chloramphenicol and treatment of...chloramphenicol in treatment of typhoid fever and the toxemic...

CHLORAMPHENICOLANDOTHERANTIBIOTICS IN THETREATMENTOF TYPHOID FEVERAND

TYPHOID CARRIERS

By THEODOREE. WOODWARD,JOSEPHE. SMADEL, ANDHERBERTL. 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 thebeneficial effect of chloramphenicol in the treat-ment of ten Malayan patients with typhoid feverwas published as a preliminary report (1). Thework has been continued in the United States andwe now wish to add to the earlier note detailedobservations on 24 patients acutely ill with typhoidfever and five typhoid carriers who have receivedthis antibiotic. In addition, the therapeutic re-

sults obtained in small groups of typhoid patientswho were given aureomycin or polymyxin are in-cluded in this report.

METHODS

Selection and observation of patients

In all of the 33 treated acutely ill patients mentionedin the present study, the clinical diagnosis of typhoid feverwas confirmed by the cultivation of Salmonella typhosafrom their blood obtained prior to the initiation of spe-cific therapy. Patients selected for treatment were in an

active phase of the disease. In most instances therapywas begun within two weeks of onset of illness but twopatients were first given chloramphenicol during a relapseof typhoid fever in the fifth and seventh weeks of illness.The course of the disease in the treated patients was fol-lowed by careful clinical observations and by laboratoryexaminations which included repeated cultures of samplesof blood, feces and urine, as well as Widal tests, bloodcounts and other. procedures when indicated. In thisstudy the patient's temperature was considered normalwhen the recording was below 99.0° F. orally, or below100.00F. rectally.

No attempt was made to treat alternate cases withchloramphenicol. During the period of the study, how-ever, nine patients with typhoid fever were observed whoreceived only supportive therapy. The diagnosis in eachof these untreated patients was proved by the cultiva-tion of S. typhosa from the blood or feces.

Antibiotic therapy

Chloramphenicol. Chloromycetin 1 of the fermentationtype was administered in the form of 0.25 gm. tablets or

1 Trade name, Parke, Davis and Company.

capsules which were furnished by Parke, Davis and Com-pany. The bitter taste of the original experimental un-coated tablets was subsequently disguised by dispensingthe drug in gelatin capsules. The usual therapeuticregime was as follows: Each patient received an initiallarge oral dose of 3.0 to 4.0 gm. of drug, calculated onthe basis of approximately 50 mgm. per kgm. of bodyweight. Throughout the febrile period the patients re-ceived a total of 2.0 to 3.0 gm. daily given in divideddoses of 0.25 gm. every two or three hours. Therapywas continued for at least five days after the temperaturereturned to normal levels by administering 0.25 gm.tablets at four-hour intervals during the first few days andat six-hour intervals during the latter portion of thisperiod. For various reasons, of which the most promi-nent was a shortage of chloramphenicol, a number of pa-tients received smaller amounts of the antibiotic for ashorter time during the afebrile period than would havebeen given according to the schedule mentioned above.In the later period of the work a simplified regime wasfollowed. Patients 20 through 23 received the usuallarge initial dose of drug after which they were givena total of 4.0 gm. daily in divided doses at eight-hourintervals during the febrile period; the dosage, still givenat eight-hour intervals, was later reduced by a series ofsteps to 1.5 gm. daily. Vomiting was encountered rarelyfollowing the initial loading dose of drug; it occurredonly when the bitter uncoated tablets were used and in noinstance did it necessitate discontinuance of therapy.

In the majority of patients blood levels of chloram-phenicol were determined at least once daily throughoutthe period of treatment. For this purpose serum wasobtained from a specimen of blood taken immediatelybefore the next dose of drug was due. Ley's modifica-tion 2 of the turbidimetric microbiological method ofJoslyn and Galbraith (2, 3) employing inhibition ofgrowth of S. sonnei was used for the assay.

Aureomycin. Aureomycin, supplied in 0.25 gm. gelatincapsules by the Lederle Laboratories Division of theAmerican Cyanamid Company, was administered orallyto four American patients included in the present study.Two adults received an initial dose of 2.0 gm. followedby 0.50 to 0.75 gm. every four hours. Two childrenwere given a smaller loading dose of 1.0 gm. and there-

2 This is available in detail in mimeographed form andwill be furnished on request.

87

THEODOREE. WOODWARD,JOSEPH E. SMADEL, AND HERBERTL. LEY, JR.

PATIENT 5 MALE, AGE15.120 LB.

SO -

40-

30-

BLOODLEVELYICC 20-

0o-

0-

DOSE

WMDAY 20

r 2 1 3 1 4 S ' 6

40.

12 1 13 * 14 *5DAY OF DISEASE

OOO + + 0 0 0 0TYPS4OSA

UPRIE 0 0 0 0CULTURE

STOOL 0 0 0

FIG. 1. CLINICAL RESPONSEOF TYPHOID PATIENT 5 TO CHLORAMPHENICOLTHERAPYA total of 21 gm. of chloramphenicol was given over a period of nine days.

after 025 gm. at four-hour intervals. Therapy was con-

tinued for two weeks in those patients who survived.Nausea and gastrointestinal irritation, such as has beennoted by others (4), occurred in our patients but theregime was not interrupted because of this. Data on

blood levels of aureomycin were not obtained.Polymyzin. Vials of dried polymyxin hydrochloride

and of special diluent were supplied by Lederle Labora-tories. One cc. of a freshly prepared solution containing40 mgm. of this antibiotic was administered intramuscu-larly every three hours for a period of about two weeksto five Chinese patients who were treated in Malaya.Certain toxic manifestations probably attributable to thepolymyxin are discussed in the section on clinical resultswith this antibiotic.

In vitro tests for sensitivity of infecting organism toantibiotic agents

Infecting organisms from ten of the 11 Malayan pa-tients who received chloramphenicol, and from all ofthose who were given polymyxin were tested for sensi-tivity to the antibiotic being used for treatment. A modi-fication of the usual zone of inhibition technique was

employed in which varying concentrations of antibiotic

are placed in cups on a seeded agar surface.3 Organismsfrom the majority of the American patients who receivedchloramphenicol were tested for sensitivity by a turbidi-metric technique using fluid cultures. Our observationswith this method agree with those of Smith and his co-

workers (3).

RESULTSIN PATIENTS GIVEN

CHLORAMPHENICOL

Observations in uncomplicated cases

Some subjective or objective improvement was

generally noted in patients acutely ill with typhoidfever within the first 36 hours after treatment was

begun. However, by the third and fourth days oftherapy, improvement was manifested by (a)abatement of fever by lysis, (b) disappearance ofrose spots, which had been present in about halfthe patients, (c) amelioration of headache, cough,

3 These tests were performed by Dr. Richard Green ofthe Institute for Medical Research, Kuala Lumpur.

88

o02 -

TEMUp

DEGF

9S F

CHL0R0M

cETN

N

CHLORAMPHENICOLIN TREATMENTOF TYPHOID FEVER

and the toxemic characteristics of this disease.Following the return of the temperature to normallevels on aboutthe fourth day, convalescence gen-

erally proceeded at a rapid rate. The usual clin-ical response to chloramphenicol treatment is il-lustrated in the abbreviated case histories andgraphical records of patients 5 and 7 which are

presented below. The record of patient 1 (desig-nated T-5 in the preliminary report) has alreadybeen published (1).

Patient 5. This 15-year-old Chinese boy entered thehospital on the fourth day of disease. His early illnesswas characterized by fever, headache, watery stools over

a three-day period, and general malaise. The significantphysical findings on admission were toxemia, dehydration,and a slightly tense and tender abdomen. Two pre-treatment blood cultures were positive for S. typhosa.There was moderate albuminuria; the white blood cellcount was 5,150, and the red blood cell count 4,400,000.Chloramphenicol treatment was initiated on the seventhfebrile day and was continued for eight days. The course

of fever, the daily amounts of drug given, the resultantblood levels, and the results of bacteriological examina-

104

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EM

Up

DEGF

tions are represented in Figure 1. The patient was de-cidedly less toxic within 36 hours after initiation of treat-ment. Within 62 hours the temperature reached normaland the patient was clearly convalescent. Blood speci-mens taken on the first, second, third and eighth daysof treatment were sterile. S. typhosa was not found inany stool or urine specimen examined. Convalescencewas uneventful and rapid and the patient was dischargedfrom the hospital on the 29th day after onset.

Patient 7. This 24-year-old Malay Indian was hos-pitalized on the sixth day of illness with the principalcomplaints of continued daily fever, anorexia, malaise,headache, and moderate cough. Examination revealedthe usual signs of typhoidal toxemia including drawnfacies, feeble dicrotic pulse and hypotension (96/70); inaddition, bilateral pulmonary rales and rhonchi, and a

slightly distended and tender abdomen were noted. Twopre-treatment blood cultures contained S. typhosa. Spe-cific treatment with chloramphenicol was instituted on

the 12th febrile day. Rapid improvement of the generaltoxic state began about 36 hours later and the tempera-ture remained permanently at normal levels after thefourth day of treatment. The antibiotic was adminis-tered for a total of eight days, i.e., three febrile and fiveafebrile days. White blood cell counts taken immediately

PATENT 7. MALE, AGE2490 LB.

100-

9. so-

40 -

C BLOODLEVEL 30-H T/ccL

0 20-R0 10

yc o

E

T

N 40-1DOSE

GMJDAY

II 2 3 4 ' S 6 7 8 9 10

DAY OF DISEASE

mo + +o0oo0&TYPH06A

URINE 0 0 0 0

F ISTOOL 0 0 0 0O

FIG. 2. CLINICAL RESPONSEOF TYPHOID PATIENT 7 To CHLORAMPHENICOLTHERAPYA total of 20 gm. of chloramphenicol was given over a period of nine days.

89


before treatment and in early convalescence were 7,200and 7,100, respectively. Numerous cultures of blood,urine and stool specimens taken after therapy was begunwere negative for typhoid bacilli. Convalescence was

rapid and the patient was discharged on the 30th day ofdisease. Figure 2 represents the graphic chart of theclinical record of this patient.

A summary of the results obtained in the 24cases of typhoid fever who received chlorampheni-col is presented in Table I. Eight of the patientswere children; the majority of the adults were inthe third and fourth decades but one was 74 yearsof age. There were a few more females than malesin the group. Drug therapy was begun on theseventh to the 21st day, average 11.9, of the ini-

duration or severity of the disease, or of the age

of the patient, the temperature returned to normallevels within five days after chloramphenicol ther-apy was instituted. The average duration offever after beginning treatment was approximately3.5 days in these 22 patients. Two persons whowere first treated during a relapse received thedrug on the 35th and 46th days after onset of theirdisease; these were the eighth and fifth febrile daysof the relapses. Both responded promptly, one

becoming permanently afebrile in two days andthe other in three.

The majority of the patients made an unevent-ful recovery, but the course was complicated inseven of the 22 who were treated during their ini-

tial attack of the 22 patients. Irrespective of the tial febrile episode.

TABLE ITYPHOID FEVER TREATEDWITH CHLORAMPHENICOL

PATIENT * TREATMENT RESPONSEAFTER TREATMENT LAST LAST DAY OFFEBRILE DISEASE

DA'YOF TOTAL DURATIONOf FEVER GOWLICATIONS DAY OF S. TYPHOSANO. AGE SEX DSEASE D DRUG AFTERTREATMENT

8EGUI ONINE (G;M.) (DAYS) NATURE ONSET, DAY DISEASE____ ~~~~~~~~~~~~~OFDIEASE FOUIND IN FECESf

I 24 F 9 9 22 2 NONE 21

2 25 M 9 10 25 4 WESA&E 16 12 0

"3 32 M 17 9 28 3 PERFORATION 21 28 18

4 9 F 10 8 15 3 NONE 13 0

5 15 M 7 9 21 3 NONE 10 0

6 25 F 12 8 17 3 RELAPSE 31 15 28

7 24 M 12 9 20 4 NONE 16 0

8 30 M 8 5 12 4 RELAPSE 23 12 50

9 O M 7 8 20 3 NONE 10 0

10 3SF 10 9 25 4 NONE 14 0

11 2 FF 9 7 17 5 RELAPSE 32 14 33

12 4 F 12 4 8 2 NONE 14 0

13 8 M 20 lI 22 4 NONE 24 23.149 F 12 10 20 3 NONE 15 14

INTTIA15 74 M 7 16 54 4 HEMOHGE 9 26 13

16 37 F 13 7 20 4 RELAPSE 31 17 38

17 5 F 10 14 25 3 NONE 13 18

18 39 M 16 12 46 5 NONE 21 IS

19 10 F 14 12 25 3 NONE 17 15

20 33 F 16 12 32 4 NONE 20 22

21 29 F 21 6 25 3 NONE 23 0

22 6 F 8 16 4 NONE 15 0

AV 11.9 92 234 35

23 ( 7 F 35 12 25 2 NONE 37 33

241 I5 M_ 46 7 17 3 NONE 49 49- wr-V e

v. .H W. UEm,- to- a^ft qp&..& eftft"% Ad se%& - riz* S.TYPHOSA US CULTURED AMBLOODTAIRN PRIOR TO TREATMIET FROMEACHFATIENT.

vZEO INDICATES THAT STOOL SECMENSWEREREPEATEDLYNEGATIVE FOR STYPHOSA THFODGHOUTHOyPITTESE RITIENTS WEREFIRST TREATED DURIN A RELAPSE

on


Observations in cases zeith complications

Intestinal hemorrhage and perforation. Two ofthe usual complications of typhoid fever, namely,intestinal hemorrhage and intestinal perforation,developed in three patients in the treated series.Severe intestinal hemorrhage occurred in patient2 and.moderate bleeding in patient 15; both madesatisfactory recoveries following supportive treat-ment which included blood transfusions. Thefirst patient began to bleed on the 16th day of thedisease, or the seventh day of therapy, at whichtime his temperature was normal. The secondshowed signs of bleeding while still febrile on theninth day of the disease or the second day of treat-ment. A brief abstract of the findings in patient3, who developed intestinal perforation, is givenbelow, and a graphic chart of his clinical recordis reproduced as Figure 3.

104 -T 103E-M 02-P 101D 100EG. 99.F 98

97

Patient 3. This severely ill 32-year-old Chinese maleentered the hospital on the 12th day of an illness char-acterized by continuous fever, headache, abdominal painand distention, occasional vomiting, and an irritating, non-productive cough. On the 17th day of illness, whentreatment was begun, additional findings consisted ofmuttering delirium, pulmonary rales, markedly increasedabdominal distention and numerous rose spots. The bloodpressure was 110/70; the pulse, 124; the white blood cellcount, 4,600; the red blood cell count, 1,140,000; and theurine contained moderate amounts of albumin. Bloodsamples taken on the 15th day of illness and on the 17thday, immediately prior to the initial dose of drug, yieldedS. typhosa upon culture.

The patient's response to chloramphenicol treatmentwas satisfactory as shown by the reduced toxemia, thegradual clearing of the mental state, the return of ap-petite and the lessening of abdominal tenderness and dis-tention. On the third day of therapy the temperaturereached normal levels and remained there for the next36 hours. The lungs were then clear, the rose spots haddisappeared and the pulse and heart sounds were of better

p

PATIENT 3 MALE AGE 32

110 LBVcHL0R0My

N

80BLOOD 60.LEVEL 40.ri/GG 20.

0 .

5.0GM/DAY 3.0

2.01.0

'12 '13'14 '15 '16 26 T'7 '2 8 '29 '30 `31

DAY OF DISEASE< PENICILLIN

-- STREPTOMYCIN -

S.TYPHOSA |BLOODJ+0DCULTURESTOOL + 0 0

THOUSANDS 46 41 33 42 139 3.9W.C97D 1 14 1.3 2.03 2.09;MILLIONS

FIG. 3. CLINICAL RESPONSEOF TYPHOID PATIENT 3 TO CHLORAMPHENICOLTHERAPYEarly convalescence was complicated by intestinal perforation on the 21st day of disease. The patient received a

total of 28 gm. of chloramphenicol over a period of nine days.

91


quality. The patient, now rational, complained of con-stipation and slight abdominal distention. At this point,on the 21st day of illness, an unwise medical attendantgave, without orders, 1.0 cc. of pituitrin in an effort torelieve the gaseous distention. Apparently the increasedperistalsis accompanied by a local rise of intra-intestinalpressure, which followed the pituitrin injection, resultedin a perforation presumably at the site of a typhoid ulcer.When observed several hours after this episode, the pa-tient was in a state of collapse. Intravenous fluids andblood transfusions were given as supportive measures, andin addition, chloramphenicol therapy was supplementedby the administration of large doses of penicillin andstreptomycin. During the next 12 hours the condition ofthe patient remained critical. There was evidence ofpneumoperitoneum and severe generalized peritonitis, andthe white blood cell count rose to 13,900. Some improve-ment was observed after 18 hours, and at the end of 36hours it appeared that the patient would survive. By thethird day after perforation active peristalsis was audibleand the patient passed soft fecal material in the usualmanner. From this point onward the improvement wassteady; the temperature dropped to normal levels by thesixth day after perforation. About the time that thepatient became afebrile the abdomen was sufficiently softto allow palpation of a mass in the right lower quadrant;this was discernible for a week before it finally dis-appeared.

S. typhosa was cultured from the stool sample obtainedon the 18th day of illness, i.e., 24 hours after therapy wasbegun. Typhoid organisms were not grown from subse-quent specimens of stool or blood. The patient was dis-charged from the hospital on the 46th day after onset ofdisease.

At the time of intestinal perforation surgical interven-tion was intensively considered but the opinion prevailedthat the patient was in too poor a condition to survive anysurgical procedure. Therefore, it was decided to attemptto control the infection with the aid of combined antibiotictherapy until the perforation could be sealed off by naturalprocesses. The results were so satisfactory that theidea of surgical intervention was no longer consideredafter the patient became a suitable operative risk.

Relapses of typhoid fever. Four of the 22 pa-tients treated during their initial illnesses developedrelapses. These persons (patients 6, 8, 11, and 16)had been started on chloramphenicol therapy be-tween the eighth and 13th days of their diseaseand had responded in the usual manner. The re-lapses occurred between the 23rd and 32nd daysafter the onset of typhoid fever, which representedperiods of ten to 16 days after drug had been dis-continued or 11 to 18 days after the patients hadbecome afebrile.

The recrudescent disease in each of these indi-viduals was characterized by fever, mild toxemia,

and the presence of S. typhosa in the blood andfeces. One of the patients, No. 11, was not givenspecific therapy during her relapse because of aninadequate supply of the antibiotic. She ran amoderately severe course with fever for ten days.The remaining members of the group were treatedbetween the first and fourth days of their relapse.The duration of the recurrent fever after treat-ment was begun varied between one and one-halfand three days. S. typhosa disappeared promptlyfrom the blood and stools of the three treated pa-tients and did not reappear. An abstract of thecase history of one of the patients whose diseaserelapsed and a graphic summary of the data repre-sented in Figure 4 are presented below.

Patient 6. A 25-year-old Chinese girl was hospitalizedon the ninth day of a febrile illness characterized bycontinuous fever, headache, moderate abdominal pain anddelirium. She showed toxemia and dehydration andthere were bilateral pulmonary rales; both the liver andspleen were palpable. Two blood cultures on the 11thand 12th days of illness contained S. typhosa. The whiteblood cell count on admission was 2,700 and the redblood cell count was 3,720,000. On the 12th day of ill-ness an initial oral dose of 2.2 gm. of chloramphenicolwas administered. The drug was continued with 0.2 gi.doses every two hours for the succeeding eight days,which was five days after the temperature became normal.A total of 16.5 gm. of drug were given.

Improvement in the clinical condition was noted aftertwo days of antibiotic treatment and the temperaturereached normal levels in less than three days. Specimensof blood taken during the second, third, and fourth daysof treatment were sterile, and frequent samples of stooland urine obtained during the third week of illness werefree of bacilli.

On the 31st day of illness, 16 days after the patientbecame afebrile and 12 days after the last dose of chloram-phenicol, the patient complained of headache and thatafternoon the temperature reached 102.20 F. The bloodwas again found to contain S. typhosa. On the secondday of this clinical relapse chloramphenicol treatment wasreinstituted; an initial dose of 3.0 gm. was followed bydoses of 0.25 gm. every two hours for seven days.Abatement of the headache was rapid and the tempera-ture reached normal in one and one-half days after thesecond course of therapy was started. The convalescencethereafter was uneventful and later blood and stool cul-tures did not yield typhoid organisms.

The prompt clinical response of these individualsindicated that the infecting organism responsiblefor the relapse was not appreciably resistant tochloramphenicol. This was further establishedby in vitro laboratory tests which showed that the

92

CHLORAMPHENICOLIN TREATMENTOF TYPHOID FEVER9

sensitivity of the organism isolated from three ofthe patients during their relapses was essentiallythe same as the sensitivity of the organisms iso-lated prior to treatment.

It is to be noted that in each of the four patientswith relapses the initial course of chloramphenicolhad been given for a period of eight days or less.Indeed, the patients had been afebrile for from one

to five days, average three, when drug was stopped.The relatively high incidence of relapses, two inten, in the early portion of the present studies ledus to the opinion that chloramphenicol therapyshould be continued for a longer period of timeafter the patients became afebrile. Subsequent

TEM

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ED AA0J2

F

observations during the latter portion of the pres-

ent work and in studies by another Army group

in Malaya (5) appeared to confirm our impres-sion. In fact, analyses of 44 cases treated by thetwo groups showed that about half the patientswho received chloramphenicol for eight days or

less suffered relapses of typhoid fever, whereasnone of those treated for 12 days or longer did so.

Laboratory findings in patients treated weithchloramphenicolIt was the general experience that within two

hours after therapy was begun the patient's bloodno longer contained demonstrable S. typhosa.

PATIENT 6, FEMALEAGE 2585 LBS.

H BLOODLEVELL gI/cc 40o0

R

0

Y

ET

N

DOSEOK/DAY

I I 91 10 11 114i

40-

20-

128129S 1301DAY OF DISEASE

BLOOD + + 0 0 0 + 0

STYPHOSACOJUREURMNE 0 0 0 0 0 0 0

STOOL o o o + 0 0 0 0

FIG. 4. CLINICAL RESPONSEOF TYPHOID PATIENT 6 To CHLORAMPHENICOLTHERAPYA total of 17 gm. of chloramphenicol was given over a period of eight days during the initial illness. A clinical

relapse occurred 12 days after treatment was discontinued, but this responded promptly to a second course ofdrug.

93

1l


Early in the work frequent cultures taken at in-tervals of several hours throughout the first dayof treatment consistently gave negative results.There was an inclination to discount these observa-tions since no method was available for inactivat-ing chloramphenicol, and it was thought possiblethat sufficient drug might be present in the sampleto prevent growth. Subsequent observations onfour of the patients in this series indicated thatsuch might not be the principal determining fac-tor 4 in the negative results. S. typhosa weregrown from specimens taken from two patients 24hours after therapy was initiated and from speci-mens obtained from two other patients at 48 hours.Except for these positive results and the culturesobtained during the clinical relapses, bacteremiawas not demonstrated after therapy was begun.

Nine of the 24 patients listed in Table I did nothave demonstrable S. typhosa in their stools atany time during the course of observation. Tenof the 24 patients had S. typhosa in their stoolsprior to treatment but two of these (patients 18and 23) did not excrete these organisms at anytime after drug was administered. Among theremaining 13, S. typhosa occurred on one or moreoccasions after beginning chloramphenicol therapy;five of these had positive cultures after the drugwas discontinued and, of these, four developedtypical clinical relapses. None of the patients inthe present group developed the chronic carrierstate during the period of observation. Each indi-vidual provided three consecutive stool specimenswhich were negative for S. typhosa before beingdischarged from the hospital. In Table I isgiven the last day of the disease on which S.typhosa was found in the stool of each patient.No cultures of urine samples from the patients inthe present series yielded S. typhosa either beforeor after treatment.

The maximum titers attained in the Widal testsperformed with type "O" antigen in all 24 patientsranged from 1: 40 to 1: 2560, geometric mean,

4 The routine method for performing blood cultures wasas follows: 3-5 cc. of fresh venous blood were imme-diately inoculated into approximately 10 cc. of fluid media.After an interval of one to 18 hours of incubation at370 C., streak subcultures of the mixture of blood andbroth were made on E. M. B. agar. Following appro-priate incubation, these plates were examined in the usualmanner and pathogenic members of the enteric groupwere identified by agglutination with specific antisera.

1: 470. Relapses of typhoid fever were not cor-related with titers of "O" agglutinins. At thetime of the relapses values of 1: 40, 1: 640, 1: 880,and 1: 1000 were recorded for the four personswho suffered from exacerbations of the disease.

Blood levels of chloramphenicol were determinedthroughout the course of treatment in 19 of thepatients. The data presented in Figures 1 to 4illustrate the typical findings. During the first daythe levels usually ranged between 40 and 80 gamma/cc. but on occasion values as high as 100 wereattained. During the subsequent three to fivedays the levels generally ranged between 20 and40 gamma/cc. Those patients treated late in theseries with a prolonged course of drug received1.5 gm. daily in divided doses of 0.5 gm. at in-tervals of eight hours during the last five to sevendays of treatment. While frequent blood levelswere not obtained in this group, other observa-tions (6) indicate that oral doses of 0.5 gm. ofchloramphenicol provide blood levels of 10 to 20gamma/cc. during the first few hours after thedose is given and that the level is barely detectableat the end of eight hours.

In this group of treated patients, as in otherspreviously studied (1, 7-9), there were no evi-dences of toxic manifestations attributable to thechloramphenicol. Abnormalities in the white andred blood cells and in the urine were recorded ina number of instances but were considered to bepart of the disease picture of typhoid or of the com-plications which developed.

The effect of chloramphenicol on the typhoid car-rier state

Results of therapy. Four adult women, whowere known to have been carriers of S. typhosafor ten or more years, were studied bacteriologi-cally until two or more specimens of duodenalcontents or stool were shown to contain typhoidbacilli. Following proof of the carrier state, eachpatient received an initial oral dose of 60 mgm.per kgm. of body weight of chloramphenicol; thiswas followed by a total of 4.0 to 6.0 gm. dailygiven in divided doses every six hours. Eachpatient received an average of 71 gm. of the anti-biotic over a 15-day period. High blood concen-trations were obtained without exception; theover-all average was 38 gamma/cc. An attemptwas made to follow the antibiotic level in bile ob-

94

CHLORAMIPHENICOLIN TREATMENTOF TYPHOID FEVER

tained by duodenal aspiration two hours aftereach dose was given, but results were erratic andunreliable, presumably because of unabsorbeddrug present in the duodenal fluids.

Duodenal drainage fluid from each patient be-came negative for S. typhosa within two to six daysafter therapy was initiated, and remained so for theduration of treatment. However, in the majorityof instances, the concentrations of chloramphenicolin these samples were sufficiently high to be ex-pected to inhibit growth of the organisms in the

90HL0

0 KEY: BLOODM 8 --- BILEYCET

N 70

LEVE 60L

GAMM 50A

PER

40CC

10

culture media. In any case the apparent bacterio-logic sterilization of the duodenal contents wasprobably of little significance since S. typhosa re-appeared in all four patients shortly after cessationof treatment. Cultures of the stool, with few ex-ceptions, were uniformly positive for S. typhosathroughout the period of treatment. No adequateexplanation is at hand for these continued positivestool cultures during the course of intensivetherapy.

The removal of the gallbladder from one patient

FEMALE, AGE 6585 KG

HOURSAFTER DOSE

FIG. 5. SIMULTANEOUSCHLORAMPHENICOLLEVELS IN BLOOD AND BILE AFTER 4.0 GM.ORAL DOSE

See text for details and interpretation.

9s


(patient D) during the period of treatment al-lowed a careful bacteriologic study to be done.Cultures of bile, obtained from the common ductand from the gallbladder, and also from scrapingsof the wall of the bladder itself, gave negative re-sults for S. typhosa. However, a crushed stoneyielded a positive culture for typhoid bacilli. It isof interest that S. typhosa subsequently reappearedin the duodenal contents of this patient in spiteof cholecystectomy and chloramphenicol therapy.

These observations indicate that chlorampheni-col therapy in four chronic typhoid carriers wasconsistently unsatisfactory in eradicating the car-rier state.

Chloramphenicol levels in bile of human beings.Two patients suitable for the study of biliary ex-cretion of chloramphenicol were observed duringthe period covered by this report. The first ofthese, an adult female, had a carcinoma of the stom-ach without evidence of biliary obstruction. Shewas given a single oral 4.0 gm. dose of chloram-phenicol three hours prior to an exploratorylaparotomy. At the time of the operation simul-taneous specimens of blood and bile were obtained,the latter by direct aspiration of the gallbladder.Bioassay5 of these samples revealed antibioticlevels of 69 and 27 gamma/cc. in blood and bile,respectively.

The second was the chronic typhoid carrier(patient D) whose gallbladder had been removedrecently. She was studied during convalescencefrom the operation at the time that a "T tube" drainwas present in the common duct. On two oc-casions single oral doses of 2.0 and 4.0 gm. ofchloramphenicol were given to this patient. Bio-assay of samples of blood and bile taken simul-taneously at intervals after the oral dose demon-strated that antibiotic levels in the bile were ap-proximately 50 per cent of those in the blood, al-though the maximum levels reached were depend-ent, of course, on dosage. The results obtained inthis patient with the 4.0 gm. test dose are shownin Figure 5.

5 The bioassay technique of Joslyn and Galbraith (2, 3)must be modified to allow satisfactory estimation ofchloramphenicol levels in bile. The specimen is cen-trifuged to remove all particulate matter and the clearsupernatant fluid is used in the assay as though it wereserum. To reduce non-specific light absorption due tothe color of the bile, the optical densities of the tubes ofthe assay are read at a wave-length of 800 millimicrons.

RESULTSIN PATIENTS GIVEN AUREOMYCINAND

POLYMYXIN

Aureomycin

Four American patients with typhoid feverwere given aureomycin orally beginning on the12th to 16th day after onset of illness. Two of thepatients died. One, a seven-year-old boy, suc-cumbed to the toxemia of the disease on the 22ndday of illness after receiving a total of 13.8 gm.of drug over seven days. His sister, patient 12in Table I, recovered promptly on chlorampheni-col therapy. The other fatal case was a 42-year-oldman who died on the 19th day of disease after tak-ing 13.0 gm. of antibiotic during the three daysprior to death. In the two remaining patientssome reduction in fever occurred for a few daysafter instituting therapy but this was not accom-panied by an obvious decrease in the toxemic mani-festations of typhoid fever. Figure 6 illustratesgraphically the course of disease in one of thesepatients who received a total of 59.1 gm. of aureo-mycin between the 12th and 26th days of illnessand became afebrile after the period covered by thechart. The other patient who survived was given22.2 gm. of drug between the 15th and 28th daysand remained afebrile after the 27th day of disease.

Although our experience with aureomycin intyphoid fever has been limited, it has been uni-formly discouraging. This is in contrast to theequivocal preliminary results reported by Collinsand his coworkers (4).

PolymyxinFive Chinese patients in Malaya who were se-

verely ill with typhoid fever were treated withpolymyxin. The mean day of illness on whichtherapy was begun was 17, range 10 to 27; the totalcourse of drug administered per patient averaged3.1 gm. given over 13.8 days; the duration offever after treatment was instituted averaged22 days, range 17 to 27; and the last febrile dayof primary illness, exclusive of relapses, averaged38.6 days. There were no fatalities. One patientsuffered a moderately severe intestinal hemor-rhage and another had severe furunculosis whichresponded to treatment with penicillin. Three ofthe five members of this group suffered relapses oftyphoid fever during which S. typhosa was againrecovered from their blood or stool. Two of the

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PATIENT T-25 MALE AGE 34175 LBS.

T 6 a _AUREOMYCIN

5.014.0

3.02.0

1.0

'5 '6 7 '8 '9 1'0'II

DAY OF DISEASE

FIG. 6. UNSATISFACTORYCLINICAL RESPONSEOF TYPHOID PATIENT T-25 TO AUREOMYCINTHERAPYA total of 59 gm. of aureomycin was given over a period of 14 days.

patients whose blood was cultured at frequentintervals after treatment was begun continuedto show bacteremia for three and six days, re-

spectively, during therapy. Two of the patientsdeveloped severe albuminuria accompanied by nu-

merous erythrocytes and casts in the urinarysediment; renal damage has been noted by others(10) following polymyxin therapy. Polymyxinapparently elicited no beneficial effects in thesepatients; indeed they pursued an unaltered course

of severe typhoid fever. Although unsatisfactoryclinical results were obtained, the strains of S.typhosa recovered from each of the patients dis-played a high degree of sensitivity to polymyxinwhen tested in vitro; concentrations of the orderof 5 gamma/cc. produced a zone of inhibition ofapproximately 23 mm. when the organisms were

examined by the cup-agar plate method.The in vitro sensitivity of the Malayan strains

of S. typhosa to polymyxin, although tested by a

different method, was of about the same order ofmagnitude as that observed by others in the UnitedStates (11).

Our clinical observations with polymyxin intyphoid fever were in contrast to the somewhat en-

couraging results reported by Schoenbach and hisassociates (10).

COURSEOF TYPHOID FEVER IN PATIENTS RECEIVING

NOANTIBIOTIC THERAPY

During the present studies nine patients withtyphoid fever were observed who did not receiveantibiotic therapy in any form. Eight of thesewere seen in Kuala Lumpur and one in Baltimore.In this group two deaths occurred, one on the 17thand the other on the 33rd day after onset of illness.Both of these displayed extreme toxemia anddied as a result of the severity of the disease with-out recognizable complications. The average du-ration of fever in the remaining seven cases was

106105

104

102

101

TE

P.

DEG.

97-

DOSEGM/DAY

'78930

91


35 days. The course-in these seven was not com-plicated by hemorrhage or perforation.

The observations on these untreated individualsagree in general with those given in one of thelast published reports on typhoid fever from theInstitute for Medical Research in Kuala Lumpurprior to the Japanese occupation. The followingparagraph summarizes the results in an explosiveoutbreak presumably traced to a single carrier.

"Fifty-three cases were closely observed in hos-pital and a complete clinical summary was made.There were great variations in clinical response towhat was presumably the same strain, or relatedstrains, of the infecting bacillus. Such variationsranged from mild symptoms among ambulant casesto severe toxaemia and death. Thirteen per centdied either from toxaemia or intestinal haemor-rhage; 8 per cent relapsed but recovered; andthere were a number of disabling complicationsand sequelae. Among all cases, 8 per cent hadperipheral neuritis (one man, severely affected,was disabled for more than five months); and4 per cent developed typhoid abscesses. Othercomplications occurred as follows: bronchitis,six; parotitis, three; intestinal haemorrhage withrecovery, three; pneumonia, two; paralysis of theurinary bladder, two; typhoid meningism, one;and severe stomatitis, one." (12)

Stuart and Pullen recently reviewed their ex-perience in New Orleans with 360 patients whocontracted typhoid fever during the interval from1939 through 1944 (13). Almost a third of thesepersons had received sulfonamide derivatives forvarious reasons, most frequently to control sec-ondary infections, while the remainder receivedother therapeutic agents or only supportive treat-ment. The unequivocal failure of all therapeuticagents to modify the fundamental course of thedisease allows the consolidation of both treated anduntreated groups in calculating the incidence ofvarious complications. On this basis, 46 of the360 patients died, yielding a mortality rate of 12.8per cent. Intestinal hemorrhages were observed in21 -per cent; intestinal perforations, in 1.9 per cent;relapses, in 12.5 per cent; and the carrier state,in 1.9 per cent.

McCrae, in 1907 (14), collected statistics froma large group of typhoid patients who were ob-served in European and American hospitals. Inhis series intestinal hemorrhage occurred in 7 per

cent of 23,271 patients; perforation, in 3.1 per centof 34,916; and relapses, in 8.8 per cent of 28,057.

DISCUSSION AND SUMMARY

Twenty-four patients with typhoid fever weretreated with chloramphenicol. There were nofatalities. In one group, consisting of 22 patients,therapy was begun within the first three weeks ofillness, average 11.9 days, while the two membersof the other group first received the drug during arelapse which occurred in the fifth or seventh week.The average duration of fever after the initial doseof drug was 3.5 days in the first group and 2.5 daysin the second. The majority of the patients inthe first group recovered without complications,but two had intestinal hemorrhage, one had in-testinal perforation, and four had clinical relapses.The group of 22 patients received on the average atotal of 23.4 gm. of drug given over 9.2 days. Itshould be noted that the relapses developed inindividuals who received less than the averagecourse of therapy, and that they were readilycontrolled when drug was again administered.

It is evident from the study of this first seriesof patients that chloramphenicol is a valuabletherapeutic agent in the treatment of typhoid fever.It must be realized, however, that the patients be-come afebrile before the intestinal lesions arehealed and, as a result, hemorrhage and perforationmay occur after defervescence. The present ob-servations indicate that a relatively high incidenceof relapses may be expected if chloramphenicoltherapy is restricted to a period of less than eightdays.

None of the patients who received chlorampheni-col therapy became chronic typhoid carriers. Innine of the 22 persons treated during their primaryillness, S. typhosa were never recovered from thestools and in none of the 24 persons in this serieswere typhoid organisms ever found in the urine.Five individuals had S. typhosa in their feces af-ter drug therapy was discontinued. Four of thesedeveloped clinical relapses. Eventually the stoolsof all five became free of S. typhosa, the last posi-tive culture being obtained on the 50th day afteronset.

Large doses of chloramphenicol given over aperiod of two weeks to four typhoid carriers failedto eradicate permanently the carrier state. Dur-ing the treatment, when the level of chlorampheni-

98


col in the bile was about half that in the blood, noS. typhosa were grown from specimens of biliaryfluid. Typhoid organisms were again cultivatedfrom the bile shortly after the drug was discon-tinued. It is worth mentioning that concentrationsof chloramphenicol as high as 1,000 gamma/cc.have no detectable in vitro bactericidal effect onS. typhosa (our unpublished data). Furthermore,in typhoid fever, as in scrub typhus (6, 9),chloramphenicol therapy apparently only sup-presses the growth of the organism; ultimate re-covery seems dependent on the development of im-munity in the host. Therefore, although not antici-pated, the discouraging results in typhoid carriersshould probably have been expected.

The results in four patients with typhoid fevertreated with aureomycin and in five given poly-myxin indicated that little value was obtained fromthese antibiotics. Indeed, the course was essen-tially unaltered from that of the nine patients withtyphoid fever who received only supportive therapyin the present investigation or the large numbersof patients reported in earlier studies by others.

ACKNOWLEDGMENTS

The authors wish to thank Dr. R. Lewthwaite, Directorof the Institute for Medical Research, Kuala Lumpur,and members of the staff of the Institute, particularlyDrs. R. Green and D. S. Mankikar, for their help andadvice. In addition, the authors wish to express theirappreciation of the assistance afforded by the members ofthe Pediatric and Medical Staffs of the University Hos-pital, Baltimore, Md. A number of the patients weremade available for study by Major C. J. Williams andLt. H. M. Giles of the Military General Hospital, KualaLumpur; Drs. F. L. Choon and C. N. Seong of theGeneral Hospital, Kuala Lumpur; Dr. F. B. Bang, JohnsHopkins Hospital, Baltimore, Md.; Dr. R. V. Campbell,Hagerstown, Md.; and Dr. F. A. Camalier, Leonardtown,Md. Miss Ann Meredith, Research Laboratory, Depart-ment of Medicine, University Hospital, Baltimore, con-tributed technical assistance.

BIBLIOGRAPHY1. Woodward, T. E., Smadel, J. E., Ley, H. L., Jr.,

Green, R., and Mankikar, D. S., Preliminary re-port on the beneficial effect of Chloromycetin inthe treatment of typhoid fever. Ann. Int. Med.,1948, 29, 131.

2. Joslyn, D. A., and Galbraith, M., A turbidimetricmethod for the assay of antibiotics. J. Bact., 1947,54, 26.

3. Smith, R. M., Joslyn, D. A., Gruhzit, 0. M., McLean,I. W., Jr., Penner, M. A., and Ehrlich, J., Chloro-mycetin: biological studies. J. Bact. 1948, 55,425.

4. Collins, H. S., Paine, T. F., Wells, E. B., and Fin-land, M., Aureomycin-a new antibiotic: evalua-tion of its effects in typhoid fever, severe salmonellainfections and in a case of colon bacillus bacteremia.Ann. Int. Med., 1948, 29, 1077.

5. Smadel, J. E., Woodward, T. E., and Bailey, C. A.,Relation of relapses in typhoid to duration ofchloramphenicol therapy. J. A. M. A., 1949, 141,129.

6. Smadel, J. E., Traub, R., Ley, H. L., Jr., Philip,C. B., Woodward, T. E., and Lewthwaite, R.,Chloramphenicol (Chloromycetin) in the chemo-prophylaxis of scrub typhus (tsutsugamushi dis-ease). II. Results with volunteers exposed inhyperendemic areas of scrub typhus. Am. J. Hyg.,1949, 50, 75.

7. Smadel, J. E., Leon, A. P., Ley, H. L., Jr., andVarela, G., Chloromycetin in the treatment of pa-tients with typhus fever. Proc. Soc. Exper. Biol.& Med., 1948, 68, 12.

8. Smadel, J. E., Woodward, T. E., Ley, H. L., Jr.,Philip, C. B., Traub, R., Lewthwaite, R., andSavoor, S. R., Chloromycetin in the treatment ofscrub typhus. Science, 1948, 108, 160.

9. Smadel, J. E., Woodward, T. E., Ley, H. L., Jr., andLewthwaite, R., Chloramphenicol (Chloromycetin)in the treatment of tsutsugamushi disease (scrubtyphus). J. Clin. Invest., 1949, 28, 1196.

10. Schoenbach, E. B., Bryer, M. S., and Long, P. H.,The clinical use of polymyxin. Ann. N. Y. Acad.Sci., 1949, 51, 987.

11. Bliss, E. A., Chandler, C. A., and Schoenbach, E. B.,In vitro studies of polymyxin. Ann. N. Y. Acad.Sci., 1949, 51, 944.

12. Green, R., An epidemic of typhoid fever, in: AnnualReport of the Institute for Medical Research for1939, published by Federated Malay States Govern-ment Press, 1940, p. 25.

13. Stuart, B. M., and Pullen, R. L., Typhoid; clinicalanalysis of 360 cases. Arch. Int. Med., 1946, 78,629.

14. McCrae, T., The symptoms of typhoid fever, in:Osler, W., and McCrae, T., Modern Medicine,Vol. II, Infectious Diseases. Lea Brothers & Co.,Philadelphia, 1907, Chapter IV, p. 104.

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