Clinically and microbiologically derived azithromycin susceptibility breakpoints for Salmonella enterica serovars Typhi and Paratyphi A.

Azithromycin is an effective treatment for uncomplicated infections with Salmonella enterica serovar Typhi and serovar Paratyphi A (enteric fever), but there are no clinically validated MIC and disk zone size interpretative guidelines. We studied individual patient data from three randomized controlled trials (RCTs) of antimicrobial treatment in enteric fever in Vietnam, with azithromycin used in one treatment arm, to determine the relationship between azithromycin treatment response and the azithromycin MIC of the infecting isolate. We additionally compared the azithromycin MIC and the disk susceptibility zone sizes of 1,640 S. Typhi and S. Paratyphi A clinical isolates collected from seven Asian countries. In the RCTs, 214 patients who were treated with azithromycin at a dose of 10 to 20 mg/ml for 5 to 7 days were analyzed. Treatment was successful in 195 of 214 (91%) patients, with no significant difference in response (cure rate, fever clearance time) with MICs ranging from 4 to 16 µg/ml. The proportion of Asian enteric fever isolates with an MIC of ≤ 16 µg/ml was 1,452/1,460 (99.5%; 95% confidence interval [CI], 98.9 to 99.7) for S. Typhi and 207/240 (86.3%; 95% CI, 81.2 to 90.3) (P < 0.001) for S. Paratyphi A. A zone size of ≥ 13 mm to a 5-µg azithromycin disk identified S. Typhi isolates with an MIC of ≤ 16 µg/ml with a sensitivity of 99.7%. An azithromycin MIC of ≤ 16 µg/ml or disk inhibition zone size of ≥ 13 mm enabled the detection of susceptible S. Typhi isolates that respond to azithromycin treatment. Further work is needed to define the response to treatment in S. Typhi isolates with an azithromycin MIC of >16 µg/ml and to determine MIC and disk breakpoints for S. Paratyphi A.

In vitro evaluation of a new cefixime-clavulanic acid combination for gram-negative bacteria.

The study was conducted to evaluate a new cefixime-clavulanic acid combination for in vitro susceptibility towards gram-negative bacteria. A total of 220 isolates of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeroginosa, Acinetobacter spp, Salmonella enterica serovar Typhi and Salmonella enterica serovar Typhimurium were included in the study. The isolates were tested for susceptibility towards the new combination antimicrobial molecule cefixime with clavulanic acid by disk diffusion and Epsilometer strip (E-strip) Minimum Inhibitary Concentration (MIC) method. Of the 101 E. coli and K. pneumoniae isolates, 62.4% were found to be extended spectrum beta-lactamase (ESBL) producers. Almost half of these were from the community and 55.6% were hospital isolates. Of the ESBL isolates, 19% were AmpC (cephalosporinases that are poorly inhibited by beta lactamase inhibitor) producers while the remaining 81% were non AmpC ESBL producers. The AmpC producers were resistant to both cefixime and the combination, while the non-AmpC producers were sensitive to the combination. The addition of clavulanate to cefixime did not improve the sensitivities of P. aeruginosa and Acinetobacter isolates. There were no ESBL isolates among the S. Typhi isolates, all of which were sensitive to cefixime. Of the S. Typhimurium, 88.9% were ESBL producers and all of these were resistant to cefixime but sensitive to the combination. The combination of cefixime with clavulanic acid offers the advantage of oral administration and appears to be a viable option for the treatment of uncomplicated community acquired infections caused by non-AmpC ESBL producing gram-negative bacteria.