Treatment of typhoid fever with azithromycin versus chloramphenicol in a randomized multicentre trial in India

Thomas Butlera,*, C. B. Sridharb, M. K. Dagac, Kamal Pathakd, R. B. Pandite, Rasik Khakhriaf, Chandrashekhar N. Potkarg, Michael T. Zelaskyh and Raymond B. Johnsonh

a Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA b Saint John's Medical College and Hospital, Bangalore c Maulana Azad Medical College, New Delhi d Baroda Hospital, Baroda e Central Railway Hospital, Bombay, India f Bureau of Microbiology, Ottawa, Ontario, Canada g Pfizer Limited, Bombay, India h Central Research Division, Pfizer Inc., Groton, CT, USA


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
To compare the clinical and bacteriological efficacies of azithromycin and chloramphenicol for treatment of typhoid fever, 77 bacteriologically evaluable adults, with blood cultures positive for Salmonella typhi or Salmonella paratyphi A susceptible to their assigned drugs, were entered into a randomized open trial at four hospitals in India. Forty-two patients were randomized to receive azithromycin 500 mg po od for 7 days and 35 to receive chloramphenicol 2–3 g po od in four divided doses for 14 days. Thirty-seven patients (88%) in the azithromycin group responded with clinical cure or improvement within 8 days and 30 patients (86%) in the chloramphenicol group responded with cure or improvement. By day 14 after the start of treatment, all patients treated with azithromycin and all except two of the patients treated with chloramphenicol (94%) were cured or improved. Blood cultures repeated on day 8 after start of therapy showed eradication of organisms in 100% of patients in the azithromycin group and 94% of patients in the chloramphenicol group. By day 14 the eradication rate in the chloramphenicol group had increased to 97%. Stool cultures on days 21 and 35 after start of treatment showed no prolonged faecal carriage of Salmonella spp. in either group. These results indicate that azithromycin given once daily for 7 days was effective therapy for typhoid fever in a region endemic with chloramphenicol-resistant S. typhi infection and was equivalent in effectiveness to chloramphenicol given to patients with chloramphenicol-susceptible infections.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Chloramphenicol has been the drug of choice for typhoid fever for more than 40 years in regions of the world where Salmonella typhi remains susceptible to the drug. However, multiple drug resistance (MDR) to ampicillin, chloramphenicol and trimethoprim–sulphamethoxazole in S. typhi has emerged in many countries of Asia and Africa and limits the usefulness of these traditional drugs.1,2,3 The cephalosporins, ceftriaxone and cefixime,4,5,6,7,8 are useful against MDR typhoid fever, but the required intravenous route of administration renders them impractical for some patients.

Azithromycin is the first of a new class of broad-spectrum antibiotics called azalides, which contain a nitrogen atom in the macrolide aglycone ring.9,10 Azithromycin has an MIC of 4–16 mg/L against isolates of S. typhi.11 Rapid movement of azithromycin from blood into tissue results in significantly higher azithromycin concentrations in tissue than in plasma (up to 50–100 times the maximum observed concentration in plasma). After oral administration, serum concentrations of azithromycin decline in a polyphasic pattern, resulting in an average terminal half-life of 68 h. The high values for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 mL/min) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues.10,12 The prolonged concentration of azithromycin in cells is advantageous in the treatment of experimental Salmonella spp. infection in mice, which is intracellular,13 and may explain the good results obtained with azithromycin in patients with typhoid fever in Chile14 and Egypt.15


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Sample size and patient selection

Eighty patients with blood cultures showing Salmonella spp. were selected for randomization of approximately 40 patients each to azithromycin and chloramphenicol treatment groups. This sample size was large enough, with a power of 80% and with an {alpha} level of 0.05, to show equivalence in bacterial eradication from blood cultures at day 8, using the 94% eradication rate observed in the chloramphenicol group, at a {delta} (lower boundary of the 95% CI on the difference in eradication rates) of -14.9.16 Males or females of at least 18 years of age with suspected typhoid fever on the basis of histories of fever for 4–15 days were considered and examined for the presence of two or more of the following features: oral temperature >38.5°C, abdominal tenderness, hepatomegaly, splenomegaly, rose spots, coated tongue with sparing of margins, toxic physical appearance or relative bradycardia. Written consent was obtained from each patient before inclusion. Patients were excluded if they were pregnant or lactating; had allergies to chloramphenicol, erythromycin or other macrolide antibiotics; had major complications of typhoid fever (pneumonia, gastrointestinal haemorrhage, intestinal perforation, shock or coma); were unable to swallow medication; had been treated with antimicrobial drugs within 7 days unless blood cultures remained positive for Salmonella spp.; or had serious underlying disease affecting bone marrow, kidneys, liver, heart, lung or nervous system. To eliminate selection bias, patients were screened for entry criteria and asked for signed consent without the knowledge by the patient or physician of their assigned treatments. Randomized treatments were assigned after entry, by the physician's opening a sealed envelope containing the coded treatment choice that was made from a table of random numbers. Patients and physicians were unblinded to the treatment after patients were entered.

Clinical and laboratory testing

The admission evaluation included history and physical examination; two blood cultures; a stool culture; blood for white blood cell count, haemoglobin, platelet count, prothrombin time, creatinine, blood urea nitrogen, bilirubin, alkaline phosphatase, AST, and ALT and urinalysis. After entry, symptoms and changes in physical examination were recorded daily during treatment, and blood cultures were obtained on days 4, 8 and 14 after start of treatment. Isolates of S. typhi and Salmonella paratyphi were confirmed by slide agglutination using specific antisera (Difco Laboratories, Detroit, MI, USA). Antimicrobial susceptibilities at the investigative sites were determined by disc diffusion. Isolates were considered resistant when zone diameters for azithromycin discs containing 15 µg were <=13 mm and for chloramphenicol discs containing 30 µg were <=12 mm. Isolates were sent to a reference laboratory at Texas Tech University Health Sciences Center for determination of MICs and to a reference laboratory in Ottawa, Canada, for Vi phage typing.17 MICs of azithromycin were measured by the tube dilution method in cation-adjusted Mueller–Hinton broth (Difco Laboratories).

Treatment and follow-up visits

Azithromycin was administered as 500 mg po (two capsules of 250 mg) od for 7 days. Doses were given 1 h before or 2 h after eating food. Chloramphenicol was administered po as 2–3 g daily in four divided doses for 14 days, with the dose determined by the patient's weight (with those <60 kg receiving the lower dose). After clinical improvement in the hospital, patients were discharged home to complete their therapies. If discharged before 14 days after start of therapy, they were asked to return daily until 14 days had elapsed. Follow-up visits were scheduled on days 21 and 35 for physical examination, cultures of stool and for the same blood tests that were performed at the time of admission. Blood cultures were repeated on days 21 and 35 if fever (>38°C) had returned at these times. Physicians and other caregivers were unblinded about patients' treatments during follow-up.

Analysis of data

Patients were considered evaluable if their admission blood cultures grew S. typhi or S. paratyphi susceptible to the assigned antibiotic and they took azithromycin for at least 4 days or chloramphenicol for at least 4 days for the day 8 analysis and at least 7 days for the day 14 analysis. Patients with negative cultures or with other infections requiring additional antibiotics were removed from the study. Patients were considered clinically cured if fever disappeared and all signs and symptoms of typhoid fever resolved, and were considered improved if fever disappeared and signs and symptoms of typhoid fever had partially resolved. Clinical failure was defined as lack of improvement or worsening of signs and symptoms or need to change antibiotic therapy. Patients were considered afebrile when the daily maximum temperature was <38°C for 2 days or longer. Bacteriological eradication was defined as negative blood cultures for S. typhi and S. paratyphi on day 8 after start of therapy, with all cultures remaining negative to the final assessment on day 35. Clinical relapse was defined as return of fever after day 14, and bacteriological recurrence was defined as a blood culture positive for S. typhi or S. paratyphi on day 21 or 35 after start of therapy. Prolonged faecal carriage was defined as a stool culture showing S. typhi or S. paratyphi on day 21 or 35 after start of therapy. Clinical and bacteriological response rates were calculated for each treatment group and 95% CI were calculated for the difference in population response rates between the two treatments. Proportions of patients reporting adverse experiences and showing abnormal laboratory values after start of therapy were compared between treatment groups. Equivalence of response rates was defined as a 95% CI of the two response rates that covered zero, with the lower value being greater than -10%. A P value of <0.05 indicated a significant difference between the two groups.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Bacteriological identification and antimicrobial susceptibilities

Ninety-two patients with blood cultures showing growth of S. typhi or S. paratyphiA were enrolled. Isolates were confirmed by biochemical reactions and agglutination by antisera as S. typhi in 82 cases and S. paratyphiA in 10 cases. The most predominant Vi phage type of S. typhi was E1 (Table I). Using zone diameters <=13 mm for azithromycin, resistance to azithromycin was reported in 11 of the 92 isolates (12%) by the Indian laboratories. Using zone diameters of <=12 mm, resistance to chloramphenicol was reported also in 11 isolates (12%). Only one isolate of S. typhi was resistant to both azithromycin and chloramphenicol. Chloramphenicol resistance occurred only among S. typhi isolates, whereas azithromycin resistance occurred in both S. typhi and S. paratyphiA (Table I). Fifty-seven isolates that had been stored and were viable at the end of the study were sent to Texas for further susceptibility testing. Five of these isolates had been reported by the Indian laboratories as resistant to azithromycin and seven resistant to chloramphenicol. All were susceptible to azithromycin by disc diffusion method and 46 (81%) isolates were susceptible to chloramphenicol. Ten of the 11 chloramphenicol-resistant isolates were also resistant to ampicillin and co-trimoxazole, whereas one isolate was resistant only to chloramphenicol. All isolates were susceptible to ciprofloxacin.


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Table I. In-vitro susceptibilities of 92 isolates of Salmonella typhi and S. paratyphi A and distribution of Vi phage types of S. typhi
 
Azithromycin MICs were in the range of 4–32 mg/L for all the tested isolates (Table I). The isolates of S. typhi had lower MICs than the isolates of S. paratyphiA, with most S. typhi inhibited by azithromycin 4 mg/L and most S. paratyphiA inhibited by azithromycin 16 mg/L. The assays using two-fold dilution series frequently showed a trailing effect of azithromycin against S. typhi, with a clear tube adjacent to a tube with light growth, which was adjacent to a tube with heavy growth. One isolate of S. typhi was more resistant in repeated testing than others, with an MIC of >=32 mg/L.

Patient enrolment, randomization and treatment

At the four sites in India, 109 patients met inclusion criteria, signed consent and were randomized to therapies. The distribution by site was 50 patients at Bangalore, 29 patients at New Delhi, 21 patients at Baroda and nine patients at Bombay. Fifty-six patients were randomized to receive azithromycin and 53 to receive chloramphenicol. Study drug was actually received initially by 106 patients.

Patients with negative blood cultures were removed from the study and offered other appropriate therapies. Blood cultures positive for S. typhi or S. paratyphi A were present in 92 patients (48 assigned to azithromycin, 44 to chloramphenicol). Four patients in each group were excluded because their isolates showed resistance to the study drug. Seven patients treated with azithromycin had isolates resistant to chloramphenicol and six patients treated with chloramphenicol had isolates resistant to azithromycin. Additionally, one patient assigned to azithromycin never took it, and five patients assigned to chloramphenicol stopped therapy early or never took it because of choices of individual physicians and their patients and not because of adverse events. Finally, one azithromycin patient was excluded from the analysis because of insufficient follow-up data. The remaining 77 patients were clinically and bacteriologically evaluable. Demographic characteristics, clinical findings and laboratory features of patients in the two treatment groups were comparable (Table II).


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Table II. Characteristics of blood culture positive patients before treatmenta
 
Response to therapy

In the patients treated with azithromycin, blood cultures on day 4 of treatment showed no growth in 83% of patients, and on days 8 and 14 after start of treatment showed no growth in all patients (Table III). In patients treated with chloramphenicol, blood cultures showed no growth in 94% of patients on days 4 and 8 after start of treatment, and in 97% of patients on day 14. Stool cultures on days 21 and 35 after start of treatment showed no growth of Salmonella spp. in all patients in both treatment groups.


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Table III. Number (percentage) of patients with blood culture-positive typhoid fever; bacterial and clinical responses
 
Clinical responses were cures or improvements within 8 days of starting treatment in 88% of patients treated with azithromycin and 86% of patients treated with chloramphenicol (Table III). There were five patients in each group who were judged as treatment failures because they had continuing fever or other symptoms. At 14 days after start of treatment, the five patients treated with azithromycin who were failures at day 8 all responded to become cured or improved, whereas two (6%) of the patients treated with chloramphenicol remained treatment failures. The mean number of days of fever after start of treatment was 4.1 for azithromycin and 4.3 for chloramphenicol. There were no relapses after the end of treatment. Adverse events occurred in five patients treated with azithromycin and none of the patients treated with chloramphenicol; in two of the patients the adverse events were gastrointestinal in nature. The adverse events were not severe and did not result in change of study medication. There was no significant difference in laboratory abnormalities between the two treatment groups.

The 10 patients infected with S. paratyphi A responded in ways comparable with the patients infected with S. typhi. Four of the patients infected with S. paratyphi A were treated with azithromycin, and all showed bacteriological eradication after treatment and all were clinically cured. The six patients treated with chloramphenicol all showed bacteriological eradication and were clinically cured.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The results of this comparative randomized trial of azithromycin and chloramphenicol for typhoid fever indicated that the two treatments were effective and equivalent, by giving clinical cures or improvements in 86–88% of patients within 8 days, and producing bacteriological eradication of Salmonella spp. from blood cultures in 97–100% of patients. The mean durations of fever after the start of treatment in the two treatment groups of 4.1–4.3 days indicate that most patients responded promptly to therapy. These results compare favourably with other antimicrobial agents tested recently in typhoid fever, including ceftriaxone, cefixime and fluoroquinolones,5,18,19,20,21,22,23,24,25,26 and confirm the findings of trials in Chile and Egypt that azithromycin is effective against infections caused by S. typhi and S. paratyphi A.14,15 Although five patients in each treatment group were considered clinical failures after 8 days of treatment because they persisted in showing fever and/or other symptoms, they did not deteriorate clinically and most of them subsequently improved or were cured by 14 days after the start of treatment. The design of clinical trials of typhoid fever should include an observation period of about 14 days to allow complete defervescence and resolution of physical signs, such as splenomegaly and hepatomegaly, after shorter courses of antimicrobial agents of 7 days or less.

The two study drugs were very different in regard to their administration, pharmacokinetics, therapeutic principles and side effects. Azithromycin was given once daily in a dose of 500 mg a day for 7 days, whereas chloramphenicol was given four times a day in doses of 2–3 g a day for 14 days. Both antibiotics penetrate into cells effectively, and this intracellular penetration explains the effective therapeutic activity against the predominantly intracellular pathogen S. typhi. On the other hand, serum concentrations of azithromycin reported to be in the range of 0.04–0.4 mg/L during treatment12,27 are less than the MIC of azithromycin against S. typhi and are less than the serum concentrations of 5.5–57 mg/L reported for chloramphenicol during treatment of typhoid fever.4 The ability of azithromycin to achieve intracellular concentrations in monocytes 231 times greater than the serum concentrations and in polymorphonuclear leucocytes 83 times the serum concentrations,28,29 as well as a long half-life of 2–3 days of the intracellular concentration,10 appears to be essential for its therapeutic activity in typhoid fever.

Adverse events, including gastrointestinal symptoms, were reported by five patients treated with azithromycin in this trial, but these events were not serious and did not require discontinuation of therapy. Although none of the patients treated with chloramphenicol reported adverse events, more patients randomized to chloramphenicol therapy than to azithromycin refused therapy or stopped therapy early (five versus one) and were excluded from analysis. The reasons were that individual patients, after reconsidering their decisions to enter the study, chose not to take chloramphenicol because of concern about possible adverse events. Additionally, in view of the fact that this was an open study, there may have been less reporting of adverse events with chloramphenicol because of investigator bias toward an older, more tried agent. The known haematological side effects of chloramphenicol cause physicians in some countries to select alternative therapies routinely, and baseline leucopenia in one of the patients in this trial was the reason his physician did not initiate treatment with chloramphenicol.

Emergence of antimicrobial drug resistance in S. typhi is a global problem1,2,3 and was the compelling reason for us to undertake this trial of a new antibiotic for typhoid fever. In-vitro resistance was reported by the Indian laboratories to chloramphenicol in 12% of isolates and to azithromycin in 12% of isolates. Chloramphenicol resistance was expected because of the high prevalence of multidrug resistance to ampicillin, chloramphenicol and co-trimoxazole on the Indian subcontinent.2,30,31 Azithromycin resistance was not expected because this drug has not been used extensively yet in India. When 57 of the isolates of S. typhi were tested in Texas for azithromycin MICs, all isolates except one were susceptible, with MICs of 4–8 mg/L. This discrepancy between results of susceptibility testing by disc zone diameters and MICs suggests that there was less azithromycin resistance in our isolates of S. typhi than was reported initially from results of disc diffusion. A tendency for zones around the azithromycin discs to show a trailing of light growth rather than the sharp demarcation noted in the Texas laboratory is a technical difficulty in obtaining reproducible results by disc diffusion. Our results of azithromycin MICs against 10 isolates of S. paratyphi A showed that seven were relatively resistant, with MICs of 16 mg/L. This is the first report of azithromycin resistance in S. paratyphi A. Although our patients with S. paratyphi A infection all did well when treated with azithromycin, this in-vitro resistance deserves attention in future studies of typhoid fever.

The place of azithromycin in the treatment of typhoid fever needs to be defined by further clinical studies in adults and children. Once-daily oral treatment for 7 days is convenient and should be favourable for out-patient compliance. At the time of this study a parenteral form of azithromycin was not available. Although parenteral azithromycin is now available, it has not yet been tested in typhoid fever. The fluoroquinolones ciprofloxacin and ofloxacin have been tested in adults in geographical areas with multidrug resistance and gave good results.5,18,19 However, the fluoroquinolones are generally not approved for use in children because of the potential for these drugs to damage cartilage in growing bones in animals. Children are affected by typhoid fever more frequently than adults.32 Children with multidrug-resistant typhoid fever have been treated successfully with furazolidone, ceftriaxone, cefixime and aztreonam.33,34,35 The availability of a paediatric suspension of azithromycin provides an opportunity to examine the efficacy and safety of this drug in young children with typhoid fever.


    Acknowledgments
 
Assistance was provided by John Vincent, Krishna Prakash, Madan M. Bahadur, Kishan Jani and Wendy Johnson. This work was supported by a grant from Pfizer Central Research, Groton, CT. These results were presented at the Fourth International Conference on the Macrolides, Azalides, Streptogramins and Ketolides in Barcelona in 1998.


    Notes
 
* Corresponding author. Tel: +1-806-743-3155; Fax: +1-806-743-3148. Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Received 23 November 1998; returned 9 February 1999; revised 3 March 1999; accepted 6 April 1999