Abstract

Chloramphenicol, Cotrimoxazole , Quinolones, Third generation cephalosporins, in addition to steroids are studied here. Chloramphenicol is the gold standard antibiotic, which clears blood from S typhi in a few hours and stool in a few days. Oral administration is preferred. However, resistance, relapse, bone marrow suppression and etc. are major disadvantages. Resistance against cotrimaxazole is high. Quinolones (e.g., ciprofloxacin which is the drug of choice in multidrug resistance) and third generation cephalosporins (e.g., ceftriaxone which is the best choice in children) are used in areas with a high prevalence rate of multidrug-resistant salmonella infection. Glucocorticoid administration is controversial, although it reduces the mortality in severe cases if used for 48 hours, steroid treatment over 48 hours may increase relapse rate. Surgical therapy is usually needed for complications (e.g., bowel perforation). Relapse of typhoid fever should be treated the same as patients with the first attack. Chronic fecal carriers (asymptomatic excretion for a year or more) should receive high doses of Ampicillin or Amoxicillin (100mg/kg/d) plus probenecid (30mg/kg/d) or Co-trimoxazole(160/800 mg twice daily ) for at least 6 weeks. Those who have gallstone need cholecystectomy. Iranian studies show that cefixime is effective on all strains.

Typhoid fever is a severe systemic infectious disease . Treatment with appropriate antibiotics is essential for recovery. In this article we review some current antibiotics used for the treatment of typhoid fever.

Chloramphenicol:
Chloramphenicol, which other antibiotics must be compared with, has been the "gold standard" therapy since its introduction in 1948.1 Within a few hours after administration S.typhi disappears from the blood. Stool cultures frequently become negative in few days. Clinical improvements are evident within 48 hours and fever and other signs of the disease commonly abate within 3 to 5 days. The patient usually becomes afebrile before the intestinal lesions heal. As a result intestinal hemorrhage and perforation may occur at a time when the clinical condition is rapidly improving. The dose of chloramphenicol prescribed for adults with typhoid fever is 1g every 6h for 2 weeks. Although both intravenous and oral routes have been used the response is more rapid with oral administion.6,24 Treatment with chloramphenical reduces typhoid fever mortality from approximately 20% to 1% and duration of fever from 1428 days to 3-5 days.1,2 chloramphenicol therapy has been associated with emergence of : - A high relapse rate (10-25%)2,4 - Resistance1,3 - A high rate of chronic carriage4 - Bone marrow toxicity5 and aplastic anemia8 - High mortality rates in some recent series from the developing world. 3 Chloramphenicol is bacteriostatic both for clinical isolates and against salmonella typhi cultured in human macrophages.7

Cotrimoxazole:

Cotrimoxazole is a second line drug for typhoid fever but resistance is an increasing problem.. In adults TMP-SMX appears to be effective when the dose is 800mg of sulfa plus 160mg of trimetoprim. every 12 hours for 15 days.24

Quinolones:
In areas with a high prevalence rate of multidrug-resistant salmonella infection (e.g. Indian subcontinent, southeast Asia and Africa) all patients suspected to typhoid fever should be treated with a "Quinolone" or third generation "Cephalosporin". 10 Quinolones are penetrant macrophages, which acheive high concentrations in the bowel and bile lumina and thus have potential advantages over other antimicrobials in the treatment of typoid fever.10,18,19, 25 Ciprofloxacin (500 mg orally twice daily for 10 days) remains the drug of choice for the treatment of multidrug resistant typhoid fever (MDRT).27 Other quinolones, including Ofloxacin, Norfloxacin, Flerofloxacin, Pefloxacin and lomefloxacine have been effective in small clinical trials. 27 Short course therapy with Ofloxacin (10-15 mg/kg) divided twice daily for 2 to 3 days appears to be simple, safe, and effective in the treatment of uncomplicated multidrug resistant typhoid fever.20 It is recommended that quinolones be avoided in children younger than 10 years or pregnant women. However, quinolones have been used to treat multidrug resistant typhoid in children and pregnant patients without adverse effects. 26

Third generation cephalosporins:

A few studies showed that shorter coursers of cefriaxone (once daily for 3 to 5 days) are not as effective and safe as 2 to 3 weeks of chloranmphenicol. 10,11 Ceftriaxone is the best choice for children,3,11 because of concerns about quinolone-induced arthropathy and cartilage damage in this age group. 12 After initial control of typhoid fever symptoms with a parenteral third generation cephalosporin, many practitioners switch to an oral agent to complete 10 to 14 days of therapy. Oral cefixime (10 to 15 mg/kg twice daily) needs further study for the initial treatment of multidrug resistant typhoid fever.29 First and second generation cephalosporins are clinically ineffective and despite adequate in vitro killing activity should not be used to treat typhoid fever. 13,14,15,16

Other Antibiotics:
Aminoglycosides are clinically ineffective 17 in treatment of typhoid fever. In some studies it has been shown that Azithromycin (500mg P.O qd for 7 days) as effective as chloramphenicol given to patients with chloramphenicol susceptible infections. 21,26,28

Role of Steroids:
The role of glucocorticoides in the management of infectious diseases in man remains controversial, although experimental data obtained both in vitro and in experimental infections in animals provide evidence of a beneficial effect of such treatment. Their use in the treatment of severe typhoid fever has been shown to be beneficial. 30

Based on a study from Jakarta which showed a significant reduction in mortality in patients with severe typhoid fever ( i.e. CNS symptoms, shock, dissiminated intravascular coagulation), Dexamethasone (3mg/kg as a loading dose over 30 min, followed by 1mg/kg every 6h for 24h to 48h) used along with parenteral antimicrobials seems to reduce mortality.22steroid treatment over 48h may increase the relapse rate.23

Treatment of complications:
In referent not cler double layer closure of the site of perforation, aggressive fluid replacement, and administration of an inexpensive broad-spectrum antibiotic regimen including chloramphenicol, gentamicin and metronidazole, reduced mortality rates from 25-30% to well under 10%. Introduction of effective antibiotic therapy has resulted in a low incidence of such great complications like intestinal perforation and hemorrhage, but reports from some regions including Indian subcontinent indicate a high incidence (near 10%) need for surgery because of intestinal perforation among patients with typhoid f ever. 30 In these areas with low access to health facilities specially for those who are emaciated, medical therapy alone with broad spectrum antibiotics has been used for intestinal perforation but results are not always acceptable, and this should not be the routine approach.

Treatment of relapse:
Patients with relapse of typhoid fever should be treated the same as patients with the first attack. Chronic fecal carriers (asymptomatic excretion for a year or more ) should

receive high doses of Ampicillin or Amoxicillin (100mg/kg/d) plus probenecid (30mg/kg/d) or Co-trimoxazole(160/800 mg twice daily ) for at least 6 weeks. 31 Patients with cholecystitis or gall stones may require cholecystectomy.21,31

Iranian Studies:
There are few published studies about typhoid fever treatment in Iran. Rastegar lari, et al from Tehran reported that 41.9%, 33.9%, 38.7%, 58.1% and 1.6% of isolated strains were resistant to chloramphenicol, Co-trimoxazole, ampicillin, tetracycline and gentamycin respectively. About one third (33.9%) of the strains showed multiple resistance to the first four mentioned antibiotics. All strains were susceptible to cefixime (MICs less than 1 mcg/ml). It was concluded that cefixime due to its effectiveness, oral administration and shorter courses of treatment could be the therapy of choice in cases of typhoid fever caused by multiple drug resistant strains. 29 In another study from Ahwaz, based on antibiograms, there was 79%, 30%, 30.6% and 7.6% resistance to Ampicillin, Chloramphenicol, Co-trimoxazole and Ceftizoxime respectively. Mean time of defervescence with Ceftizoxime was 8.5 days compared to 4-5 days with other three antibiotics. 32

Tips:
> Quinolones are highly effective treatment for multidrug resistant typhoids. >
Aminoglycosides are clinically ineffective in treatment of typhoid fever.

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Azithromycin may have a role in the short treatment of typhoid fever. Steroid may reduce mortality in severe typhoid fever.