AN EVALUATION OF CHLORAMPHENICOL THERAPY IN
TYPHOID FEVER IN CHILDREN
By ABRAHAM FRIEDMAN, M.D.
Haifa, israel
28
T
HF: NUMBER of reports in the worldmedical literature on the treatment of
typhoid and paratyphoid fever with
chlo-ramphenicol has been accumulating rapidly
ever since the first report of Woodward
et al.’ appeared on this subject in 1948.
However, the number of such reports
deal-ing exclusively with children is relatively
small, and in the American literature, in
particular, most reports on the subject deal with a rather small number of cases.
The author believes that the present
re-port should be of interest, dealing as it does with 122 cases of typhoid fever in children treated with chloramphenicol and observed by the same persons.
vIATERIAL AND METHODS
The 122 cases of typhoid which serve as
the basis of the present report were treated
in the Pediatric Departments A and B of this hospital from the end of 1949-when chloram-phenicol first became available in the hospital -to the end of 1952.
During this same period, 122 other children with typhoid were treated at the hospital with-out chloramphenicol. Although equal in num-ber to the treated group these cannot be used
as a control series since the selection of the
2 groups was not carried out on a random
basis, with a view to establishing 2 statistically
comparable groups. Selection was based rather on the availability of the drug and the severity
of the condition, and it was pure coincidence that the number turned out to be the same in
the 2 groups. No attempt will therefore be
made to draw statistical conclusions as to the effectiveness of chloramphenicol therapy from the results in these 2 groups. However, com-parisons will be made occasionally.
From the Department of Pediatrics B, Rambam
Government Hospital, Haifa, Israel.
(Received for publication July 15, 1953.)
Panatyphoid fevers were not included in the report because the number of such cases treated with chloramphenicol was comparatively small.
The diagnosis, suggested clinically, was defi-nitely established in each case by laboratory examinations. Most cases had their diagnosis confirmed bacteniologically, the others only serologically. Table 1 shows the incidence of
diagnostic signs, physical as well as bacterio-logic and serologic.
Chloramphenicol was administered most
commonly in a dosage of 50 mg./kg./day dur-ing the initial febnile period. Usually this dos-age was reduced to about 50% after the tem-perature returned to normal. The total daily dose was divided into 3, 4 or 6 equal parts,
and administered at intervals of 8, 6 or 4
hours, respectively, depending on convenience in each individual case. Chloramphenicol was administered usually for about 9 to 10 days, which meant that it was continued for vari-ous lengths of time after the temperature
re-turned to normal. The total dose most
com-monly administered was 500 to 600 mg./kg.
No initial “priming” dose or “loading” dose
TABLE 1
INCIDENCE OF l)IAGN05TIc SIGNS IN
I2 TREATED CASES
No. of cases
Per-centage
A. Physical diagnosis
a. Continuous pyrexia above
39#{176}C. 117 96
h. Coated tongue 94 77
c. Enlarged spleen 83 68
d. Enlarged liver 71 58
e. Rose spots 36 30
B. Bacteriologic diagnosis
a. Positive blood cultures 53 43
b. Positive stool cultures 38 31
c. Positive urine cultures 8 7
C. Serologic diagnosis
TABLE ‘2
FIIEQUENCY OF VARIOUS DURATIONS OF
CIILORAMPHENICOL THERAPY
,
lotal . duration of
therapy . (in days)
,
No. of
cases
l)uration of -therapy (in days) after temperature
. normalization
.
No. of
cases
3 2 ‘3 3
4 4 4 7
5 5 5 21
6 6 6 10
7 9 7 11
8 13 8 22
9 25 9 19
10 25 10 7
11 12 11 2
12 8 12 1
13 4 13 22
14 4 14 1
15 2
-16 ‘3 106*
122
* In the remaining 16 cases chloramphenicol therapy
was terminated, for one reason or another, before
tent-perature normalization.
was ever employed in any of the cases. Table 2 shows the frequency of the various durations of chloramphenicol therapy.
CLINICAL EFFECTS
Excellent results have been reported in the
treatment of typhoid with chioramphenicol.
Improvement in general condition occurs
shortly after starting therapy, and within a
few days the temperature returns to normal.
Complications as well as mortality, although
not entirely eliminated, are nevertheless
re-duced in frequency. The main shortcoming,
pointed out by practically everyone, is the frequency of relapses after such therapy.
The author would like to record the
ob-servations on these subjects, based on this
series of cases.
Temperature: The effect of chloramphenicol
therapy on the pyrexia of typhoid has been
described variously by different authors. Most
reports give 84 to 96 hr. of therapy (3% to 4
days) as the period most commonly required
for the temperature to return to normal.16
Others set a longer time limit, viz.: 5 days,7
6 days,8 7 1 or 10 days.”2 Some cases
are recorded in the literature, which, despite
adequate and prolonged chloramphenicol
ther-apy, continued to run a temperature for 1 1 days,
12 days and 20 days” and one continued for as
long as several “
In 109 of the 122 cases treated by the
au-thor the temperature returned to normal, by
lysis, within 1 to 9 days from beginning chloramphenicol therapy. As regards the other 13 cases, 2 terminated fatally without their
temperature ever returning to normal; in 3
the drug had to be stopped before temperature normalization because of toxic side effects;
in 6 the drug was stopped between the 8th and the 10th day because of lack of response; in
one the temperature returned to normal within 1 1 days and in another it remained slightly elevated in spite of 14 days continuous chlo-ramphenicol therapy and returned to normal
only 3 days after cessation of the therapy.
As regards the rapidity with which the 109
other cases became fever-free : as many as 11 cases (9%) became fever-free within the 1st 2 days; as few as 52 cases (42.5%) became
fever-free within the 1st 4 days of therapy; whereas in 16 cases (13%) the temperature re-turned to normal only after a period of 6 to 9 days of continous therapy. It is thus obvious that the response is not always as dramatic
as one might be led to believe from the litera-ture.
The rapidity with which the temperature returned to normal was found by the author,
as by everybody else. to be unrelated to the
age and sex of the patients. Nor did the
severity of the disease influence the course of
the temperature response, which finding,
how-ever, differs from those of some authors.”
Neither was the course of the temperature re-sponse influenced by the stage of the disease at which chloramphenicol therapy was started. Relapses: The problem of relapse prevention has occupied the attention of workers in this field right from the beginning. Smadel et al.’6
reported a close relationship existing between
relapse rate and duration of chloramphenicol
therapy and suggested that in order to prevent
relapses adequate dosage should be given for
more than 8 days but that no advantage was to
be expected by prolonging treatment beyond
14 days. Similar opinions were expressed by
Of the 122 patients treated by the author 16 relapsed, of whom 15 were still in the ward at the time of the relapse, while one was
re-admitted a few days after discharge. This gives
a relapse rate of 13%, as compared with the relapse rates reported in the literature,
amount-ing mostly to between 10% and 28%’ ‘#{176}‘ ‘‘
and even up to 46%.24
Considering the age distribution of the cases relapsed, it was found that out of the 42 pa-tients below 4 yr. of age 9 or 21.5% relapsed,
whereas out of the 80 patients above 4 yr. of age, only 7 or 8.75% relapsed. This would in-dicate a greater tendency to relapses in the age group below 4 yr. No such difference was re-ported in the literature.
The author has seen no late relapses, that is, relapses occurring 18 to 35 days after cessa-tioti of chloramphenicol therapy, as seen by
11 All the relapses observed occurred
during the 18 days following the end of
chlo-ramphenicol therapy with the exception of one
that occurred in a patient still getting adequate
chloramphenicol therapy. Of the remaining 15
relapses, 3 occurred during the first week after
the end of therapy, 7 occurred during the
sec-ond week and 5 during the third week. Eleven
of the 16 relapses occurred between the 11th and 18th day, that is, in the second decade after the end of the chloramphenicol therapy. These findings would clearly indicate that the patients should not be discharged from hospital before 18 days following the termination of
chloram-phenicol therapy and should in any case
re-main under supervision for about 3 wk. after
the end of therapy.
The relapse rate was found to be closely
related to the stage of the disease at which
chloramphenicol therapy was started. Only 5%
relapsed when treatment was started during
the third week of illness, 14% relapsed when treatment was started during the second week, whereas 40% relapsed when therapy was started during the first week of illness. This finding is
in disagreement with the finding of some
au-,526 but is in complete accord with present concepts on the effect of
chlorampheni-col upon the development of immunity, in
which such therapy is believed to interfere
con-siderably, as suggested by some.’7 At first
glance these findings would indicate, as al-ready suggested,’8 that from the point of view
of relapse prevention, it would be preferable
not to start chloramphenicol therapy during the
first week of illness, and to postpone it to the
second week. However, as will be seen later,
this is not the case.
The relapse rate was found unrelated to
the daily dose of chloramphenicol/kg. body weight, so long as such daily dose exceeded
a minimum of about 40 to 60 mg/kg. Thus
the relapse rate was about the same when the patient got between 40 to 60 mg./kg
chloram-phenicol a day as when a higher dose was
ad-ministered. It would appear, in fact, that the
prime consideration in determining minimum
adequate daily dosage should be the response
of the fever, and not the prevention of relapse.
So long as the fever responds to a certain dosage such dosage ought to be considered
adequate, because it cannot be hoped to
de-crease the relapse rate by increasing that
dos-age.
The relapse rate was also found unrelated
to the total dosage of chloramphenicol in a
course of therapy/kg. body weight. Thus, for
example, the relapse rate was just as large on
a total dose of 800 to 1000 mg./kg. as on a
total dose of 200 to 400 mg/kg.
As regards the duration of treatment, it was
found that the relapse rate was completely
un-i-elated either to the total duration of
chloram-phenicol therapy, or to the duration after
temperature normalisation. No decrease in
re-lapse rate was observed on prolonging the
total period of chloramphenicol therapy, and
the relapse rate was the same whether chlo-ramphenicol therapy was stopped immediately after normalisation of temperature or whether it was continued for 2, 4, 6 or 8 days longer.
The author’s findings stand in distinct
con-trast to those of others. Whereas the relapse
rate of cases treated up to 8 days was only 7.7%
(3 out of 39 cases), that of cases treated for more than 8 days is 15.6% (13 out of 83 cases).
On the basis of this finding, that the relapse rate is not affected by the prolongation of
chloramphenicol therapy, it appears justified
to stop chloramphenicol therapy as soon as the
temperature remains normal for a day or 2.
At present the cases in this Department are
being treated according to this scheme and a
further report will be published later.
A consideration of the relapse rate in cases
of typhoid not treated with chloramphenicol
is also of interest in this connection. Although
the “nontreated” group is not statistically
of the 122 “nontreated” patients, 20 relapsed. This gives for the “nontreated” group a relapse
rate of 16% which is not dissimilar to the re-lapse rate of 13% in the “treated” group. The
similarity of these figures strengthens the
be-lief that chloramphenicol therapy has no effect
upon the incidence of relapses.
Complications : The classical complications
of typhoid were singularly few in the series.
There was only one case of intestinal per-foration in the “treated” group and the perfo-ration occurred before reaching the hospital, on
the 15th day of illness and in spite of 5 days
of chloramphenicol therapy. He was operated
on and eventually recovered. In contrast to this
there were 2 cases of intestinal perforation in
the “nontreated” group and both eventually
died.
There was only one case of intestinal hemor-rhage in the “treated” group and this
termi-nated fatally. The bleeding, however, was due
to severe thrombocytopenia and not to the
rupture of a blood vessel of a typhoid ulcer.
This was proved by autopsy. There was also
one other case of thrombocytopenia in the
“treated” group with eventual recovery. In the
“nontreated” group there were no cases of
in-testinal hemorrhage but there was one of
thrombocytopenia which terminated fatally.
There was one case of parotitis in the
“treated” group, and none in the “nontreated”
group.
Typhoid meningitis occurred once in the
“treated” group. This child was admitted on
his 8th day of illness with a meningitis which
was shown within a few days to be a
complica-tion of typhoid fever. The child eventually
re-covered.
Encephalopathy due to typhoid occurred
once in each of the 2 groups and both cases
recovered.
Myocarditis was also present, one case iii
each group. Both patients recovered.
There were 3 cases of hepatitis and 2 cases
of acute nephritis in the “nontreated” group.
In the “treated” group there was none.
By far the most common complication in the
series was acute hemolysis with
hemoglo-binuria, which occurred in 11 cases. In most
of these hemolysis was present on admission
before chloramphenicol therapy was started so that the drug cannot be incriminated. Since these cases serve as basis for another report they will not be dealt with any further here.
From the foregoing it appears that although
complications occurred a beneficial effect due to chloramphenicol is nevertheless discernible. This conclusion should be regarded as all the more valid since, as already mentioned, only
the more severe cases were treated with
chloramphenicol, thus making for a higher ex-pectancy of complications.
Table 3 shows the relationship in the
“treated” group between the day of appearance
of complications and beginning of
chloramphe-nicol therapy. It shows that starting
chlo-ramphenicol therapy in the second week of
illness or later does not prevent complications.
The author’s observations confirm the ex-perience of others that chloramphenicol does not prevent complications with certainty, but
does reduce their frequency, especially if
started early enough, namely, during the first
week of illness.
Mortality: It is generally agreed that
chlo-ramphenicol markedly reduces the mortality
TABLE 3
COMPLICATIONS
Case No. Complication .
I)ay of illness
on which . chioramphenicol
was started
Day of illness on which
. .
complication
occurred
Outcome
Ii Thrombocytopenia 9 16 reCovere(l
37 Thrombocytopenia 10 12 died
67 Parotitis 8 12 recovere(l
69 Encephalopathy ? recovered
71 Myocarditis P 8 recovered
127 Meningitis 18 8 recovered
37
Z.8.
10 F
+ + + +
10 12 8 9
40.2#{176}
75 mg.
10 days Intestinal
henior-rhage, severe di-arrhea
Thrombopenia; hemorrhages, internal and ex-ternal
40.4#{176} 50 lug.
11days Severe
diar-rhot
40.4#{176} 46 111g.
8 (lays Severe
diar-rhea,
he-molysis Ilypertoxic
form of ty-phoid
41 50 lug.
4 days Severe
diar-rhea
In none of the 4 patients in the “treated”
TABLE 4
SUMMARY OF FATAL CASES
Case No.
Initials Age (yr.)
Sex
Day of illness on admission Total hospital stay
I)iagnosis confirmed bacteriologically 1)iagnosis confirmed by autopsy
1)ay of illness on which chloramphenicol was
started
‘retuperature at commencement of therapy
Chloramphenicol daily (lose/kg. 1)uration of chlorampheiiicol therapy Special manifestations
Cause of death
88
XE.
12
F
8 10
12 10
+
102 120
8.8. B.O.
7 6
M M
4 6
15 7
+ +
Low-salt ilypertoxic
syndrome form of
ty-phoid
rate. Table 4 summarises the important data
of the 4 fatal cases that occurred in the
treated group. Two of them presented a hyper-toxic form of the disease which ended fatally
in spite of what appeared to be adequate
chioramphenicol therapy for 8 and 4 days, re-spectively. One patient died of a hematologic
o m p lie at i o n-thrombocytopenia-most prob-ably due to the disease itself although one can-not exclude the possibility of the complication being due to the therapy. The fourth died pos-sibly as a result of chloramphenicol therapy,
and death might have been avoided in this
case had the chloramphenicol been stopped
earlier.
In spite of the fact that the 2 groups are not statistically the same it is nevertheless interest-ing to compare the mortality of the
“non-treated” group with that of the “treated”
group. In the “nontreated” group were 5 fatal cases as compared to the 4 in the “treated” group. The causes of death of these 5 cases were: intestinal perforation in 2,
thrombocyto-penia in 1, and the hypertoxic form of the
disease in 2.
It should be remembered, however, that the treated cases were of a severer type. It there-fore seems justified to conclude that although chioramphenicol does not entirely ‘eliminate the mortality of typhoid, it does reduce its rate.
group who eventually died was ehlorampheni-col therapy started during the first week of the illness. The numbers are too small to permit the drawing of definite conclusions, but they would seem to suggest that by starting chlo-ramphenicol therapy earlier, namely, during the first week, the rate may perhaps be reduced
further.
The two cases in the treated group with the
hypertoxic form of the disease which ended
fatally deserve special mention. They both terminated fatally in spite of adequate chlo-ramphenicol therapy for 8 and 4 days, respec-tively. It appears, however, that these 2 cases
may perhaps have died not in spite of
chloramphenicol therapy, but rather as a re-sult of such therapy. In such severely toxic
cases the drug has been found to hasten
death.’9
ToxIc SIDE-EFFECTS
Few toxic side-effects were seen in these pa-tients, but those that have been observed may be worth considering in detail.
Gastrointestinal Disturbances: Chloramphe-nicol has been repeatedly reported to cause gastrointestinal disturbances such as nausea, vomiting and diarrhea.#{176}’ 3’ The frequency and
some-CHLORAMPHENICOL THERAPY IN TYPHOID FEVER times and cause serious secondary disturbances
in the serum electrolytes and acid-base
equilib-rium; and the resulting acidosis, hypokaliemia,
hypochloremia and uremia may constitute a
real hazard to the life of the patient. Thus the death of 5 children has been reported as a
re-sult of severe gastrointestinal disturbances oc-earring in 17 out of 53 children treated with chloramphenicol, the other 12 recovering Un-eventfully on discontinuing the drug.3’ The
low-salt syndrome has also been reported to
have resulted from diarrhea caused by inges-tion of chloramphenicol in 4 patients.33
Among the author’s patients 44 cases (36%) had vomiting, and/or diarrhea of a variable de-gree of severity. Most of these were mild in nature not necessitating any special measures. In 14 cases, however, the disturbances in blood electrolytes were severe enough to require treatment by intravenous fluid and electrolyte therapy.
These severe electrolyte disturbances appear to have resulted directly in the death of one patient and to have contributed partially to the fatal outcome in 2 more of the fatal cases.
Case Report 1: S. S., male, aged 7 yr., was admitted on account of a febrile illness of 4 days’ duration. Positive stool cultures con-firmed the diagnosis of typhoid. Chloramphe-nicol therapy was started on the 4th hospital day, and the temperature returned to normal
on the 11th day. On the 13th hospital day,
that is, on the 10th day of chioramphenicol
therapy, he suddenly started vomiting and
later diarrhea also appeared. The vomiting and
diarrhea grew in severity. His temperature rose to 38#{176}C.His alkali-reserve dropped to 22 vol. % of CO2 and the serum potassium to 10.6 mg./100 cc. In spite of intensive intravenous
fluid and electrolyte therapy the child died on his 15th hospital day. Autopsy did not re-veal any significant finding.
This hazard of severe and sometimes fatal gastrointestinal disturbances is, in the author’s opinion, another point in favour of the early
cessation of chloramphenicol therapy, namely, as soon as the temperature has definitely re-turned to normal.
Intestinal Perforation-like Syndrome: This syndrome is not the result of the toxicity of chloramphenicol proper since it has never been
observed during chloramphenicol therapy of
other diseases. The syndrome is the result of a
fulminant endotoxin intoxication caused by
massive bacterial disintegration and liberation
of large amounts of endotoxin, which in turn is caused by the destructive action of chloram-phenicol on the Salmonellae.34 This syndrome has been observed, although only rarely, when severe cases of typhoid were treated with high doses of chloramphenicol. It has been observed
more frequently when severe eases were
treated with priming doses.” In such
cases death sometimes resulted during the first few days of chloramphenicol treatment.
The clinical picture presented by such pa-tients resembles an acute abdominal catastro-phe such as intestinal perforation accompanied by severe shock and pronounced cerebral
symp-toms including delirium. The syndrome is
actually not unlike the clinical picture of un-treated patients dying early in the disease.
The author has never observed the complete syndrome in any of the cases he treated,
pos-sibly because he has not employed priming
doses. He has, however, seen one such case that was admitted to the Department after 4 days
of chloramphenicol therapy outside. The
pa-tient presented, on admission, the classical clinical picture of perforation, was operated on
immediately with no perforation being
dis-covered, and eventually recovered. Whether this patient received a priming dose before admission was impossible to ascertain.
The consensus of opinion at present is that “priming” doses or “loading” doses are not to
be employed under any circumstances. They
are valueless in obtaining a quicker reduction in temperature or in preventing recurrences, and in severe cases run the additional hazard of intestinal perforation-like syndrome. The re-verse has been suggested, namely, that in
severe cases of typhoid fever the initial doses
should really be smaller than standard and
then increased gradually.3’ The idea behind this suggestion is that when the body is already
flooded with large amounts of bacterial endo-toxin, any additional massive destruction of bacteria and consequent liberation of endotoxin
cannot but have a detrimental effect on the
patient.
The course of some of the fatal cases leads the author to subscribe wholeheartedly to this view.
HEMATOLOGIC CHANGES
The depressing effect that chloramphenicol may exert on the bone marrow with consequent changes in the peripheral blood picture has
of chloramphenicol therapy. Thus a definite and occasionally considerable drop in total leucocyte and absolute neutrophil count
has been observed in a large proportion of cases by various authors.” #{176}“ Severe
anemia due to an erythroid maturation arrest
in the bone marrow has also been observed.42 More recently numerous cases of fatal aplastic
anemia due to chloramphenicol therapy have
been reported in the literature.45”
The author has not seen any case of aplastic anemia due to chloramphenicol, whether given for typhoid or for any other condition in this
Department or outside. He has, however,
ob-served in the blood picture of typhoid patients
treated with chioramphenicol, that both
hemoglobin and erythrocytes, as well as leuc-ocytes tended in the majority of cases to de-crease upon administering the drug, while all 3 tended in the majority of cases to increase again after the cessation of such therapy. These
tendencies were well marked in the case of
hemoglobin and erythrocytes, but not nearly so much in the case of leucocytes. Upon com-paring the results of examinations before and after the therapy, the values appeared on the
whole to remain unaffected in each of the
three constituents.
No thrombocyte counts were performed
routinely or systematically and therefore noth-ing can be said concerning the effect of
chlo-ramphenicol therapy on thrombocytes. There
were, however, 2 cases of severe
thrombocyto-penia during chloramphenicol therapy, one of
which was terminated fatally while the other patient recovered. The report of the case that terminated fatally follows.
Case Report 2: Z. S., female, aged 10 yr., was admitted after 8 days of high fever. The diagnosis of typhoid was established by
posi-tive stool culture, and chloramphenicol was
started on the day following admission. Within 3 days the temperature returned to normal but
at the same time bleeding appeared into the
skin, and from the mouth and nose. The plate-let count showed 6000 only. On the ninth
hos-pital day the patient had melena and on the
11th she had a cerebral hemorrhage. On the
12th day the patient died in spite of repeated blood transfusions. Autopsy showed: typhoid ulcers of the ileum and colon, purpura of the gastrointestinal tract, epidural hemorrhage in
the right posterior cranial fossa, slight subarach-noid hemorrhage in the right hemisphere and aspiration of blood into the lung.
There are some interesting questions con-cerning these blood changes : are they due to the chloramphenicol therapy or are they due to the disease itself? On the one hand it is well-known that the typhoid infection in itself is capable of exerting a depressing effect on the
various elements of the bone marrow, with
consequent hematologic changes. On the
other hand similar blood changes were
ob-served not only in the chloramphenicol
treat-ment of typhoid but also in the therapy of
other conditions with chloramphenicol.’ Un-fortunately no systematic blood examinations
were carried out in the “nontreated” group
upon which adequate comparisons could be
made. In the absence of further data, there-fore, it would be unjustified to incriminate
chloramphenicol in the blood changes
ob-served.
SUMMARY AND CoNc’usIoNs
In the light of the author’s experience
with chioramphenicol therapy of typhoid
fever in 122 children, the following
con-clusions appear to be valid:
I. Prolonged chloramphenicol therapy is
unnecessary, undesirable and sometimes
even harmful. The course of therapy should
be limited to the period of fever and
con-tinued for just one or two days after the
temperature has become normal. This view
is based upon the following considerations:
A. The finding that relapses were just
as frequent on longer courses as on shorter
ones.
B. Prolonged courses of chloramphenicol
expose the patient more intensely to the
hazard of severe and sometimes fatal gastro-intestinal disturbances.
C. Prolonged courses may expose the
pa-tient more seriously to severe and
some-times fatal bone marrow depressions.
D. This conclusion is of special
impor-tance where the availability of the drug
and the expense involved are factors to be
taken carefully into consideration.
II. Except in hypertoxic forms of typhoid,
chloramphenicol therapy should be
insti-tuted as early as possible and should not
be delayed for any reason. This view is
chiorampheni-col is started early, during the first week of illness, the relapse rate is higher in
corn-parison to the relapse rate when therapy is
started later.
B. On the other hand, complications and
mortality rates are considerably higher
when therapy is postponed to the second
week or later.
C. Weighing these two hazards against
each other, it appears that the latter
out-weighs the former and that it would
cer-tainly be wiser to take the risk of a relapse than of a severe complication or a fatality
and therefore therapy should be started in
every case as early as diagnostic
considera-tions permit.
III. In hypertoxic forms of typhoid,
chloramphenicol therapy should be
with-held at the beginning, trying supportive therapy, including blood transfusions. Later
chloramphenicol may be started but with
small doses only, perhaps 12.5 mg./kg./day. If no deterioration in the general condition
takes place it may then be increased, say
3 to 4 days later, to 25 mg./kg./day and
3 to 4 days later again, to 50 mg./kg./day,
provided the general condition of the
pa-tient does not deteriorate.
IV. If in spite of special care in institut-ing chloramphenicol therapy in hypertoxic forms of typhoid an intestinal perforation-like syndrome develops, chloramphenicol
therapy should be stopped immediately and
general supportive measures instituted as
soon as possible. The same applies when
the intestinal perforation-like syndrome de-velops suddenly in a patient not previously severely toxic.
V. Gastrointestinal disturbances during
chloramphenicol therapy should be taken
seriously, and any degree of severity in such disturbances warrants the immediate cessa-tion of chioramphenicol with the immediate institution of corrective measures to combat
the electrolyte disturbances which might
have resulted.
ACKNOWLEDGMENTS
The author wishes to thank Dr. W. Falk, head of this Department, for his encourage-ment, criticism and advice, in the
prepara-tion of this paper; Dr.
J.
Barhai, head ofDepartment of Pediatrics A of this hospital,
for his kind permission to make use of the
case material of his Department; Dr. A.
Wilder, of this Department, for valuable
assistance in connection with this paper.
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Pediat. 41:340, 1952.SPANISH ABSTRACT
Terap#{233}utica con Cloranfenicol de Ia
Fiebre Tifoidea
El autor presenta los resultados observados en 122 ni#{241}oscon fiebre tifoidea tratados con
cloromicentina y comparados con otro grupo de
122 ni#{241}ostambi#{233}n con fiebre tifoidea que no recibieron cloromicetina; ambas series no son
propiamente comparables ya que Ia selecci#{243}nse bas#{243}en Ia facilidad de obtener Ia droga y en Ia
severidad de los cuadros.
El diagnOstico se hizo tanto clInicamente
como con pruebas de laboratorio.
El cloranfenicol se administrO a raz6n de 50
mgrs. por kilo de peso y por dia durante el
perIodo febril inicial; Ia dosis se redujo a Ia
mitad al observarse temperatura normal; la
dosis diana se dividi#{243}en 3, 4 y 6 partes iguales durante un perlodo de 9 a 10 dIas, alcanzando una dosis total generalmente comprendida entre
500 y 600 gmrs. por kilo. Los resultados clinicos fueron en general favorables en los t#{233}rminos que m#{225}sadelante se exponen. La mejorla del
estado general se present#{243} pocos dIas despu#{233}s de iniciada la terap#{233}utica; las complicaciones y la mortalidad se redujeron en frecuencia pero
sin eliminarse por completo las recaldas. El autor hace consideraciones sobre los efectos
en las temperaturas, las recaidas, las
complica-ciones, la mortalidad, los efectos t#{243}xicosde la
droga y los cambios hematOlogicos, y resume sus conclusiones de Ia siguiente manera:
La terap#{233}utica prolongada con cloranfenicol
es innecesaria y en ocasiones danina por lo que debe concretarse al perlodo febril y suspenderse
uno o dos dIas despu#{233}s de que se ha normali-zado la temperatura; esta aseveraci#{243}n se basa
en las siguientes consideraciones : recaldas tan frecuentes en cursos largos como en cursos
cortos de terap#{233}utica, mayor frecuencia de trastornos gastrointestinales con perlodos m#{225}s prolongados de terap#{233}utica, mayor probabilidad de lesiones medulares #{243}seasa veces fatales y por #{225}ltimoel aspecto pr#{225}ctico de facilidad de
obtenci#{243}n y costo de la droga.
La terap#{233}utica con cloromicetina en Ia tifoidea debe iniciarse tan pronto como sea posible excepto en formas hipert#{243}xicas, de acuerdo con las consideraciones siguientes : a]
darse tempranamente Ia droga, es decir, durante Ia primera semana de Ia enfermedad, Ia frecuencia de las recaIdas es mayor que cuando se inicia tardlamente Ia terap#{233}utica, en
con-traste con la mayor frecuencia de complica-ciones y mortalidad cuando Ia terap#{233}utica se
inicia en Ia segunda semana o m#{225}starde;
analizando estos dos peligros el autor prefiere el
primero al segundo y por lo tanto que la tera-p#{233}uticacon cloromicetina se inicia a Ia mayor brevedad.
En las formas hipert#{243}xicas tifoldicas reco-mienda que Ia terap#{233}utica con cloranfenicol no
realice inmediatamente, y mientras tanto el
enfermo se mantenga con terap#{233}utica de sost#{233}n incluyendo transfusiones sangulneas; iniciar la administraci#{243}n de la droga con dosis bajas, como de 12.5 miligramos por kilo y por dia y aumentarlas 3 6 4 dIas despu#{233}s a 25 miligramos
y m#{225}starde a 50 miligramos por kilo y por dia,
siempre que no se venga abajo el estado general
del paciente.
Si a pesar de estos cuidados en las formas hipert#{243}xicas de Ia tifoidea se presenta un
cuadro de vientre agudo debe suspenderse Ia
terap#{233}utica inmediata y mantener al paciente solo con medidas generales de sost#{233}n.Esta con-ducta Ia sugiere el autor tambi#{233}n cuando se
presente el cuadro de vientre agudo en
pacientes que no est#{233}npropiamente en con-diciones t#{243}xicasseveras.
Los trastornos gastro intestinales que se
pre-sentan durante Ia terap#{233}utica con cloromicetina
han de aceptarse como hechos serios que
indican suspension de la droga e instalaciOn inmediata de medidas correctivas para combatir los desequilibrios electroliticos, tan pronto como
Ia gravedad de los trastornos gastro-intestinales
aumente en intensidad.
Julian D. Levinson Research Foundation,
