Journal of Infection (I982) 5, I39-I5O

T y p h o i d f e v e r in a S w e d i s h h o s p i t a l for i n f e c t i o u s d i s e a s e s - a 2o -year r e v i e w

Bo S v e n u n g s s o n

Department of Infectious Diseases, Roslagstull Hospital, Stockholm, Sweden

S u m m a r y

Sixty-one patients with typhoid fever were treated at the Roslagstull Hospital, Stockholm, Sweden over the zo-year period 1961-1980. All but three patients probably contracted their infection abroad, mainly in the Mediterranean area of Europe, and for half of the patients the stay abroad was only one to three weeks. At least 2o per cent of the patients had been adequately vaccinated against typhoid fever before departure. The onset of disease was more often abrupt than insidious, with fever reaching a maximum of at least 39 °C in all patients. Diarrhoea was the next most common symptom, found in 75 per cent and was in 48 per cent an initial symptom besides fever. Relative bradycardia and rose spots were the most common physical findings, seen in 7o per cent and 46 per cent respectively. Blood cultures were positive for Salmonella typhi in 85 per cent. Among nine patients with negative blood cultures three were positive on bone-marrow culture and another three on blood clot culture. Complications were infrequent. Myocarditis was suspected in 15 patients, gastroint- estinal hemorrhage occurred in two, septic shock in one and psychotic reaction in one patient. All patients recovered fully. Most were treated with chloramphenicol (group A), t r imethoprim-sulphamethoxazole (group B), ampicillin alone or combined with pivmecillinam (group C). The average number of days until defervescence was 4'9, 3'6 and 5"9 for group A, B and C, respectively. Relapses were seen in I5 per cent, most of them in patients treated with chloramphenicol. On the whole the clinical course of the disease was more benign than that usually seen in the pre-antibiotic era, and classical symptoms and signs were often lacking.

Introduction

T y p h o i d fever is n o w a ra re disease in S w e d e n , b u t increas ing t o u r i s m to e n d e m i c areas makes it still an i m p o r t a n t one. T h e r e is m u c h l i t e ra tu re on the clinical and ep idemio log ica l aspects o f t y p h o i d fever b u t on ly ra re ly f r o m the Scand inav i an coun t r i e s . T h e fo l lowing rev iew inc ludes 61 consecu t ive pa t ien ts t r ea t ed at a hospi ta l for infec t ious diseases in S t o c k h o l m ove r the z o - y e a r pe r i od I 9 6 I - I 9 8 0 .

Patients and methods

T h e pa t i en t s were a d m i t t e d to the Roslags tu l l Hosp i t a l f r o m S t o c k h o l m and s u r r o u n d i n g dis t r ic ts d u r i n g the years I 9 6 I - I 9 8 o . T h e diagnosis was based on clinical p i c tu r e and pos i t ive cu l tu re for Salmonella ryphi f r o m e i the r b lood , b o n e m a r r o w or faeces. R e c o r d s o f the 61 pa t ien t s were s tud ied r e t ro spec t ive ly wi th r ega rd to r e cen t t rave l l ing ab road , vacc ina t ion , clinical s y m p t o m s and signs, l abo ra to ry inves t iga t ions , t r e a t m e n t , and clinical course o f the disease. D u r i n g the first I o - y e a r p e r i o d 3o pa t ien ts were t r ea t ed at the hosp i ta l and 31 pa t ien t s d u r i n g the second.

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14o B. SVENUNGSSON

Table I Age and sex distribution in 61 patients with typhoid fever treated at the Roslagstull Hospital, Stockholm, Sweden 1961-198o

Age (years) Male Female Total

0-- 5 2 2 4 6--10 3 I 4

11--20 3 5 8 21--30 8 12 20 31--40 5 2 7 41--5 ° 3 5 8 51--60 2 4 6 61-7o I 3 4

Subtotal 27 34 61

Another seven patients, who were positive for S. typhi in faeces, were excluded from the study. They were healthy carriers with a history of typhoid fever in the past.

Results Age and sex d i s tr ibut ion

Table I shows the age and sex distribution of the patients. Thir ty-three per cent were aged 21-3o years. The youngest patient was two years old, the oldest 69 years. There were 27 males and 34 females.

Probable area o f or ig in o f the disease

Most of the patients contracted their infection in Europe (52 per cent), mainly in the Mediterranean area (39 per cent) (Table II). Half of the patients had been on holiday abroad for only one to three weeks. The longest time from the day of return home to onset of disease was 38 days. The highest incidence was in the months of July to October during which 40 (66 per cent) of the patients were admitted, with August and October being the peak months. Three patients had not been abroad during the year before the disease.

Subcutaneous vaccination against S. typhi had been performed in 12 of the 61 patients (2o per cent). Thirty-eight patients had not been vaccinated and in 18 patients information on vaccination was lacking. The vaccine used was a heat-inactivated TAB-vaccine, which in 1976 was replaced by a monovalent typhoid vaccine. 1,2

Clinical s y m p t o m s and signs

The symptoms and signs are summarised in Table III . Fever was always present and reached a maximum of at least 39 °C in all patients. The onset of fever was abrupt in 75 per cent. The remaining patients had a more insidious onset of the disease with temperature gradually rising over a few days.

Diarrhoea was found in 75 per cent of the patients and was, besides fever, an initial s3~mptom in 48 per cent of them. Less common symptoms were, in order of frequency, headache, abdominal pain, vomiting, myalgia, constipation and cough.

Typhoid fever in Sweden 141

T a b l e I I Area where S. t yph i was most probably contracted by 61 patients treated at the Roslagstull Hospital, Stockholm, Sweden, 1961-198o

Area No. of patients

Europe Excluding Mediterranean 8

area and Sweden Mediterranean area 24 Sweden 3

Africa 3 The Canary Islands 5 Middle East 9 Asia 5 Mexico 3 South America I

Total 61

T a b l e I I I Clinical symptoms and signs in 61 patients with typhoid fever, treated at the Roslagstull Hospital, Stockholm, Sweden, I 9 6 1 - 1 9 8 o

Symptoms and signs No. of patients (%)

Max temperature ~> 39 °C 6I (Ioo) /> 4 ° °C 44 (72)

Diarrhoea 46 (75) Headache 3I (51) Abdominal pain 24 (39) Vomiting 17 (28) Myalgia 14 (23) Constipation 8 (13) Cough 6 (io) Relative bradycardia 43 (70) Rose spots 28 (46 ) Exhaustion 23 (38) Coated tongue I2 (20) Hepatomegaly IO (I6) Splenomegaly 5 (8)

A m o n g phys ica l f indings re la t ive b r a d y c a r d i a (def ined as a pu lse ra te ~< IOO) was f o u n d in 7o pe r cent . T h e pu lse ra te in the febr i le state was ~< 80 in seven pa t ien t s (x I pe r cent) and <~ 9o in 22 pa t ien t s (36 pe r cent) . Rose spots were f o u n d in 46 pe r cent , pa lpab le l iver in I6 pe r cen t and pa lpab le sp leen in e ight pe r cent . E x h a u s t i o n was f o u n d in 38 pe r cent . Six pa t ien ts were s o m n o l e n t and m e n t a l l y dul l on admiss ion , one was i n t e r m i t t e n t l y comatose , and th ree had visual ha l luc ina t ions .

T h e p r e l i m i n a r y diagnosis on admiss ion was sa lmonel los is ( inc lud ing t y p h o i d and p a r a t y p h o i d ) in 32 pa t ien ts (52 pe r cent) . T h e m o s t c o m m o n di f ferent ia l d iagnosis c o n s i d e r e d was malar ia , fo l lowed by vi rus infec t ions inc lud ing

142 B. SVENUNGSSON

Table IV Results of culture in 61 patients with typhoid fever, treated at the Roslagstull Hospital, Stockholm, Sweden, 1961-198o

Culture No. of patients positive (%)

Blood 52/6I (85) Bone marrow I3/I4 (93) Blood clot I2/I2 (IOO) Faeces 32/6i (52) Urine 3/6I (5)

hepatitis, as well as meningitis, shigellosis, pneumonia, and septicaemia of other origin. Before admission to hospital, 23 patients (38 per cent) had been treated with antibiotics, mostly penicillin, on suspicion of other bacterial infections, and two patients had been operated on for suspected appendicitis.

Laboratory invest igat ions

The mean value for erythrocyte sedimentation rate (ESR) was 33 mm/hour (range 5-78), haemoglobin (Hb) I2.6 g/dl (range 8.2-i 7"0), and for white blood cell count (WBC) 6"3× Io9/1 (range 3"I-I3"2). Normal values for these measurements were i-2o mm/1 hour, 12"o-17-o g/dl, and 4"0-9"0 x io9/1, respectively. In seven patients (II per cent) WBC was ~< 4"0 × IO9/1 and in eight patients (I3 per cent) it was elevated. A shift to the left was found in 80 per cent. A slight elevation of the liver enzyme concentrations was seen in 75 per cent.

The electrocardiogram (ECG) showed non-specific changes in the S-T segment and T waves, suggestive of myocarditis, in I5 patients (25 per cent), and in two patients pneumonic infiltrations were seen on chest X-ray. X-ray of the abdomen was performed in 27 patients. An enlarged liver was seen in I3 patients (48 per cent) and an enlarged spleen in I6 (59 per cent).

On admission at least three blood cultures were performed on each patient, as well as cultures from faeces and urine. Cultures from bone-marrow were performed in I4 and from blood clot in I2 patients. The results are summarised in Table IV. Among the nine patients negative on blood culture three were positive on bone marrow and another three on blood clot culture. S. typhi was found in the faeces of 32 patients (52 per cent) and in urine in three (5 per cent).

In nine (I5 per cent) patients one or more other enteric pathogens were found, in order of frequency: Trichuris trichiura (six), Giardia intestinalis (three), Ascaris lumbricoides (three), Shigella (one), other Salmonella types (two), Ancylostoma duodenale (one) and Campylobacter (one). All but one of these nine patients had been outside of Europe.

T r e a t m e n t and cl inical course

Treatment was started with chloramphenicol, trimethoprim-sulphamethoxa- zole (T-S), ampicillin, or a combination of ampicillin and pivmecillinam (Table V and VI). Over the first io-year period chloramphenicol was most frequently used. The treatment was in most cases given intravenously until defervescence and thereafter orally. Chloramphenicol alone was used in 3I

Typhoid fever in Sweden I43

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patients (group A). The dose was 29-67 m g / k g / d a y (mean 48"4). T - S alone was given to I I patients (group B) with a dose of 320-480 mg t r imethopr im and I6OO--24oo mg sulphamethoxazole daily. Either ampicillin alone or a combinat ion of ampicillin and pivmecil l inam was used in seven patients (group C). The ampicillin dose was 6 3 - I 8 9 m g / k g / d a y (mean I I 8 " 4 ) . a n d the pivmecil l inam dose 21-43 m g / k g / d a y (mean 35"3). In I I of the remaining i2 patients (group D) the t rea tment was started with one or the other of the antibiotics ment ioned, bu t therapy was subsequent ly changed, usually because of slow response of tempera ture (Table VII) . One patient received no antibiotic treatment. H e became spontaneously afebrile in IO days. S. typhi was not cul tured from the blood bu t stool cultures were positive. In all patients the S. typhi strain isolated was sensitive to the antibiotic given, as de termined by the disc diffusion m e t h o d ?

The n u m b e r of days from onset of disease to start of t reatment, the n u m b e r of days from start of t reatment to defervescence, as well as the n u m b e r of drug complications, and relapses in the different t reatment groups are summarised in Tables VI and VII . The first afebrile day is defined as the first day on which the patient 's temperature d ropped below 37'6 °C to remain there for at least three days? A t reatment failure was considered to occur if a patient, after Io days of therapy, in addit ion to remaining febrile, had not improved clinically? Relapse is here defined as re turn of fever and isolation of the original salmonella type from the blood at least three days after that the patient first became asymptomat i c? The durat ion of t reatment was shortest in group A, 8-21 days (mean I 2.8). In the other three groups the mean values were 19'3, 19"9 and 2o.2, respectively. The numbers of days from start of t reatment until the first afebrile day were on an average 4'9, 3"6, 5"9 and 8.6 in group A, B, C and D respectively. Relapses were seen in 6 /3 I (I9 per cent) patients in group A and 3 / I I (27 per cent) in group D, whereas no relapses were seen in group B and C. O f all the 6I patients nine relapsed with bacteraemia. The relapses occurred 16-28 days (mean 2I'3) after defervescence and I I - I 9 days (mean I5"5) after s topping treatment. Another five patients had a second fever spike, bu t no bacteria were isolated from the blood. O f these five patients two were in group A, one in group B, one in group C, and one in group D.

Therapeut ic failure, as defined above, was not seen in t reatment groups A, B, and C. In group D three patients had fever more than IO days after start of t reatment. All three patients were first given T - S bu t the t reatment was changed to chloramphenicol after seven to nine days. Of these three patients two had a relapse (Table VI).

In group A two patients showed an unexplained leukopenia during t reatment and one patient in group D developed a haemolytic anaemia. N o side-effects of t rea tment could be found in group C and D.

As complications of the disease I5 patients (25 per cent) had E C G changes suggestive of myocardit is , two patients developed pneumonia , two had a gastrointestinal hemorrhage severe enough to require b lood transfusions, one had septic shock, one had a suspected septic cerebral embolism, and one developed a psychosis with mania and paranoid misconceptions. However , all patients recovered fully and no deaths occurred.

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Typhoid fever in Sweden I47

t reatment in 56 of the 6I patients. All patients negative for S. typhi on admission were also negative after treatment. O f 27 of the 32 patients with S. typhi in the faeces on admission five were also positive during treatment. The length of the carrier state, defined as the t ime from onset of disease to the last positive faecal culture, followed by five negative ones, was three to 2I I days ( m e a n 29 .8 ) . Fifty per cent of the patients were free from bacteria after two weeks.

D i s c u s s i o n

In Sweden, with a populat ion of approximately eight million, about 2000-4000 human cases of salmonellosis are repor ted every year. 6 Among them about two-thi rds are imported, most ly f rom Southern Europe. v As in other countries the serotypes most often isolated are S. typhirnuriurn and S. enteritidis. Enteric fever, caused by S. typhi, is u n c o m m o n and repor ted in about 10-20 cases. 6 Despi te increasing tour ism to endemic areas there have only been small variations in the numbers of annual cases during the last 20 years. 6,s This tendency seems to be similar in other European countries 9 but unlike the increasing t rend of travel-associated typhoid in the U. S.A. 10 Improved hygienic conditions in popular tourist resorts in some endemic areas may be the reason for the stable annual f requency of typhoid cases in Sweden. Over the period I96I - I98O, 290 cases of typhoid fever were repor ted in Sweden, 6 the 6I patients presented in this s tudy amount ing to about 2i per cent of the total.

All bu t three of the 6i patients probably contracted S. typhi abroad, mainly in the Medi ter ranean part of Europe. This reflects the high f requency of Swedish tourists to ,~hese areas rather than a high endemicity, v O f all patients only three had not been abroad during the year before onset of the disease. However , two of them had close relatives with known typhoid fever contracted in endemic areas and must be considered as secondary cases. The third patient had visited Lebanon one year earlier and may have been carrier since then. Thus , all patients had direct or indirect connect ion with foreign countries.

Mos t of the patients belonged to an age group in which travelling is common and high incidence of cases in late summer and early au tumn corresponds well to the seasonal habits of travelling abroad.

Informat ion on vaccination against typhoid fever was lacking in many patients bu t at least 2o per cent had been adequately vaccinated before the travel. The re are different opinions whether travellers to all endemic areas should be vaccinated or only such that will visit countries with an especially high risk of infection.9,11 Since no vaccine available gives complete protect ion 1'. 13 and as the side-effects are considerable, ~ it seems reasonable to limit immuni- sation to the latter ones. Steffen, Sch/ir and Moismann 9 recently presented a one-year -s tudy on salmonella and shigella infections in Switzerland. T h e y r ecommended immunisat ion against typhoid fever for travellers to regions with a risk of at least I / 5 o o o o . This includes all countries in Africa, Asia, and South America, bu t not the European countries, unless local epidemics are reported. Since elderly people and persons with predisposing diseases, especially hypo- chlorhydria, run a higher risk, vaccination is considered most important in these groups. These recommendat ions also apply to Scandinavian travellers. Wi th a view to avoiding the local and general reactions seen after subcutaneous

I48 B. S V E N U N G S S O N

vaccination, trials with intradermal administrat ion have been performed.1 This route of administrat ion seems to give as high a serum ant ibody response as subcutaneous immunisat ion and is therefore preferable.

T h e clinical symptoms and signs in the 61 patients agree with the findings in other studies. 5.14-18 However , many differences f rom the classical descriptions of typhoid fever were seen. 1~,17 T h e onset of disease was rather abrupt than insidious and prodromal features were lacking. Diarrhoea is most ly said to occur in the second week of disease 15,17 bu t was in our patients often an initial symptom. However , the possibil i ty of concomitant infections as the cause of diarrhoea cannot be ruled out.

Tab le VII compares the symptoms and signs in the present s tudy with those observed in five others, one from the pre-antibiotic era, 17 two from outbreaks in U S A and Scotland, 5,18 one from South India, 16 and one from Canada, 14 the latter per formed at approximately the same time as the present study. Fever was a dominant symptom, found in 75-x00 per cent of all cases. Diarrhoea was more common in the present series, whereas symptoms like constipation, cough, myalgia, and vomit ing seem to have been more common in the pre-antibiot ic era27 Relative bradycardia and rose spots were more frequent among our Swedish patients, than in the other series. The higher f requency of rose spots among the Europeans may be caused by the difficulty of detecting them in dark-skinned p e r s o n s . 15.17

The spleen was seldom palpable on admission, only in eight per cent, as compared with 3o-65 per cent in other series (Table VII) . In the patients on whom X-ray of the abdomen was per formed however , splenomegaly was seen in 5 9 % , which indicates the difficulty of palpating an enlarged spleen.

On the whole the symptoms and signs in our patients were rather mild and the complications were few, as in other studies per formed during the last 2o years. 5,14,1~,18 N o patient died and all recovered wi thout known sequelae. This benign course of the disease, which differs f rom that seen in the pre-antibiot ic era, ~7 is probably due to early diagnosis and treatment, and to the fact that all patients were essentially healthy before the disease.

Labora to ry investigations showed an only moderate ly elevated E S R and in 76 per cent of the patients the W B C was within normal limits. This agrees with observations in o the r series ~,9,14 and discriminates typhoid from most other bacterial infections. Leukopenia was found in only I I per cent of our patients.

Blood culture was positive in 52 patients (85 per cent). Antibiot ic t reatment before admission could explain the negative cultures in five of the nine remaining patients. Three additional patients were diagnosed by bone marrow culture and three by blood clot culture. Comparisons of different culture procedures in typhoid fever have been made and the advantage of bone marrow culture, especially in patients treated with antibiotics, is well documented. 4.19.2o Clot culture has also been found to be superior to conventional b lood culture. 18.21'22 Maybe , clot culture has the same advantage as bone marrow culture in this respect and it causes less t rauma to the patient. T he risk of getting a septic focus after marrow puncture 23 also speaks in favour of clot culture. A comparison be tween the efficacy of mar row culture and blood clot culture would be desirable.

Faecal cultures on admission were positive in 52 per cent of the patients. T he

Typhoid fever in Sweden I49

shedding of bacteria lasted for 29"8 days on an average. Only one patient carried S. typhi for more than three months and he was cleared after a three week course of ampicillin.

T h e mortal i ty and complication rate in typhoid fever were dramatically decreased when chloramphenicol was in t roduced for the t reatment of the disegse~in I948. ~4 The severe side-effects of the drug, especially aplastic an~.emia, and the recent findings of S. typhi strains with R-factor mediated rqsistance against chloramphenicol , have made it urgent to find suitable aRernatives.25,26 The ones most used have been ampicillin and t r imethopr im- sUlphamethoxazole? ,~7-29 Many studies have indicated that chloramphenicol ad o T - S are equally effective, as judged by tempera ture response and failure rat~, whereas ampicillin has been inferior in these respects. 27 Compar ison of diffdr, ent t reatment schedules requires a prospect ive s tudy with different treatrflent of similar groups. In a Swedish hospital with only a few annual cases of typla0id fever such a s tudy is hardly possible. T h e t reatment groups presented\ here cannot therefore be used for a decisive comparison. The numbers of patients in each group differ too much and therapy was changed • \ , •

m I i of th e 6I pauents . Never the less a rough comparison of the three t reatment groups, in which therapy was not changed coincides with the statements Of other investigators that chloramphenicol and T - S are superior to ampicillin in respect to the rapidity of defervescence. The relapse rate was highest in the chloramphenicol group, which may be partly due to a shorter durat ion of t reatment , causedby~ the awareness of the greater risk of severe side-effect with increasing total d o s e . 23 The over all relapse rate was 15 per cent as compared with 7 - I 8 per cent ih,other series. 5,16,17,3°.~t

T rea tmen t failures were seen in three p~ ien t s first treated with T - S bu t later on with chloramphenicol (Table VII) . O n e ~ f these patients developed ataxia and a slight hearing loss, suspected to be due to a septic embolus , bu t recovered fully. Side-effects of the antibiotic t reatment were few and no serious adverse reactions were seen.

In conclusion, typhoid fever, an u n c o m m o n disease in Sweden, mostly acquired abroad in endemic areas, may take a rather mild course and will not always present with all the classically described symptoms• The fact that 38 per cent of the patients had been treated with antibiotics for other suspected bacterial infections prior to admission stresses the importance of knowing the clinical symptoms and signs of the disease. In a patient with high fever of unknown origin and a history of recent travelling abroad, typhoid fever, besides malaria, must be considered a strong possibili ty since early diagnosis and t reatment have great prognostic importance.

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vaccine. J Hyg (Camb) I98o; 84: I I-I6. 2. Mentzing L-O, Ringertz O. Salmonella infection in tourists. Prophylaxis against salmo-

nellosis. Acta Pathol Mzcrobiol Scand I968; 74: 4o5-413. 3- Ericsson HM, Sherris JC. Antibiotic sensitivity testing. Report of an international collabo-

rative study. Acta Pathol Microbzol Scand [B] I97I ; Suppl 217. 4- Robertson RP, Wahab MFA, Raasch FO. Evaluation of chloramphenicol and ampicillin in

salmonella enteric fever. N Engl J Med x968 ; 278 : 17 I-176.

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7. B6ttiger M, Engstr6m B. New tourist destinations - increasing risks of infection. L~ikartid- ningen i977; 74: 25Ol-25o4.

8. Ringertz O, Mentzing L-O. Salmonella infection in tourists. An epidemiological study. Acta Pathol Microbiol Scand 1968; 74: 397-404.

9. Steffen R, Sch~r G, Moismann J. Salmonella and shigella infections in Switzerland, with special reference to typhoid vaccination for travellers. ScandJ Infect Dis I98I ; 13 : I2 I - I27.

IO. Rice PA, Baine WB, Gangarosa EJ. Salmonella typhi infections in the United States, 1967-I972: increasing importance of international travellers. Am J Epidemiol I977; lO6: 16o--166.

I I. Anonymous. Immunization for travellers. Med Lett 1979; 2I : 57-60. 12. Edwards WM, Crone RI, Harris JF. Outbreak of typhoid fever in previously immunized

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Typhoid fever: pathogenesis and immunologic control. N Engl J Med I97O; 283: 739-745. I4. Briedis D J, Robson HG. Epidemiologic and clinical features of sporadic Salmonella enteric

fever. Can Med AssocJ 1978; 119: I I83 - I I87 . 15. Huckstep RL. Typhoid fever and other salmonella infections. Edinburgh and London:

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Intern Med 1946; 78: 629-661. I8. Walker W. The Aberdeen typhoid outbreak of 1964. Scott MedJ I965; lO: 466-479. I9. Gilman RH, Terminel M, Levine MM, Hernandez-Mendoza P, Hornick RB. Relative

efficacy of blood, urine, rectal swab, bone-marrow, and rose spot cultures for recovery of Salmonella typhi in typhoid fever. Lancet I975 ; 1 : 121I-I213.

20. Guerra-Caceres JG, Gotuzzo-Herencia F, Crosby-Dagnino E, Miro-Quesada M, Carillo- Parodi C. Diagnostic value of bone-marrow culture in typhoid fever. Tram R Soc Trop Med Hyg 1979; 73: 68o-683.

21. Thomas JC, Watson KC, Hewstone AS. The use of streptokinase bile salt broth for clot cultures in the diagnosis of enteric fever. J Clin Pathol I954; 7 :5o-53 •

22. Watson KC. Effect of chloramphenicol on the isolation of S. typhi from the blood stream. J Clin Pathol I955; 8: 55-57.

23. Christie AB. Infectious diseases : epidemiology and clinical practice 2nd Edn. Edinburgh and London: Churchill Livingstone, I974.

24. Woodward TE, Smadel JE, Ley HL, Green R, Mankikar DS. Preliminary report on the beneficial effect of chloromycetin in the treatment of typhoid fever. Ann Intern Med 1948; 29: 131-134.

25. Anderson ES, Smith HR. Chloramphenicol resistance in the typhoid bacillus. Br Med-7 1972; 3:329-331.

26. Cherubin CE, Neu HC, Rahal JJ, Sabath LD. Emergence of resistance to chloramphenicol in Salmonella. ,7 Infect Dis 1977; 135: 8o7-812.

27. Herzog C. Chemotherapy oftyphoid fever: A review of literature. Infection 1976;4: i66- i73. 28. Snyder MJ, Gonzalez O, Palomino C. Comparative efficacy of chloramphenicol, ampicillin

and co-trimoxazole in the treatment of typhoid fever. Lancet I976; 27: I I55-I 157. 29. Uwaydah M, Matossian R, Balabanian B. Co-trimoxazole compared to chloramphenicol in

the treatment of enteric fever. Seand -7 Infect Dis 1975 ; 7; 123-126. 3o. Gadeholt H, Madsen ST. Clinical course, complications and mortality in typhoid fever as

compared with paratyphoid B. A survey of 2647 cases. Acta 214ed Scand I963 ; 174 : 753-76o. 3I. Rowland HAK. The complications of typhoid fever, ff Trop Med Hyg I96I ; 64: I43-I52.