Nationwide survey of the development of drug resistance in the pediatric field in 2000-2001, 2004, 2007, 2010, and 2012: evaluation of the changes in drug sensitivity of Haemophilus influenzae and patients' background factors.

The Drug-Resistant Pathogen Surveillance Group in Pediatric Infectious Disease has conducted surveillance of pediatric patients with respiratory tract infections, meningitis, and sepsis five times (in 2000-2001 [period 1], 2004 [period 2], 2007 [period 3], 2010 [period 4], and 2012 [period 5]). With respect to the clinically isolated Haemophilus influenzae, the drug susceptibility, the frequency of drug-resistant strains, and patients' background factors in each period have already been reported. Here we evaluate trends in the development of drug resistance in H. influenzae, and the relationship between the development of drug resistance and patients' background factors in the aforementioned five periods. H. influenzae derived from pediatric patients with respiratory tract infections that had been previously collected (period 1, 448 isolates; period 2, 376 isolates; period 3, 386 isolates; period 4, 484 isolates; and period 5, 411 isolates) were analyzed. The proportions of ß-lactamase-nonproducing ampicillin (ABPC)-intermediate resistant (BLNAI) strains + β-lactamase-nonproducing ABPC-resistant (BLNAR) strains were 28.8% in period 1, 59.3% in period 2, 61.1% in period 3, 58.1% in period 4, and 63.5% in period 5, showing a rapid increase from period 1 to period 2 followed by an almost constant rate of approximately 60%. The proportion of ß-lactamase-producing ABPC-resistant (BLPAR) strains + ß-lactamase-producing clavulanic acid/amoxicillin-resistant (BLPACR) strains was 4.4% in period 3, which was somewhat low; however, there were no significant changes in the proportions of these strains, which ranged between 6.4% and 8.7% throughout the surveillance period except for period 3. The drugs whose MIC90 values against BLNAR strains were low throughout the surveillance included piperacillin (0.25 μg/mL) and tazobactam/piperacillin (0.125-0.25 μg/mL) in the penicillins; cefditoren and ceftriaxone (0.25-0.5 μg/mL for both) in the cephems; meropenem (0.5-1 μg/mL) and tebipenem (1 μg/mL) in the carbapenems; and levofloxacin, tosufloxacin, and garenoxacin (≤ 0.06 μg/mL for all) and norfloxacin (0.06-0.125 μg/mL) in the quinolones. We investigated the relationship between the frequency of BLNAS strains/BLNAI + BLNAR strains and patients' background factors in each surveillance period. Significant differences were shown on age category (< 3 years or ≥ 3 years) in all periods except period 4, and the presence/absence of prior administration of antimicrobial agents within one month in period 2 and period 3. In all periods, the frequency of BLNAI + BLNAR strains were higher in patients aged < 3 years than in patients aged ≥ 3 years, and were also higher in patients with presence of prior treatment than in patients without prior treatment. We consider that it is important to promote the proper use of antimicrobial agents by conducting surveillance continuously in the future to clarify the relationship between the development of drug resistance in H. influenzae and patients' background factors and provide those information to clinical setting.