670 TRANSACTIONS OF THE ROYALSOCIETY OF TROPICALMEDICINEAND HYGIENE(1991)8.5,67&671

Randomized treatment of patients with typhoid using norfloxacin or chloramphenicol P. S. A. Sarma’ and P. Durairaj’ and Research Centre, Bhilainagar,

and paratyphoid

Departments of ‘Medicine and ‘Microbiology, Madhya Pradesh-490 006, India

Abstract Forty adult patients with Salmonella typhi and S. paratyphi infections were studied in a randomly assigned prospective study to receive norfloxacin (12 drug-sensitive and 8 drug-resistant cases)or chloramphenicol (20 cases). No complication occurred in either group and no side effect was noted in the norfloxacin-treated group. The results suggest that a 7 d course of twice daily norfloxacin promises to be an alternative to a 14 d course of chloramphenicol for treating chloramphenicol-sensitive and multidrugresistant typhoid and paratyphoid fevers. Introduction Norfloxacin is a potent antibacterial agent that inhibits the action of topoisomerase II (WOLFSON & HOOPER, 1985; NEU, 1987; EPSTEIN, 1988). It is

effective against Salmonella species (WOLFSON & HOOPER, 1988). In the present study the activity of norlloxacin was compared with that of chloramphenico1 in viva against chloramphenicol-sensitive and multidrug-resistant typhoid and paratyphoid fevers. Materials and Methods Forty previously healthy adult outpatients, 38 with uncomplicated typhoid fever (19 men, 19 women; age range 17-32 years) and 2 with paratyphoid fever (both men, aged 18 and 22 years), attending the medicine unit of Jawaharlal Nehru Hospital and Research Centre, Bhilai, India, were entered into the study with their informed consent. The study design was open, randomized and prospective. By random assignment, 20 patients received norfloxacin and 20 received chloramphenicol. The sex ratios, mean ages, and duration of fever and diarrhoea before admission were similar in both treatment groups. Frequencies of splenomegaly, hepatomegaly, coated tongue, mild obtundation, and rose spots were also comparable in the 2 groups. The temperature was measured every 4 h until the patient was afebrile, then twice daily till the completion of treatment, and then on the days of follow-up. Hepatic and renal function and haematology were assessedbefore and during treatment. Thirty drug-sensitive S. typhi strains (phage A) and 2 drug-sensitive S. paratyphi A strains (phages UT, 1) were isolated from blood cultures. Four strains of S. typhi (phage A) exhibited partial drug sensitivity (to chloramphenicol, trimethoprim-sulphamethoxazole, notioxacin, and gentamicin), and 4 (phage A) were sensitive only to norfloxacin and gentamicin. Oral chloramphenicol was administered at 60 mgi kg body weight per day in 4 divided doses until defervescenceand then 40 mg/kg/d in 3 divided doses Address for correspondence: Dr P. S. A. Sarma, 2A/6/9, Bhilainagar-9, Madhya Pradesh-490 006, India.

Jawaharlal

fevers

Nehru Hospital

to complete 14 d. Oral norfioxacin was administered, 400 mg every 12 h for 7 d, to 10 patients with drug-sensitive typhoid fever, 2 with drug-sensitive paratyphoid fever, and 8 with drug-resistant typhoid fever. Blood culture and antibiotic sensitivity (standardized disc method; RAMIREZ et al, 1985) were repeated 3, 5, and 7 d after drug administration. Stool cultures were made 14, 21, and 28 d after norfloxacin administration in the 4 multidrug-resistam typhoid fever cases only. Clinical cure was defined as disappearanceof all signs and symptoms of infection, and bacteriological cure was documented when blood cultures were negative 7 d, and stool cultures were negative 14, 21, and 28 d, after norfloxacin administration. Follow-up examinations 14, 21, 28 and 56 d after drug administration in both groups included a thorough clinical examination, blood culture, Widal test, haematology, and laboratory tests for renal and hepatic function. Results The clinical characteristics of the patients and their response to treatment are shown in Tables 1 and 2. No appreciable side effect was observed except for nausea (3), vomiting (3)! and headache (2) in the group receiving norfloxacm. In the chloramphenicoltreated group, the mean haematocrit decreasedin 2 patients, the white blood cell count was depressedin 3 patients, and the platelet count was reduced in 2 patients. Table 1. Clinical paratyphoid

characteristics of patients with typhoid fever and fever, according to treatment group Drug treatme&

NoriIoxacin

Chloramphenicol No. of patients (males/females) 20 (1218) 20 (11/9) Age (years);mean and range 19.8(E-30) 19.6(17-32) Duration of fever before admission 5.4 (3-10) (d); meanand range 5.8 (3-11) Duration of diarrhoea(d)b 4.2 4.6 Number with 13 Splenomegaly’ 12 Hepatomegaly 12 11 Mild obtundation 3 3 16 Coatedtongue 17 “No significantdifferencewas noted betweenthe two treatment groups (EYO.5). bThree or more stoolsin the 24 h before admission. ‘Spleentip palpable2-3 cm belowthe costochondral marginin the mid-clavicularline.

671 Table 2. Results of treatment: comparison between norfloxacin and chloramphenicol groups

Drug treatment Mean defervescence time (h) Mean blood culture sterilization time (h) Disappearance of splenomegaly (d)

Norfloxacin

Chloramphenicol

88+12

124+ 16

72+18 6.2

98+14 6.4

Discussion

Clinical and bacteriological cure was achieved in both the groups and there were no relapses. The reported efficacy of norfloxacin against Salmonella species in vitro (WOLFSON & HOOPER, 1985; NEU, 1987)justified its trial in typhoid fever. Norfloxacin is rapidly absorbed from the gastrointestinal tract and widely distributed in the body, a single oral dose of 400 mg achievesa mean peak serum concentration of 1.5 pg/ml, and its elimination half-life ranges from 3.5 to 6.5 h (WOLFSON & HOOPER,1985). Fluorine atom 6 in norfloxacin is thought to account for the stability of the molecule and its greater potency (WOLFSON & HOOPER, 1985). Toxic and adverse reactions to this drug and other newer fluoroquinolones have been fairly rare (WOLFSON & HOOPER, 198s; RAMIREZ et al., 1985). Crprofloxacin belongs to the samegroup of quinolones as norfloxacin, and was tried successfully in infections with chloramphenicol-sensitive (RAM~REZ et al., 1985) and multidrug-resistant S. tvahi strains (EYK$N & WILLIAMS, 1987), and also i~‘Salmonella carriers (HUDSONet al., 1985). The 7 d course of oral norfloxacin is simpler than other drug regimens for typhoid fever. Defervescence time and bacterial clearance time (time taken for blood cultures to becomesterile) of norfloxacin are comparable to those of ciprofloxacin (RAMIREZet al., 1985; HUDSONet al., 1985) and better than those of chloramphenicol (GUERRANT,

1987).

Chloramphenicol is likely to remain the drug of choice for typhoid fever causedby susceptible strains, becauseit is cheaper, readily available for both oral and parenteral use, and regularly renders patients afebrile within 10 d after the start of treatment (HERZOG& GEDDES,1982). Recent clinical trials suggestedthat the median time for disappearanceof pyrexia after commencing treatment with either chloramphenicol or amoxycillin was 7 d for adults (ADAMS, 1983). The recommended total duration of treatment with chloramphenicol or amoxycillin is not less than 14 d (ADAMS, 1983). Either ampicillin or co-trimoxazole may be used for 14 d if chloramphenico1 fails, but they are not its equal in the great majority of cases (ADAMS, 1983). Trials have been reported with cephalosporins, especially third generation ones such as ceftriaxone (LESSERREet al., 1985) and moxalactam (UWAYADAH et al., 1986). These

drugs, although effective, have a number of shortcomings; they must be given in high doses or over a period of 10 d to reduce the incidence of relapse, and they are expensive.

Nevertheless chloramphenicol, which has remained the drug of choice for typhoid fever for more than 35 years, has its own disadvantages of toxicity and resistance(GUERRANT,1987). Shorter course of chloramphenicol are not advised,.becauserelapsesoccur in lO-20% of treated casesone or 2 weeks after theraev. The ease of administration of norfloxacini~ ;he relative lack of side effects, resolution of the problem of treating non-responding and drug-resistant strains, fairly early response, shorter course of treatment, and avoidance of the bone marrow suppression sometimes resulting from chloramphenicol treatment, are the potential advantages of using norfloxacin in typhoid and paratyphoid fevers. Our preliminary study has shown that norfloxacin is effective against chloramphenicol-sensitive and multidrug-resistant SaZmaneZZa strains and may well replace chloramphenicol

in any case of typhoid fever.

for use

References

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1991;