt test). Results
.
Bacteriological Findings The bacteriological findings are set out in table I. These figures include some types of cases (such as pilonidal abscesses and carbuncles) which it was originally intended to study but were later excluded from the analysis of healing-times. There were 379 cases in which there was a positive report. Table 11 shows the positive reports according to the organism present. In 85% of cases this infection was due solely to staphylococci; and in most cases of mixed infection one of the organisms was a staphylococcus.
Thus, in about 88% of
cases,
staphylococci
present. In about 7% of cases the lesions TABLE III-ANALYSIS
were
OF GROUPS OF STAPHYLOCOCCI
ACCORDING TO ANTIBIOTIC RESISTANCE
were
due to
CLASSIFIED
(323 CULTURES)
t test.
either proteus or coliform organisms and this was true not only of lesions all over the body but also of lesions in the hands. Table ill shows the staphylococci classified according to their resistance to antibiotics. Only 22% of the staphylococci were sensitive to all the antibiotics. The largest single group is that with resistance to penicillin only (62%), 2% of organisms were resistant to two or more antibiotics, mostly penicillin and one other. There were 12 cases where the organisms showed resistance to over three antibiotics-in two cases the resistance being to seven different antibiotics. Table iv shows analysis of the proportions of staphylococci resistant to the various antibiotics. 73% of the organisms were resistant to penicillin. The second highest rate of resistance was to cephaloridine 8%, and tetracycline resistance was 7%. Of the antibiotics considered, only two, cloxacillin and methicillin, were active against all organisms on in-vitro testing.
Healing-times Of 542 patients who entered the trial, 9 were withdrawn and 183 (89 given treatment A and 94 given treatment B) failed to report when the lesion had healed (table v). Table VI shows the number of patients whose results are plotted in figs. 1 and 2 in the order in which the patients entered the trial. Both analyses show, for all clinical groups and-subgroups combined, that there was no significant difference between the two treatments.
TABLE IV-ANALYSIS OF PROPORTIONS OF STAPHYLOCOCCI RESISTANT TO VARIOUS ANTIBIOTICS (323 REPORTS)
Fig. 2-Analysis of preferences.
1079 TABLE V-NUMBERS OF PATIENTS COMPLETING TRIAL
hospital staphylococci 30% penicillin resistance is to be expected. However, in 1960 Logan 6 reported 40% resistance in Belfast; in 1968Price et al. reported 50% resistance in London, and commented on the steady rise of resistance since 1949 when the rate was 6%; Harris and Wise, in 1969,8 reported a rate of 42%. In the United States, Bauer et al.9 reported rates between 60% and 70% for the years between 1956 and 1960, and stated that these were 10% below resistance-rates in hospital organisms. Lowden3 reported that in Sunderland the rate rose steadily to 30% but has remained stationary at that figure for some
TABLE VI-AVERAGE HEALING-TIME
(DAYS)
There is little evidence that this is
years.
a
general law. Unless penicillin does kill penicillinresistant organisms, there would seem little justification for its use for these kinds of lesions in Britain today. In 1957 Burns et al.1o reported a trial comparing the use of procaine penicillin and penicillin V orally. They noted that results were equally good whether the organisms were penicillin-sensitive or penicillin-resistant. From this they concluded that penicillin was effective in infections with penicillin-resistant organisms well
as
as
sensitive
ones.
While this is
a
possible
explanation, it is obviously not the only one. Anderson 11 reported a trial somewhat similar to our His trial was limited to the treatment of hand infections and he used penicillin, although some of his cases were due to penicillin-resistant organisms. However, his finding was substantially the same as our own, and he concluded that antibiotics were not necessary for the treatment of hand infections. Ellis 12criticised Anderson’s work on the grounds that the average healing-times were very long; but Anderson’s average healing-time of nine days can be explained partly by his rigorous criteria of complete healing and partly by the effect of a few slow healing cases upon the averages. Our trial differs from Anderson’s in that we used cloxacillin and treated other lesions as well as those of the hand: nevertheless, our results closely accord with his. Price et al. reported an interesting trial where lesions similar to those in our trial were treated with antibiotics and no incision. Three antibiotics were own.
*
Indicates that
non-significant boundary line of fig.
1 has been crossed.
The non-significant boundary line in fig. 1 was crossed after seventy-three differences had been recorded and that of fig. 2 after fifty-six preferences (thirty-one for treatment A and twenty-three for treatment B) had been observed. Several patients were still under treatment when these boundary lines were crossed and the trial was stopped. Healing-times for these patients were obtained, where possible, and are recorded in both figures and in table vi. Table vi also shows the results of applying a sequentialt test to the differences obtained within each clinical group and also within each subgroup. The numbers of patients available are too small for any conclusion to be made for some of these categories. However, non-significant differences in average healing-times between the two treatments were found for patients with hand infections, patients aged under 50 years, and patients who had had no previous antibiotic treatment. Discussion
The surgical treatment used in this trial is that recommended by Rains and Capper,22 Lowden,3 McNair,4 and Ellis,5 the important point in technique being the complete removal of pus or slough and the obliteration of the resulting cavity by pressure bandage or suture. All these workers recommend that surgery be done under penicillin cover. The rationale for giving penicillin appears to be twofold, firstly that penicillin resistance is uncommon in the causative organisms, and secondly that even in penicillin-resistant organisms it is effective. Most textbooks seem to agree with Lowden3 that in non-
compared-phenoxymethyl penicillin, phenothicillin, and lincomycin-the first two being susceptible to penicillinase and the latter not. Only 5% of cases be withdrawn from the trial because incision The healing-time was equal in all three groups, and corresponded almost exactly with ours. Considering these results and ours together, two
had
to
was
required.
possible explanations suggest themselves: (1) Penicillin is effective for the treatment of these lesions, and it makes no difference whether or not the organisms are resistant. Its efficacy is equal to that of lincomycin, and antibiotics alone are as effective as surgery in 95% of cases. If surgery is resorted to, antibiotic cover does not necessarily shorten healing-time. (2) Penicillin and lincomycin do not substantially alter the basic tendency to heal of these lesions, and in 95% of
cases
surgery is also unnecessary.
It would unravel the
that further trials are necessary to problem further. We thank Beecham Laboratories for supplying the cloxacillin for this trial, Prof. P. C. Elmes for help with the pharmacological side of the trial, Dr. G. Gibson and his staff for carrying out the bacteriological tests; and especially we should like to thank all seem
1080 the nursing and clerical staff of the accident and emergency service who took on extra work in this trial on top of the daily round of the department. Requests for reprints should be addressed to W. H. R., Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BA. REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Armitage, P. Sequential Medical Trials. Oxford, 1960. Rains, A. J. H., Capper, H. M. Bailey & Love’s Short Practice of Surgery. London, 1965. Lowden, T. G. in The Hand (edited by R. G. Pulvertaft); chap 12. London, 1966. McNair, Y. J. Hamilton Bailey’s Emergency Surgery. Bristol, 1967. Ellis M. The Casualty Officer’s Handbook. London, 1970. Logan, C. J. H. Ulster med. J. 1960, 29, 22. Price, D. J. E., O’Grady, F. W., Shooter, R. A., Weaver, P. C. Br. med. J. 1968, iii, 407. Harris, D. M., Wise, P. J. Practitioner, 1969, 203, 207. Bauer, A. W., Perry, D. M., Kirby, W. M. J. Am. med. Ass. 1960, 173, 475. Burns, J. I., Curwen, M. P., Huntsman, R. G., Shooter, R. A. Br. med. J. 1957, ii, 193. Anderson, J. ibid. 1958, ii, 1569. Ellis, M. ibid. 1959, i, 299.
ESTABLISHMENT OF IMMUNOLOGICAL COMPETENCE IN A CHILD WITH CONGENITAL THYMIC APLASIA BY A GRAFT OF FETAL THYMUS
R. H. LEVEY F. S. ROSEN
C. S. AUGUST A. I. BERKEL
Departments of Medicine and Surgery, Children’s Hospital Medical Center, and Departments of Pediatrics and Surgery, Harvard Medical School, Boston, Mass. 02115 H. E. M. KAY
Royal
Marsden
Hospital, London
S.W.3
Fetal thymus tissue was implanted into Summary a 21-month-old patient with congenital
aplasia of
the
thymus gland (DiGeorge’s syndrome).
Clinical and immunological studies carried out for 16 months thereafter revealed prompt and long-lasting improvement in previously defective cellular immune functions including dermal sensitivity to monilia antigen and dinitrofluorobenzene, skin allograft rejection, and the responses of peripheral blood leucocytes in vitro to phytohæmagglutenin and to monilia antigen. It is suggested that implanting fetal thymus tissues into patients with DiGeorge’s syndrome offers at present the best hope of improving their deficient cellular immune function. Introduction
DiGeorge described four patients with hypoparathyroidism and absent thymus glands which he attributed to an error in the development of structures derived from the third and fourth pharyngeal pouches during embryonic life.1,2 The immunological consequences which were subsequently found in these and similar children involved a profound inability to mount cellular immune responses.3-6 It was speculated that these patients would be ideal recipients for transplants of fetal thymus tissue,5and indeed two apparently successful attempts to establish cellular immune function in this way have been reported6,8 Descriptions of the two immunologically corrected patients have stimulated many questions as to whether IN 1965
the recovery was in fact spontaneous or was mediated by the implanted fetal thymus tissue.99 This report
provides further details about one of the previously reported patientsand describes the immunological tests that have been performed over an 18-month period since the fetal thymus tissue was implanted. We believe that the data strengthen the previous conclusion that the rapid acquisition of immunological competence in our patient was due to the implanted fetal thymus and
not to
spontaneous recovery.
Case-report An infant developed hypocalcasmic tetany on his 3rd day of life. Although seizures disappeared with calcium-
gluconate therapy, hypocalcxmia persisted for a longer time. During his lst year, he had oral moniliasis, otitis media, recurrent upper and lower respiratory-tract infections, and a deep-seated abcess of the skin. During that year he was admitted to hospital six times; growth and development were retarded. Immunological studies when he was 10 months oldrevealed mild lymphopenia, defective delayed hypersensitivity, poor responses of his lymphocytes to phytohaemagglutinin (P.H.A.) in vitro, and normal levels of serum-immunoglobulins. He had primary and secondary antibody responses to typhoid vaccine and to tetanus and diphtheria toxoids, respectively. A skin-graft from an unrelated donor apparently was accepted. When studied again at 21 months of age, the patient’s immunological deficiency was still marked,8 although an ambiguous response to dinitrofluorobenzene (D.N.F.B.) at the highest concentration tested-500 jig. per ml.-suggested that immunological function might have improved slightly. The serum-calcium concentration was 9-3 mg. per 100 ml. Implantation of thymus fragments from a female fetus estimated to be 16 weeks’ gestation was carried out as described previously.8 When tested 4 days later, the peripheral blood leucocytes responded normally to P.H.A., whereas 2 days before the implant they had been virtually unresponsive. When tested 2 weeks later, the patient responded normally to challenge doses of D.N.F.B. and monilia. He promptly rejected a skin-graft from an unrelated donor. Since discharge from the hospital in September, 1968, he has had occasional upper-respiratory-tract infections and three bouts of uncomplicated otitis media. Although he has grown at a normal rate since the implantation, both height and weight remain below the third percentile. Intellectual and motor development have been rapid. Although speech development has been slower, he is no longer thought to be globally retarded. No masses have ever been palpable at the site of the implanted thymic fragments. Immunological studies consisting of complete bloodcounts, a number of skin-tests, and in-vitro studies of lymphocyte function were carried out 2, 4, 8, 12, and 14 months after thymic implantation. During the last study the patient received a skin-graft from an unrelated donor. 14 days later, when the graft appeared to be undergoing rejection, it was excised and a regional lymph-node was biopsied.
Methods
Immunological testing was performed by methods previously. 10 Skin tests with monilia antigen (Hollister-Stier), streptokinase-streptodornase (S.K.S.D., Lederle), diphtheria toxin and toxoid (Massachusetts Biological Laboratories) were injected intradermally on the
described
forearm in 0.1ml. sterile saline solution and read 48 hours later. Only induration greater than 5 mm. in diameter was considered to be unequivocally positive. Contact sensitivity to D.N.F.B. and dinitrochlorobenzene (D.N.C.B.) were patchtested by applying the appropriately diluted chemical to the patient’s skin for 48 hours. The tests were read when the patches were removed and again 24 hours later. Only redness associated with vesiculation was considered to represent a specific immune response.
platelet
London W.C.I. REFERENCES
3. 4. 5. 6. 7. 8.
Dacie, J. V., Lewis, S. M. Practical Hæmatology. London, 1968. Joske, R. A., McAlister, J. M., Prankerd, T. A. J. Clin. Sci. 1956, 15, 511. Scholar, H. Am. Heart J. 1965, 69, 701. Laurence, J. H., Berlin, N. Y. Yale J. Biol. Med. 1952, 24, 498. Harman, J. B., Ledlie, E. M. Br. med. J. 1967, ii, 146. Modan, B., Lilienfield, A. M. Medicine, Baltimore. 1965, 44, 305. Szur, L., Lewis, S. M. Br. J. Radiol. 1966, 39, 122. Perkins, J., Israels, M. C. G., Wilkinson, J. F. Q. Jl Med. 1964,
9. 10. 11.
132, 499. McFadzean, A. J. S., Todd, D., Tsang, K. C. Blood, 1958, 13, 524. Prankerd, T. A. J. Br. med. J. 1963, ii, 517. Bowdler, A. J. Proc. R. Soc. Med. 1967, 60, 44.
1. 2.
ANTIBIOTICS IN SURGICAL TREATMENT OF SEPTIC LESIONS W. H. RUTHERFORD D. HART
J. W. CALDERWOOD J. D. MERRETT
Accident and Emergency Service, Royal Victoria Hospital, Belfast, and Department of Medical Statistics, Queen’s University, Belfast
controlled clinical trial of the of three types of septic lesions it was found that the penicillin-resistance rate of staphylococci was 73% and that the average healingtime of a group of patients who had been given cloxacillin was about half a day less than that of similar patients who had not been given any antibiotic; this difference was not significant at the 5% level. An analysis of the results by the preference technique showed that the excess of preferences for cloxacillin was not significant at the 5% level. There is, therefore, no evidence to suggest that antibiotic cover with cloxacillin reduced the healing-time of these septic lesions by an amount likely to be of clinical value.
Summary
In
a
treatment
Introduction
WE describe here
trial of
.
penicillinase-resistant penicillin (cloxacillin) as an adjunct to surgery in the septic conditions treated on an outpatient basis. a
a
Antibiotic resistance of the causative was tested at the same time.
staphylococci
Method
Type of Lesion The trial
done on the three most common types of for which outpatient surgery is done in the accident and emergency service of the Royal Victoria Hospital, Belfast-hand infections, excluding cases of suppurative tenosynovitis, deep palmar abscesses, and cases complicated by vascular diseases; boils and subwas
pyogenic abscesses; and infected sebaceous cysts. Within each of these " clinical groups," patients were allotted to one of four subgroups according to their age ( < 50 years and > 50 years) and by whether or not they had had antibiotic treatment before coming to hospital. Age was considered in this way in case the lesions of older patients took longer to heal because of poorer circulation. cutaneous
Choice of Drug Previous experience suggested that over 80% of lesions under consideration would be caused by staphylococci, many of which would be resistant to penicillin. To test the efficacy of antibiotics without getting involved in the question of antibiotic resistance, we chose cloxacillin as a drug likely to be efficaceous, and to which few organisms would be likely to be resistant. Treatment Regimen Within each subgroup of each clinical group, patients were allotted at random to one of the following treatment
regimens: Treatment A.-For lesions operated on under a local an oral dose of 500 mg. of cloxacillin and an intramuscular dose of 250 mg. were given half an hour before operation. When a general anxsthetic was given, the whole 750 mg. of cloxacillin was given by injection half an hour before operation. In both cases postoperatively 500 mg. was given orally at approximately 6-hourly intervals during the day for the next 5 days. Treatment B.-Surgery only; placebos were not given. Only the nursing sister who gave the patients their treatment according to the random treatment plan had access to this plan during the trial.
anaesthetic,
Dressings Simple dry dressings were used for the vast majority of lesions. However, if a wet dressing seemed to be required, a normal saline dressing was used. Patients were asked to attend for dressings every 48 hours. Healing-time This was assessed as the interval, in days, between the day of operation and the day on which absolutely no discharge was found on the dressing. Consequently the lesion had been healed for 48 hours before this end-point was reached. However, this overstatement of healing-time applies equally to treatment A and treatment B. Statistical Design of Trial Within each of the four subgroups of each clinical group, patients were considered in pairs by taking the first patient given treatment A with the first patient given treatment B, the second patient given treatment A with the second patient given treatment B, and so on. The difference in healing-time between members of a pair (treatment B minus treatment A) was calculated for each pair so that positive differences suggested that the antibiotic was effective and negative differences that it was not. These differences were analysed in two ways, namely: By a sequential t test.-We decided that an average difference (IL) in healing-time of 3 days would be clinically important. However, we knew nothing about the likely variability of these differences (i.e., the standard deviation, a). An analysis of the first forty pairs suggested that an estimate of 6 days for a would be reasonable. The design adopted has a 95 % chance ( 1- (i) of detecting an average difference of at least 3 days as being significant at the 5% level (2cx). In Armitage’s1 notation this design has the following specification:
septic lesion
By preference.-A preference was defined as a difference which was numerically 3 days or more; the sign of the difference determining whether the preference was for treatment A or for treatment B. The design used is such
1078 TABLE I-BACTERIOLOGICAL REPORTS
TABLE II-ANALYSIS OF 379 POSITIVE BACTERIOLOGICAL REPORTS ACCORDING TO CAUSATIVE ORGANISMS
Fig. 1-Sequential
that if the probability (61) of a preference for treatment A is as high as 0-75, there is a 95 % chance (1- p) of detecting it as a significant at the 5% level (2or). Again in Armitage’s notation1 : This alternative method of analysis was used because analysis of the first forty differences suggested that these were not normally distributed (a prerequisite for a valid
analysis by sequentialt test). Results
.
Bacteriological Findings The bacteriological findings are set out in table I. These figures include some types of cases (such as pilonidal abscesses and carbuncles) which it was originally intended to study but were later excluded from the analysis of healing-times. There were 379 cases in which there was a positive report. Table 11 shows the positive reports according to the organism present. In 85% of cases this infection was due solely to staphylococci; and in most cases of mixed infection one of the organisms was a staphylococcus.
Thus, in about 88% of
cases,
staphylococci
present. In about 7% of cases the lesions TABLE III-ANALYSIS
were
OF GROUPS OF STAPHYLOCOCCI
ACCORDING TO ANTIBIOTIC RESISTANCE
were
due to
CLASSIFIED
(323 CULTURES)
t test.
either proteus or coliform organisms and this was true not only of lesions all over the body but also of lesions in the hands. Table ill shows the staphylococci classified according to their resistance to antibiotics. Only 22% of the staphylococci were sensitive to all the antibiotics. The largest single group is that with resistance to penicillin only (62%), 2% of organisms were resistant to two or more antibiotics, mostly penicillin and one other. There were 12 cases where the organisms showed resistance to over three antibiotics-in two cases the resistance being to seven different antibiotics. Table iv shows analysis of the proportions of staphylococci resistant to the various antibiotics. 73% of the organisms were resistant to penicillin. The second highest rate of resistance was to cephaloridine 8%, and tetracycline resistance was 7%. Of the antibiotics considered, only two, cloxacillin and methicillin, were active against all organisms on in-vitro testing.
Healing-times Of 542 patients who entered the trial, 9 were withdrawn and 183 (89 given treatment A and 94 given treatment B) failed to report when the lesion had healed (table v). Table VI shows the number of patients whose results are plotted in figs. 1 and 2 in the order in which the patients entered the trial. Both analyses show, for all clinical groups and-subgroups combined, that there was no significant difference between the two treatments.
TABLE IV-ANALYSIS OF PROPORTIONS OF STAPHYLOCOCCI RESISTANT TO VARIOUS ANTIBIOTICS (323 REPORTS)
Fig. 2-Analysis of preferences.
1079 TABLE V-NUMBERS OF PATIENTS COMPLETING TRIAL
hospital staphylococci 30% penicillin resistance is to be expected. However, in 1960 Logan 6 reported 40% resistance in Belfast; in 1968Price et al. reported 50% resistance in London, and commented on the steady rise of resistance since 1949 when the rate was 6%; Harris and Wise, in 1969,8 reported a rate of 42%. In the United States, Bauer et al.9 reported rates between 60% and 70% for the years between 1956 and 1960, and stated that these were 10% below resistance-rates in hospital organisms. Lowden3 reported that in Sunderland the rate rose steadily to 30% but has remained stationary at that figure for some
TABLE VI-AVERAGE HEALING-TIME
(DAYS)
There is little evidence that this is
years.
a
general law. Unless penicillin does kill penicillinresistant organisms, there would seem little justification for its use for these kinds of lesions in Britain today. In 1957 Burns et al.1o reported a trial comparing the use of procaine penicillin and penicillin V orally. They noted that results were equally good whether the organisms were penicillin-sensitive or penicillin-resistant. From this they concluded that penicillin was effective in infections with penicillin-resistant organisms well
as
as
sensitive
ones.
While this is
a
possible
explanation, it is obviously not the only one. Anderson 11 reported a trial somewhat similar to our His trial was limited to the treatment of hand infections and he used penicillin, although some of his cases were due to penicillin-resistant organisms. However, his finding was substantially the same as our own, and he concluded that antibiotics were not necessary for the treatment of hand infections. Ellis 12criticised Anderson’s work on the grounds that the average healing-times were very long; but Anderson’s average healing-time of nine days can be explained partly by his rigorous criteria of complete healing and partly by the effect of a few slow healing cases upon the averages. Our trial differs from Anderson’s in that we used cloxacillin and treated other lesions as well as those of the hand: nevertheless, our results closely accord with his. Price et al. reported an interesting trial where lesions similar to those in our trial were treated with antibiotics and no incision. Three antibiotics were own.
*
Indicates that
non-significant boundary line of fig.
1 has been crossed.
The non-significant boundary line in fig. 1 was crossed after seventy-three differences had been recorded and that of fig. 2 after fifty-six preferences (thirty-one for treatment A and twenty-three for treatment B) had been observed. Several patients were still under treatment when these boundary lines were crossed and the trial was stopped. Healing-times for these patients were obtained, where possible, and are recorded in both figures and in table vi. Table vi also shows the results of applying a sequentialt test to the differences obtained within each clinical group and also within each subgroup. The numbers of patients available are too small for any conclusion to be made for some of these categories. However, non-significant differences in average healing-times between the two treatments were found for patients with hand infections, patients aged under 50 years, and patients who had had no previous antibiotic treatment. Discussion
The surgical treatment used in this trial is that recommended by Rains and Capper,22 Lowden,3 McNair,4 and Ellis,5 the important point in technique being the complete removal of pus or slough and the obliteration of the resulting cavity by pressure bandage or suture. All these workers recommend that surgery be done under penicillin cover. The rationale for giving penicillin appears to be twofold, firstly that penicillin resistance is uncommon in the causative organisms, and secondly that even in penicillin-resistant organisms it is effective. Most textbooks seem to agree with Lowden3 that in non-
compared-phenoxymethyl penicillin, phenothicillin, and lincomycin-the first two being susceptible to penicillinase and the latter not. Only 5% of cases be withdrawn from the trial because incision The healing-time was equal in all three groups, and corresponded almost exactly with ours. Considering these results and ours together, two
had
to
was
required.
possible explanations suggest themselves: (1) Penicillin is effective for the treatment of these lesions, and it makes no difference whether or not the organisms are resistant. Its efficacy is equal to that of lincomycin, and antibiotics alone are as effective as surgery in 95% of cases. If surgery is resorted to, antibiotic cover does not necessarily shorten healing-time. (2) Penicillin and lincomycin do not substantially alter the basic tendency to heal of these lesions, and in 95% of
cases
surgery is also unnecessary.
It would unravel the
that further trials are necessary to problem further. We thank Beecham Laboratories for supplying the cloxacillin for this trial, Prof. P. C. Elmes for help with the pharmacological side of the trial, Dr. G. Gibson and his staff for carrying out the bacteriological tests; and especially we should like to thank all seem
1080 the nursing and clerical staff of the accident and emergency service who took on extra work in this trial on top of the daily round of the department. Requests for reprints should be addressed to W. H. R., Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BA. REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Armitage, P. Sequential Medical Trials. Oxford, 1960. Rains, A. J. H., Capper, H. M. Bailey & Love’s Short Practice of Surgery. London, 1965. Lowden, T. G. in The Hand (edited by R. G. Pulvertaft); chap 12. London, 1966. McNair, Y. J. Hamilton Bailey’s Emergency Surgery. Bristol, 1967. Ellis M. The Casualty Officer’s Handbook. London, 1970. Logan, C. J. H. Ulster med. J. 1960, 29, 22. Price, D. J. E., O’Grady, F. W., Shooter, R. A., Weaver, P. C. Br. med. J. 1968, iii, 407. Harris, D. M., Wise, P. J. Practitioner, 1969, 203, 207. Bauer, A. W., Perry, D. M., Kirby, W. M. J. Am. med. Ass. 1960, 173, 475. Burns, J. I., Curwen, M. P., Huntsman, R. G., Shooter, R. A. Br. med. J. 1957, ii, 193. Anderson, J. ibid. 1958, ii, 1569. Ellis, M. ibid. 1959, i, 299.
ESTABLISHMENT OF IMMUNOLOGICAL COMPETENCE IN A CHILD WITH CONGENITAL THYMIC APLASIA BY A GRAFT OF FETAL THYMUS
R. H. LEVEY F. S. ROSEN
C. S. AUGUST A. I. BERKEL
Departments of Medicine and Surgery, Children’s Hospital Medical Center, and Departments of Pediatrics and Surgery, Harvard Medical School, Boston, Mass. 02115 H. E. M. KAY
Royal
Marsden
Hospital, London
S.W.3
Fetal thymus tissue was implanted into Summary a 21-month-old patient with congenital
aplasia of
the
thymus gland (DiGeorge’s syndrome).
Clinical and immunological studies carried out for 16 months thereafter revealed prompt and long-lasting improvement in previously defective cellular immune functions including dermal sensitivity to monilia antigen and dinitrofluorobenzene, skin allograft rejection, and the responses of peripheral blood leucocytes in vitro to phytohæmagglutenin and to monilia antigen. It is suggested that implanting fetal thymus tissues into patients with DiGeorge’s syndrome offers at present the best hope of improving their deficient cellular immune function. Introduction
DiGeorge described four patients with hypoparathyroidism and absent thymus glands which he attributed to an error in the development of structures derived from the third and fourth pharyngeal pouches during embryonic life.1,2 The immunological consequences which were subsequently found in these and similar children involved a profound inability to mount cellular immune responses.3-6 It was speculated that these patients would be ideal recipients for transplants of fetal thymus tissue,5and indeed two apparently successful attempts to establish cellular immune function in this way have been reported6,8 Descriptions of the two immunologically corrected patients have stimulated many questions as to whether IN 1965
the recovery was in fact spontaneous or was mediated by the implanted fetal thymus tissue.99 This report
provides further details about one of the previously reported patientsand describes the immunological tests that have been performed over an 18-month period since the fetal thymus tissue was implanted. We believe that the data strengthen the previous conclusion that the rapid acquisition of immunological competence in our patient was due to the implanted fetal thymus and
not to
spontaneous recovery.
Case-report An infant developed hypocalcasmic tetany on his 3rd day of life. Although seizures disappeared with calcium-
gluconate therapy, hypocalcxmia persisted for a longer time. During his lst year, he had oral moniliasis, otitis media, recurrent upper and lower respiratory-tract infections, and a deep-seated abcess of the skin. During that year he was admitted to hospital six times; growth and development were retarded. Immunological studies when he was 10 months oldrevealed mild lymphopenia, defective delayed hypersensitivity, poor responses of his lymphocytes to phytohaemagglutinin (P.H.A.) in vitro, and normal levels of serum-immunoglobulins. He had primary and secondary antibody responses to typhoid vaccine and to tetanus and diphtheria toxoids, respectively. A skin-graft from an unrelated donor apparently was accepted. When studied again at 21 months of age, the patient’s immunological deficiency was still marked,8 although an ambiguous response to dinitrofluorobenzene (D.N.F.B.) at the highest concentration tested-500 jig. per ml.-suggested that immunological function might have improved slightly. The serum-calcium concentration was 9-3 mg. per 100 ml. Implantation of thymus fragments from a female fetus estimated to be 16 weeks’ gestation was carried out as described previously.8 When tested 4 days later, the peripheral blood leucocytes responded normally to P.H.A., whereas 2 days before the implant they had been virtually unresponsive. When tested 2 weeks later, the patient responded normally to challenge doses of D.N.F.B. and monilia. He promptly rejected a skin-graft from an unrelated donor. Since discharge from the hospital in September, 1968, he has had occasional upper-respiratory-tract infections and three bouts of uncomplicated otitis media. Although he has grown at a normal rate since the implantation, both height and weight remain below the third percentile. Intellectual and motor development have been rapid. Although speech development has been slower, he is no longer thought to be globally retarded. No masses have ever been palpable at the site of the implanted thymic fragments. Immunological studies consisting of complete bloodcounts, a number of skin-tests, and in-vitro studies of lymphocyte function were carried out 2, 4, 8, 12, and 14 months after thymic implantation. During the last study the patient received a skin-graft from an unrelated donor. 14 days later, when the graft appeared to be undergoing rejection, it was excised and a regional lymph-node was biopsied.
Methods
Immunological testing was performed by methods previously. 10 Skin tests with monilia antigen (Hollister-Stier), streptokinase-streptodornase (S.K.S.D., Lederle), diphtheria toxin and toxoid (Massachusetts Biological Laboratories) were injected intradermally on the
described
forearm in 0.1ml. sterile saline solution and read 48 hours later. Only induration greater than 5 mm. in diameter was considered to be unequivocally positive. Contact sensitivity to D.N.F.B. and dinitrochlorobenzene (D.N.C.B.) were patchtested by applying the appropriately diluted chemical to the patient’s skin for 48 hours. The tests were read when the patches were removed and again 24 hours later. Only redness associated with vesiculation was considered to represent a specific immune response.