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congestion with foci of necrosis, and the wall of the

appendix may be seen to be cedematous. The absence offaecal matter from the lumen of such appendices is a

frequent finding, and appendices without fxcal contentsin the lumen are seldom normal. Again, surgeon andpathologist will usually agree on the diagnosis of acuteappendicitis. Difficulty arises in the appendices withoutgross naked-eye changes; these often contain semi-fluidmatter not clearly either fxcal or purulent. Such appen-dices are often regarded by the surgeon as normal, andwhen the pathologist later reports them as abnormal thisassessment is usually not taken as being clinically signifi-cant. The histological changes in these appendices areusually circumscribed, defined as being characteristic oflimited acute appendicitis. Most of the specimens in thisinvestigation diagnosed as complete acute appendicitiswere apparently recognised by the surgeon as such,whereas some at least of those showing limited acuteappendicitis were diagnosed by the surgeons as normal.

It may be argued that the histological criteria are notvalid. When cases of complete acute appendicitis are

excluded, the proportion of specimens from patients withpain in the right iliac fossa showing limited but notcomplete acute appendicitis (19%) equals that from

symptom-free controls (18%). This could be used to

support the view that limited acute appendicitis is a

normal variant of no clinical significance. When thesame group of 28 patients with pain in the right iliac fossaand limited acute appendicitis is taken as a proportion ofall patients with pain in the right iliac fossa (400), theproportion falls to 7% of the series. I suggest that the

discrepancy between this value and the 18% of the controlasymptomatic group represents the number of patients inwhom limited acute appendicitis has advanced to completeacute appendicitis.

Foci of acute inflammation in the mucosa of the

appendix must by their very presence represent acuteappendicitis, and rather than deny their existence it seemsworth trying to find out why minor attacks suddenlybecome severe; and why some patients with the sameappendicular changes display typical symptoms, whereasothers remain symptom-free.

There are two reasons for presenting this work at itspresent stage. One is that the proposed division of limitedfrom complete acute appendicitis is not difficult; and fromthis starting-point useful clinicopathological research

might well proceed. The other is that some relevant find-ings seem already to have emerged from the investigation(table i).

First, if the histological criteria are valid, it is evidentthat the appendix is often mildly inflamed and may at anytime become seriously inflamed.

Secondly, surgeons who favour a radical approach tosuspected appendicitis remove more abnormal appendicesthan do conservative units (tables I and II). The differenceis not confined to limited acute appendicitis, and this con-clusion remains valid whether or not the histologicalcriteria are accepted in their entirety. Hence many patientswho are admitted with pain in the right iliac fossa whichsettles quickly without operation have nevertheless prob-ably had acute appendicitis. This issue therefore becomesa problem of treatment based on solution of the equation:morbidity and mortality of operation against morbidityand mortality of non-operation. The morbidity of appen-dicectomy has been well documented (Wright 1963); butthe morbidity, and perhaps even mortality, of failing to

remove abnormal appendices has not been calculated,The third clinical implication of this work is that there

is no histological proof that peritonitis is the cause of thepain of appendicitis. We simply do not know what deter-mines whether a patient with limited acute appendicitisdevelops symptoms or not. The suggestion that the painis caused by distension of the appendix wall with oedemafluid is attractive, but not readily provable or disprovable.My finding of a high proportion of cases of symptomless

appendicitis is not new. Aschoff (1932) examined 145appendices removed incidentally at laparotomy and foundthat 49 showed evidence of acute inflammation. He wrote:" in view of the conclusions which we are forced to drawfrom the histological evidence, it is clear that the appendixshould always be removed during a laparotomy if suchremoval is surgically possible and free from danger."Although some surgeons believe and act on this apparentlyreasonable conclusion, others do not.From the figures in tables I and 11, I conclude that

surgical units adopting a conservative approach to sus-

pected acute appendicitis fail to remove a significantnumber of abnormal appendices.Many patients undergoing intra-abdominal operations

where removal of the appendix is free from danger mightbe saved the risks of later appendicitis by prophylacticappendicectomy. Acute appendicitis requiring emergencylaparotomy is not uncommon in old people, and may bevery serious.

SummarySimple histological criteria of acute appendicitis were

applied in a clinicopathological study of 460 appendices.Surgeons with a radical approach to pain in the right

iliac fossa remove significantly more abnormal appendicesthan do the more conservative surgeons.

18 % of appendices removed from symptomless patientsshow changes fulfilling the defined criteria of acute

appendicitis.The appendix is always liable to become inflamed, and

probably many appendices which are microscopicallyabnormal are not removed.

It is a pleasure to record my sincere thanks to all the surgeons andresidents of the Western Infirmary for making material available forexamination. I am indebted to Dr. R. A. Robb of the mathematicsdepartment of the University of Glasgow for help with the statisticalanalysis.

REFERENCES

Aschoff, L. (1932) Appendicitis—its Ætiology and Pathology; p. 145.London.

Barnes, B. A., Behringer, G. E., Wheelock, F. C., Wilkins, E. W. (1962)J. Amer. med. Ass. 180, 122.

Wright, R. B. (1963) Lancet, ii, 475.

THE TREATMENT OF TYPHOID FEVER

WITH AMPICILLIN

MARWAN UWAYDAH*M.D. Beirut

MUNIR SHAMMA’AM.D. Beirut

OF THE DEPARTMENT OF MEDICINE,AMERICAN UNIVERSITY HOSPITAL, BEIRUT, LEBANON

* Present address: Massachusetts General Hospital, Boston, Mass.

AMPICILLIN (x-aminobenzylpenicillin, ’Penbritin’) isa semisynthetic penicillin, first synthesised by Doyle,Nayler, and Smith in 1961 (Brown and Acred 1961).Rolinson and Stevens (1961) demonstrated its efficacyagainst salmonella organisms in vitro and in laboratoryanimals. Clinical trials in typhoid fever have been fewand inconclusive (Maddock 1962, Ross et al. 1962,

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Kennedy et al. 1963). Recently Sleet et al. (1964)compared it with chloramphenicol in the treatment ofparatyphoid fever.We here report the use of ampicillin as a therapeutic

agent in typhoid fever.

The Patients

Eight patients with typhoid fever, admitted to the AmericanUniversity Hospital of Beirut, were included in this study(see table). Their ages ranged between 9 and 37 years, andthere were 4 males and 4 females. The duration of illnessbefore the start of treatment was 30 days in one patient, 25days in another, and 3-12 days in the rest. Blood-culturesfrom every patient grew Salmonella typhi. In-vitro sensitivitywas tested by the disc method in seven cases. All were sensi-tive to ampicillin and chloramphenicol. Each disc of ampicillincontained 25 g.

Ampicillin was the only therapeutic agent used in all saveone case. The initial dose was 1 g. given by mouth every 6hours until the fever subsided, after which the dose was reducedto 0-5 g. or 0-75 g. 6-hourly, and this was continued for 7-10days more. The total amount of ampicillin used ranged from26 to 60 g. The duration of treatment in all but one patient,in whose case the medication was discontinued, averaged 16days and ranged from 13 to 19 days.

ResultsIn seven out of eight cases early response, as evidenced by

improvement of symptoms and partial drop of temperature,occurred within 2 or 3 days of starting therapy. In two casesthe temperature remained normal after 4 days’ treatment.

The average duration of fever after beginning treatment was7 days, and it ranged from 4 to 12 days (see table). In one

THE CASES TREATED WITH AMPICILLIN

case treatment was given for 5 days only, and it was then

replaced with chloramphenicol because there was no apparentresponse.

Ampicillin was well tolerated by all the patients, and noside-effects were detected. In particular, there was no clinicalor laboratory evidence of hsematological disturbances. Noneof the patients had intestinal bleeding or perforation duringor after treatment. All seven patients who were givenampicillin alone have been followed up for 5 weeks, and therehas been no relapse. Stools were cultured in 6 patients aftertreatment was discontinued, and they were all negative forS. typhi.

Discussion

The three previously published clinical trials with

ampicillin in S. typhi fever comprise a total of sevencases, of which only three received the medication forlong enough (Maddock 1962, Ross et al. 1962, Kennedyet al. 1963). The child mentioned by Ross et al. (1962)had the antibiotic for 31/2 days only, and then, becausethe fever persisted, chloramphenicol was used instead.Two of the three cases reported by Maddock (1962)received chloramphenicol for 12 days before the adminis-tration of ampicillin. The third patient had the drug for

2 days only. It seems, therefore, that no definite con-clusions regarding the therapeutic effect of ampicillincan be drawn from these two reports. Kennedy et al.

(1963), however, reported that ampicillin successfullyeradicated the organism from one of their three patientswith S. typhi fever. The other two patients relapsed,and a second course of the drug with larger doses wasrequired to control the disease.

In the present study, patients with paratyphoid feverwere not included because of the unpredictable febrilecourse of this illness. Since the average duration of feverafter starting therapy was 7 days, and this ranged from4 to 11 days, the lack of response in one patient in ourseries who received ampicillin for only 5 days may bethe result of incomplete treatment. It could be arguedthat the first and fifth cases represent the natural courseof the untreated illness since treatment was started 30and 25 days respectively after the onset of the disease.The five other cases, however, demonstrate the effective-ness of ampicillin in controlling the disease. In thesecases the fever subsided permanently within an averageof 7 days after the start of treatment. This is about 2

days longer than the interval observed with chloram-

phenicol-treated patients. The total duration of the ill-ness in these five patients ranged from 7 to 19 days, withan average of 13-6 days. This contrasts sharply with thecourse of the disease in the untreated cases, which is

reported to range from 30 to 50 days (Stuart and Pullen1946, Woodward et al. 1948). The dosage schedule was4 g. daily until the fever subsided, after which it wasreduced to 2-3 g. daily for about 10 days more. Furthertrials with larger numbers of patients are necessary toestablish the smallest dose requirement and the durationof therapy in typhoid fever. In a similar way to itsaction on penicillin, probenecid maintains a highblood-level of ampicillin, and combined administration-of the two may decrease the dose requirement of theantibiotic.

Although the number of patients in our series is small,the results already obtained suggest that ampicillin hasa place in the treatment of typhoid fever. It becomes theonly effective drug when patients have evidence of

chloramphenicol toxicity. Furthermore, because of itsbactericidal properties, it might prove more effectivethan a bacteriostatic agent in controlling the disease, its

complications, and the carrier state.

Summary

Eight patients with typhoid fever were treated withampicillin (oc-aminobenzylpenicillin, ’Penbritin’), andin seven patients this antibiotic effectively controlled theinfection.

°

Further investigation with more patients is necessaryto establish the dose-duration regimen for ampicillin,and its effect on typhoid complications and the carrierstate.

We wish to thank Messrs. G. Abu Adal & Co., of Beirut, Lebanon,who donated part of the ampicillin used in this study.

REFERENCES

Brown, D., Acred, P. (1961) Brit. med. J. ii, 197.Kennedy, W. P. U., Wallace, A. T., Murdoch, J. M. (1963) ibid. ii, 962.Maddock, C. R. (1962) Lancet, i, 918.Rolinson, G., Stevens, S. (1961) Brit. med. J. ii, 191.Ross, S., Lovrien, E. W., Zaremba, E. A., Bourgeois, L., Puig, J. R. (1962)

J. Amer. med. Ass. 182, 238.Sleet, R. A., Sangster, G., Murdoch, J. M. (1964) Brit. med. J. i, 148.Stuart, B. M., Pullen, R. L. (1946) Arch. intern. Med. 78, 629.Woodward, T. E., Smadel, J. E., Ley, H. L., Green, R., Mankikar, D. S.

(1948) Ann. intern. Med. 29, 131.