Azithromycin for Typhoid Fever

Abstract & Commentary

Synopsis: Five days of oral treatment with azithromycin appeared to be at least as effective as a similar duration of treatment of treatment with ceftriaxone in children in Cairo with typhoid fever.

Source: Frenck RW Jr, et al. Short-Course Azithromycin for the Treatment of Uncomplicated Typhoid Fever in Children and Adolescents. Clin Infect Dis. 2004;38:951-957.

Frenck and colleagues randomized 68 children in Cairo with typhoid fever to treatment with either orally administered azithromycin (20 mg/kg po daily) or ceftriaxone (75 mg/kg IV daily), each for 5 days. The maximum daily doses allowed were 1000 mg and 2500 mg, respectively.

Both treatments were highly effective, with 94% of azithromycin and 97% of ceftriaxone recipients achieving clinical cure by day 7. The 2 clinical failures in the azithromycin group were due to mild gastrointestinal symptoms that resolved by 7 days without further intervention, and the single clinical failure in the ceftriaxone group was due to persisting fever, which also resolved without changes in management. The mean time to defervescence was 4.5 ± 1.9 days for azithromycin recipients and 3.6 ± 1.6 days for ceftriaxone recipients, a difference that was not statistically significant.

Only 1 patient, a ceftriaxone recipient, failed to achieve microbiologic cure. None of the isolates demonstrated in vitro resistance to ceftriaxone. The azithromycin MIC90 was 6 mcg/mL, with 7 isolates having an MIC > 8 mcg/mL, and thus considered resistant. Four of these 7 were recovered from patients randomized to receive azithromyin and, despite the in vitro results, all 4 were successfully treated with this azalide antibiotic.

Blood culture after 3 days of therapy was still positive in 12 of 31 (37.5%) patients treated with azithromycin, but in none of the 36 given ceftriaxone (P = 0.0001). Blood isolates from all 12 of those bacteremia persisting to day 3 on azithromycin remained susceptible to this antibiotic. All 12 patients were asymptomatic by the time the results of the blood culture were known. The only positive blood culture at day 8 was in a ceftriaxone recipient.

Bacteremic relapse after hospital discharge was detected in 5 patients, all of whom had been treated with ceftriaxone; each isolate remained susceptible in vitro to this antibiotic. Stool cultures were negative in all patients examined at a follow-up visit at 1 month. Both treatments were well tolerated.

Comment by Stan Derensinski, MD, FACP

It is estimated that 16 million cases of typhoid fever occur each year in the world. Unfortunately, many strains of Salmonella enterica serovar Typhi have acquired resistance to a number of antibiotics commonly used for treatment of this infection, resulting in the emergence of multidrug resistance (although this problem appears to be inexplicably receding in some areas).1 Such isolates are commonly resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole. Of great concern, is the decreasing susceptibility to fluoroquinolones.

While frank in vitro resistance (the NCCLS breakpoint is 4 mcg/ml) to fluoroquinolones among S. enterica serovar Typhi remains uncommon, reduced susceptibility is increasingly common. In 1998, 19% of isolates had an MIC to ciprofloxacin > 0.25 mcg/mL; most were from the Indian subcontinent.2 While these would be reported as susceptible, most are resistant to nalidixic acid, providing a clue to reduced fluoroquinolone susceptibility.

Treatment of typhoid fever due to infection with such isolates as ciprofloxacin has been associated with an increase in time to defervescence and a need for prolongation of therapy and, in some cases, with frank therapeutic failure.

The Sanford guide currently recommends treatment of typhoid fever with either ciprofloxacin or ceftriaxone, listing azithromycin as an alternative choice. Ceftriaxone of course, can only be administered parenterally.

The current study confirms, previous studies that used a longer duration of antibiotic administration, that azithromycin is an excellent choice for the treatment of typhoid fever. In this study, clinical cure rates did not differ between azithromycin and ceftriaxone recipients, despite a longer duration of bacteremia in the former group. On the other hand, no bacteremic relapses were detected among the azithromycin recipients, in contrast to a 14% relapse rate in ceftriaxone recipients, a finding seen in previous evaluations of this antibiotic.

The longer duration of bacteremia in azithromycin recipients may be due to a number of factors, including the relatively low serum concentrations achieved with this drug and the presumed more rapid bactericidal activity of ceftriaxone. The absence of relapses in azithromycin recipients may be related to the extraordinarily high intracellular concentrations achieved with this drug, and the fact that Salmonella is an intracellular pathogen. These high intracellular concentrations may also account for the success of therapy in a number of cases, despite in vitro susceptibility test results that are interpreted by NCCLS standards as indicating resistance.

The increasing resistance of bacterial enteric pathogens to fluoroquinolones in some parts of the world, including the Indian subcontinent and southeast Asia, raises concern regarding the optimal self-treatment for travelers’ diarrhea. The recent FDA approval of rifaximin provides a novel alternative, but this rifampin derivative has a more limited antibacterial spectrum and is poorly absorbed from the gastrointestinal tract.3 Azithromycin may prove a better choice in some instances, and would have the potential to abort cases of typhoid fever in travelers.

References

1. Parry CM. Typhoid Fever. Curr Infect Dis Reports. 2004;6:27-33.

2. Threlfall EJ, et al. Ciprofloxacin-Resistant Salmonella typhi and Treatment Failure. Lancet. 1999;353:1590-1591.

3. Rifaximin (Xifaxan) for Travelers’ Diarrhea. Med Lett. 2004;46:74-75.

Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor of Infectious Disease Alert.