ARCHIVED - International Note - Antibiotics in the management of shigellosis

Shigellosis is becoming an increasingly significant public health problem because of the development of multiple antimicrobial resistances that result in frequent treatment failure, leading to complications and deaths. The use of an effective antimicrobial against shigellosis alleviates the dysenteric syndrome, fever and abdominal cramps, reduces the duration of pathogen excretion, interrupts disease transmission and reduces the risk of potential complications. In ideal situations, a stool or rectal swab sample should be processed for laboratory confirmation of diagnosis and drug sensitivity testing before institution of antimicrobial therapy. However, this is rarely possible, and empiric antimicrobial therapy is instituted based on the knowledge of the antimicrobial resistance pattern of Shigella strains circulating locally.

Antibiotics used to date

The choice of antimicrobials effective in treating shigellosis has become very limited. Tetracycline, ampicillin and co-trimoxazole, once used as first-line antimicrobials, are no longer effective. Shigella strains are often sensitive in vitro to some antimicrobials such as furazolidone, gentamicin, early generation cephalosporin and amoxicillin. However, these antibiotics, including gentamicin if given orally, are not clinically effective against Shigella and should therefore not be recommended or used. At present, nalidixic acid is widely used as the first-line antimicrobial against Shigella in many countries; however, it is becoming increasingly ineffective in many parts of the world.

Nalidixic acid versus ciprofloxacin

Nalidixic acid and ciprofloxacin both belong to a group of antimicrobials known as "quinolones", nalidixic acid being the first antimicrobial agent developed in this family of antibiotics. In a few clinical trials conducted in the 1970s and 1980s, nalidixic acid was shown to be clinically effective against Shigella. When resistance against the commonly used antibiotics (ampicillin, co-trimoxazole) became increasingly prevalent in the 1980s, nalidixic acid became the drug of choice for treating shigellosis despite the failure of nalidixic acid to terminate fecal excretion of Shigella rapidly. The newer quinolones, such as ciprofloxacin, have been shown to have some significant advantages over nalidixic acid. Firstly, their activity against Enterobacteriaceae is several thousandfold greater than that of nalidixic acid. Secondly, ciprofloxacin is 100 to thousandfold less prone than nalidixic acid to selection of single-step spontaneous highly resistant organisms. And thirdly, simplified treatment regimens (two doses per day for 3 days instead of four doses per day for 5 days with nalidixic acid) have been shown to be very effective against all species of Shigella.

In countries where nalidixic acid is still effective against shigellosis, ciprofloxacin is often used as a second-line antimicrobial for treating strains resistant to nalidixic acid. However, as they belong to the same antibiotic family, it is not surprising that strains resistant to nalidixic acid, show some degree of cross-resistance to ciprofloxacin and other newer quinolones. In fact, the minimum inhibitory concentration (MIC) of ciprofloxacin is increased in strains already resistant to nalidixic acid, and appearance of full resistance to ciprofloxacin is probably hastened when this antibiotic is used as a second-line treatment against strains already resistant to nalidixic acid.

New recommendations for the management of shigellosis

Based on these findings, experts meeting in Bangladesh in February 2004 recommended that nalidixic acid should no longer be recommended for the management of Shigella infection and that ciprofloxacin should become the first-line antibiotic to treat shigellosis.

Two major concerns were considered by the experts when making this recommendation: (i) the safety of ciprofloxacin in children; and (ii) the cost of this antibiotic compared with previously recommended treatment.

1. Safety
   Concern about the safety of quinolones came from the results of studies showing that both nalidixic acid and the newer quinolones could cause arthropathy in young animals. However, in developed countries nalidixic acid has been used in children for more than 30 years to treat urinary tract infections, sometimes for prolonged periods, with no reports of resultant arthropathy. In developing countries, nalidixic acid has been the recommended first-line treatment for shigellosis for many years, and has been used routinely to treat children, again without reports of arthropathy. Extensive use of the newer quinolones in children during the past few years has also confirmed the remarkable safety of these antibiotics, including the lack of reported arthropathies. There is, therefore, no reason to consider the potential toxicity of newer quinolones to be any greater than that of nalidixic acid.

2. Cost
   The cost of treatment with ciprofloxacin was an issue a few years ago when the drug was still under patent. However, the cost of ciprofloxacin has dropped significantly since the patent expired and the drug became available as a generic. The cost of treatment with ciprofloxacin is now about one-third that of treatment with nalidixic acid. For example, a 5-day course of treatment with nalidixic acid for a 15 kg child costs about US$ 0.34, while treatment of the same child for 3 days with ciprofloxacin costs about US$ 0.10.

Based on its safety, efficacy and reduced cost, ciprofloxacin is now the recommended first-line antibiotic for shigellosis. The use of nalidixic acid should be discontinued, even in areas where it is still effective against Shigella.

Source: WHO Weekly Epidemiological Record, Vol 79, N^o 24, 2004.