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Chloramphenicol and Other Antibiotics in the Treatment of Typhoid Fever and Typhoid Carriers

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Chloramphenicol and Other Antibiotics in the Treatment of Typhoid Fever and Typhoid Carriers CHLORAMPHENICOL AND OTHER ANTIBIOTICS IN THE TREATMENT OF TYPHOID FEVER AND TYPHOID CARRIERS Theodore E. Woodward, … , Joseph E. Smadel, Herbert L. Ley Jr. J Clin Invest. 1950;29(1):87-99. https://doi.org/10.1172/JCI102238. Research Article Find the latest version: https://jci.me/102238/pdf CHLORAMPHENICOL AND OTHER ANTIBIOTICS IN THE TREATMENT OF TYPHOID FEVER AND TYPHOID CARRIERS By THEODORE E. WOODWARD, JOSEPH E. SMADEL, AND HERBERT L. LEY, JR. (From the University of Maryland School of Medicine, Baltimore, the Army Medical Depart- ment Research and Graduate School, and the Commission on Immunization of the Army Epidemiological Board, Washington, D. C.) (Received for publication July 28, 1949) The initial experience of our group with the capsules which were furnished by Parke, Davis and Com- beneficial effect of chloramphenicol in the treat- pany. The bitter taste of the original experimental un- coated tablets was subsequently disguised by dispensing ment of ten Malayan patients with typhoid fever the drug in gelatin capsules. The usual therapeutic was published as a preliminary report (1). The regime was as follows: Each patient received an initial work has been continued in the United States and large oral dose of 3.0 to 4.0 gm. of drug, calculated on we now wish to add to the earlier note detailed the basis of approximately 50 mgm. per kgm. of body observations on 24 patients acutely ill with typhoid weight. Throughout the febrile period the patients re- ceived a total of 2.0 to 3.0 gm. daily given in divided fever and five typhoid carriers who have received doses of 0.25 gm. every two or three hours. Therapy this antibiotic. In addition, the therapeutic re- was continued for at least five days after the temperature sults obtained in small groups of typhoid patients returned to normal levels by administering 0.25 gm. who were given aureomycin or polymyxin are in- tablets at four-hour intervals during the first few days and cluded in this report. at six-hour intervals during the latter portion of this period. For various reasons, of which the most promi- nent was a shortage of chloramphenicol, a number of pa- METHODS tients received smaller amounts of the antibiotic for a Selection and observation of patients shorter time during the afebrile period than would have In all of the 33 treated acutely ill patients mentioned been given according to the schedule mentioned above. in the present study, the clinical diagnosis of typhoid fever In the later period of the work a simplified regime was followed. Patients 20 through 23 received the usual was confirmed by the cultivation of Salmonella typhosa large initial dose of drug after which they were given from their blood obtained prior to the initiation of spe- a total of 4.0 gm. daily in divided doses at eight-hour cific therapy. Patients selected for treatment were in an active phase of the disease. In most instances therapy intervals during the febrile period; the dosage, still given at eight-hour intervals, was later reduced by a series of was begun within two weeks of onset of illness but two steps to 1.5 gm. daily. Vomiting was encountered rarely patients were first given chloramphenicol during a relapse of typhoid fever in the fifth and seventh weeks of illness. following the initial loading dose of drug; it occurred only when the bitter uncoated tablets were used and in no The course of the disease in the treated patients was fol- lowed by careful clinical observations and by laboratory instance did it necessitate discontinuance of therapy. examinations which included repeated cultures of samples In the majority of patients blood levels of chloram- phenicol were determined at least once daily throughout of blood, feces and urine, as well as Widal tests, blood counts and other. procedures when indicated. In this the period of treatment. For this purpose serum was obtained from a of blood study the patient's temperature was considered normal specimen taken immediately before the next dose of drug was due. Ley's modifica- when the recording was below 99.0° F. orally, or below 100.00F. rectally. tion 2 of the turbidimetric microbiological method of Joslyn and Galbraith (2, 3) employing inhibition of No attempt was made to treat alternate cases with chloramphenicol. During the period of the study, how- growth of S. sonnei was used for the assay. Aureomycin. Aureomycin, supplied in 0.25 gm. gelatin ever, nine patients with typhoid fever were observed who received only supportive therapy. The diagnosis in each capsules by the Lederle Laboratories Division of the American Cyanamid Company, was administered orally of these untreated patients was proved by the cultiva- to four American patients included in the present study. tion of S. typhosa from the blood or feces. Two adults received an initial dose of 2.0 gm. followed Antibiotic therapy by 0.50 to 0.75 gm. every four hours. Two children Chloramphenicol. Chloromycetin 1 of the fermentation were given a smaller loading dose of 1.0 gm. and there- type was administered in the form of 0.25 gm. tablets or 2 This is available in detail in mimeographed form and 1 Trade name, Parke, Davis and Company. will be furnished on request. 87 88 THEODORE E. WOODWARD, JOSEPH E. SMADEL, AND HERBERT L. LEY, JR. PATIENT 5 MALE, AGE 15. 120 LB. T E M o02 - Up D E G F 9S F SO - 40- C 30- H L BLOOD LEVEL 0 YICC 20- R 0 M 0o- c 0- E T N N DOSE 40. WMDAY 20 ' r 2 1 3 1 4 S 6 12 1 13 * 14 *5 DAY OF DISEASE OOO + + 0 0 0 0 TYPS4OSA UPRIE 0 0 0 0 CULTURE STOOL 0 0 0 FIG. 1. CLINICAL RESPONSE OF TYPHOID PATIENT 5 TO CHLORAMPHENICOL THERAPY A total of 21 gm. of chloramphenicol was given over a period of nine days. after 025 gm. at four-hour intervals. Therapy was con- are placed in cups on a seeded agar surface.3 Organisms tinued for two weeks in those patients who survived. from the majority of the American patients who received Nausea and gastrointestinal irritation, such as has been chloramphenicol were tested for sensitivity by a turbidi- noted by others (4), occurred in our patients but the metric technique using fluid cultures. Our observations regime was not interrupted because of this. Data on with this method agree with those of Smith and his co- blood levels of aureomycin were not obtained. workers (3). Polymyzin. Vials of dried polymyxin hydrochloride and of special diluent were supplied by Lederle Labora- RESULTS IN PATIENTS GIVEN One cc. of a solution tories. freshly prepared containing CHLORAMPHENICOL 40 mgm. of this antibiotic was administered intramuscu- larly every three hours for a period of about two weeks Observations in uncomplicated cases to five Chinese patients who were treated in Malaya. Certain toxic manifestations probably attributable to the Some subjective or objective improvement was polymyxin are discussed in the section on clinical results generally noted in patients acutely ill with typhoid with this antibiotic. fever within the first 36 hours after treatment was In vitro tests for sensitivity of infecting organism to begun. However, by the third and fourth days of antibiotic agents therapy, improvement was manifested by (a) Infecting organisms from ten of the 11 Malayan pa- abatement of fever by lysis, (b) disappearance of tients who received chloramphenicol, and from all of rose spots, which had been present in about half those who were given polymyxin were tested for sensi- the patients, (c) amelioration of headache, cough, tivity to the antibiotic being used for treatment. A modi- fication of the usual zone of inhibition technique was 3 These tests were performed by Dr. Richard Green of employed in which varying concentrations of antibiotic the Institute for Medical Research, Kuala Lumpur. CHLORAMPHENICOL IN TREATMENT OF TYPHOID FEVER 89 and the toxemic characteristics of this disease. tions are represented in Figure 1. The patient was de- Following the return of the temperature to normal cidedly less toxic within 36 hours after initiation of treat- ment. Within 62 hours the temperature reached normal levels on aboutthe fourth day, convalescence gen- and the patient was clearly convalescent. Blood speci- erally proceeded at a rapid rate. The usual clin- mens taken on the first, second, third and eighth days ical response to chloramphenicol treatment is il- of treatment were sterile. S. typhosa was not found in lustrated in the abbreviated case histories and any stool or urine specimen examined. Convalescence graphical records of patients 5 and 7 which are was uneventful and rapid and the patient was discharged presented below. The record of patient 1 (desig- from the hospital on the 29th day after onset. nated T-5 in the preliminary report) has already Patient 7. This 24-year-old Malay Indian was hos- been published (1). pitalized on the sixth day of illness with the principal complaints of continued daily fever, anorexia, malaise, Patient 5. This 15-year-old Chinese boy entered the headache, and moderate cough. Examination revealed hospital on the fourth day of disease. His early illness the usual signs of typhoidal toxemia including drawn was characterized by fever, headache, watery stools over facies, feeble dicrotic pulse and hypotension (96/70); in a three-day period, and general malaise. The significant addition, bilateral pulmonary rales and rhonchi, and a physical findings on admission were toxemia, dehydration, slightly distended and tender abdomen were noted. Two and a slightly tense and tender abdomen. Two pre- pre-treatment blood cultures contained S. typhosa.
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