February 03, 2016
3 min read

Fluoroquinolones fail to treat patients with enteric fever in Nepal

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A randomized controlled trial of gatifloxacin, a fourth-generation fluoroquinolone, for the treatment of enteric infections was forced to end early due to the emergence of drug resistance, according to researchers. In addition, the trial’s comparator drug, ceftriaxone, was suboptimal in a large number of patients with culture-negative enteric fever.

“This study is important because fluoroquinolones, the commonly used drugs in the treatment of enteric fever, are clearly shown to be now ineffective,” Buddha Basnyat, MD, professor at Oxford University-Patan Academy of Health Sciences in Kathmandu, Nepal, told Infectious Disease News. “The scary news is that this may hold true for not only the treatment of enteric fever in Nepal, but also most of South Asia because resistant isolates of the organisms that cause enteric fever also seem to be prevalent there. Returning Western travelers who suffer from enteric fever should also not be treated with fluroquinolones as most of them who suffer from this disease will give a history of travel to South Asia.”

Buddha Basnyat, MD

Buddha Basnyat

Every year, enteric fever affects 27 million people and kills 200,000 worldwide, as antibiotic resistance remains a major challenge to treatment, the researchers wrote. To treat enteric fever in South Asia, clinicians often use the IV antibiotic ceftriaxone, a third-generation cephalosporin, which has been associated with slow clinical improvement and high relapse burden. However, another commonly used antibiotic, gatifloxacin, a fourth-generation oral fluoroquinolone, was associated with rapid fever clearance and low relapse burden when taken for 7 days. Thus, the researchers hypothesized that gatifloxacin would be superior to ceftriaxone in treating enteric fever.

From Sept. 18, 2011 to July 14, 2014, Basnyat and colleagues performed an open-label, randomized controlled trial comparing gatifloxacin with ceftriaxone in patients with uncomplicated enteric fever at two medical centers in the Kathmandu Valley, Nepal. Patients were considered to have enteric fever if they presented with a temperature greater than 100.4° F for at least 4 days without a focus of infection. The researchers enrolled 239 patients and administered treatment for 7 days in two groups of patients. Each day patients in the first group (n = 120) received 10 mg/kg oral gatifloxacin. In the second group (n = 119), patients aged 2 to 13 years received between 60 mg/kg and 2 g IV ceftriaxone, and those aged 14 years and older received 2 g IV ceftriaxone daily. The researchers confirmed enteric fever by performing a blood culture test alongside treatment for all patients.

According to Basnyat and colleagues, 15% of patients who received gatifloxacin and 16% who received ceftriaxone had failed treatment (HR = 1.04; 95% CI, 0.55-1.98) — a nonsignificant difference. Among those with culture-confirmed enteric fever, 26% who had received gatifloxacin and 7% who received ceftriaxone failed treatment (HR = 0.24; 95% CI, 0.08-0.73). In patients with a negative blood culture, the researchers said 3% of those who received gatifloxacin and 23% who received ceftriaxone failed treatment (HR = 7.5; 95% CI, 1.71-32.8). The emergence of Salmonella Typhi strains that were resistant to gatifloxacin led the trial to stop.

The researchers wrote that fluoroquinolones will shortly become globally ineffective in treating enteric fever due to the emergence of resistant strains. In addition, they said that a large proportion of patients with a negative blood culture but who showed symptoms of enteric fever might have had other bacterial infections. Because there is no rapid diagnostic test that can accurately differentiate between enteric fever and other bacterial infections, the researchers suggested that clinicians should combine ceftriaxone with doxycycline for patients without a positive blood culture who do not respond to ceftriaxone alone.

“Antimicrobials, specifically fluoroquinolones, are one of the only routinely used control measures for enteric fever,” the researchers said. “Effective surveillance programs, the assessment of novel diagnostics, new treatment options, and the use of existing vaccines and development of next-generation vaccines are now a greater priority than ever.”

In an accompanying editorial, Edward T. Ryan, MD, professor in the department of immunology and infectious diseases at Harvard T.H. Chan School of Public Health, wrote that treating enteric fever will not be possible in the future if inappropriate antibiotic use does not stop.

“The study by Arjyal and colleagues strongly suggests that time is running out for effective antimicrobial drugs for enteric fever, and that the widespread inappropriate use of antimicrobial agents must be curtailed,” Ryan said. “With the loss of fluoroquinolones, treatment will be reduced to a few advanced antimicrobials that need to be given intravenously, oral agents such as cefixime (that has been associated with a high occurrence of clinical relapse in initial field studies), and azithromycin (the so-called ‘back-to-the-wall’ option). Soberingly, Salmonella strains that have acquired resistance to extended-spectrum beta-lactamases and carbapenemases will probably soon spread globally, further curtailing these already scarce options. Then, when azithromycin-resistant strains emerge (and they will), options will simply no longer exist.

“In the meantime, crucial methods that enhance our ability to care for these patients are either absent or have been lost. Now is the time to initiate coordinated control programs against typhoid before the storm hits — we have been warned.” – by Will Offit

Disclosures: The researchers and Ryan report no relevant financial disclosures.