Decreased Erythromycin Use after Antimicrobial Reimbursement Restriction for Undocumented Bacterial Upper Respiratory Tract Infections Significantly Reduced Erythromycin Resistance in Streptococcus pyogenes in Taiwan

SIR—Taiwan has become one of the epicenters of antibiotic resistance worldwide [1]. Because of the high rates of resistance among commonly encountered bacteria, many measures to control resistance problems, including more-rigorous enforcement of prescription-filling practices in the pharmacy (starting in 1997) and educational programs about appropriate antibiotic use for physicians and patients (starting in 1998), were instituted in Taiwan before 2001, but there was minimal impact [1, 2]. Beginning in February 2001, an additional restrictive governmental policy was added to deny reimbursement through the National Health Insurance (NHI) system for use of antibiotics for the treatment of acute upper respiratory tract infections for which there was no evidence of bacterial involvement. The prevalence of erythromycin resistance among Streptococcus pyogenes was remarkably high (40%-70%) in Taiwan before 2000 [1, 2]. These macrolide antibiotics (i.e., erythromycin, clarithromycin, roxithromycin, and azithromycin) were widely used for the treatment of unspecified upper respiratory tract infections, suspected lung infection due to atypical pathogens (Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae), and Helicobacter pylori infection. Widespread physician overuse of macrolides for treatment of undocumented bacterial upper respiratory tract infection was considered the biggest contributor to macrolide resistance. To assess the relationship between the impact of reimbursement policy on macrolide (erythromycin) resistance in S. pyogenes, the annual rates of erythromycin resistance from 3 major teaching hospitals in different regions of Taiwan and data on annual use of macrolides obtained from Intercontinental Marketing Service Health (Taipei, Taiwan) were evaluated for the periods before and after the implementation of the policy in February 2001. The 3 hospitals included National Taiwan University Hospital (NTUH; Taipei), a 2000-bed hospital located in the northern region of Taiwan; Taichung Veterans General Hospital (VGH-Taichung; Taichung), a 1400-bed hospital in the central region; and National Cheng-Kung University Hospital (NCKUH; Tainan), an 1800-bed hospital in the southern region. The total rate of use of 4 macrolides (erythromycin, clarithromycin, roxithromycin, and azithromycin) increased steadily from 1997 (0.484 defined daily doses [DDDs] per 1000 inhabitants per day) to 2000 (0.640 DDDs per 1000 inhabitants per day) and decreased thereafter (mainly for erythromycin), as a result of the restrictive reimbursement policy, to 0.559 DDDs per 1000 inhabitants per day in 2001 and 0.301 DDDs per 1000 inhabitants per day in 2003 (figures 1 and 2). Although there was a slight increase in the use of all macrolides from 1997 to 2000, use of erythromycin decreased from 0.543 DDDs per 1000 inhabitants per day in 1998 to 0.447 DDDs per 1000 inhabitants per day in 2000 (an 18% reduction), which may have been associated with the restrictive governmental policy in the pharmacy. As a result of the implementation of the restrictive antibiotic reimbursement policy by the NHI, a 71% reduction in the rate of erythromycin use was found from 2000 to 2003 (0.129 DDDs per 1000 inhabitants per day). Although the use of azithromycin increased steadily from 1997 to 2003 and that of clarithromycin and roxithromycin increased from 1997 (0.047 DDDs per inhabitant per day) to 2002 (0.216 DDDs per 1000 inhabitants per day), a 49% reduction was also found in clarithromycin and roxithromycin consumption (0.216 DDDs per 1000 inhabitants per day in 2002 and 0.137 DDDs per 1000 inhabitants per day in 2003). Trend of resistance to erythromycin among Streptococcus pyogenes isolates recovered from patients treated at 3 major hospitals in Taiwan (National Taiwan University Hospital [NTUH], Taichung Veterans General Hospital [VGH-Taichung], and National Cheng Kung University Hospital [NCKUH]) and amount of macrolide consumption (in defined daily doses/1000 inhabitants per day [DID]) in Taiwan during 1997–2003. White arrow, year that pharmacy restrictions were implemented; gray arrow, year that educational programs were instituted; black arrow, year that National Health Insurance nonimbursement policy for restriction of antibiotic use was implemented. Relationship between erythromycin resistance in Streptococcus pyogenes (with use of pooled data from 2 hospitals in 1997–1998 and 3 hospitals in 1999–2003) and erythromycin use. Pearson's correlation coefficient (r) was used to assess the correlation between erythromycin resistance and erythromycin consumption. The number in parentheses indicates the number of isolates tested in the indicated year. DID, defined daily doses/1000 inhabitants per day. A total of 1326 isolates of S. pyogenes recovered from the 3 health care centers were tested, including 724 isolates from NTUH from the period of 1997–2003, 283 isolates from VGH-Taichung from the period of 1997–2003, and 319 isolates from NCKUH from the period of 1999–2003. Eight-six percent of these isolates were recovered from throat swabs, and the rest were recovered from pus or blood samples. Disk diffusion susceptibility data from the 3 hospitals, as well as analysis of pooled data, demonstrated a similar trend of decrease in erythromycin resistance, for which there was a parallel reduction in the use of macrolides (mainly erythromycin) (figure 1). Overall, the pooled rates of erythromycin resistance were 61% of isolates in 1998 (data were from only 2 hospitals), 39% in 2000, and 17% in 2003. The decrease in the rate of erythromycin resistance among S. pyogenes was significantly correlated with the decreased use of erythromycin at NTUH (r = 0.896 [Pearson's correlation coefficient]; P <.001), VGH-Taichung (r = 0.886; P <.001), and NCKUH (r = 0.959; P <.01). A linear relationship (r = 0.928; P ⩽.001) was noted between the rates of erythromycin resistance in S. pyogenes (from pooled data from 2 hospitals during 1997–1998 and from 3 hospitals during 1999–2003) and erythromycin use (figure 2). This study found that an NHI policy to restrict reimbursement for antibiotic treatment of undocumented bacterial upper respiratory tract infection, combined with continuous use of preexisting antibiotic-control measures for overcoming antibiotic resistance in Taiwan, significantly reduced the use of erythromycin by 53% (from 0.640 DDDs per 1000 inhabitants per day in 2000 to 0.301 DDDs per 1000 inhabitants per day in 2003), resulting in a remarkable decrease of erythromycin resistance in S. pyogenes (a 22% reduction from 2000 to 2003). The present finding that a reduction in use of macrolides (mainly erythromycin) was linked to a decrease in the rate of erythromycin resistance in S. pyogenes parallels previous findings from Japan, Italy, and Finland [3–5], but this study was more informative about the importance of the specific policy steps needed to achieve these goals. Our results suggest the primary importance of the reimbursement policy and that it is a more effective measure against macrolide use than are pharmacy restriction and education, all of which are key components of a successful strategy to decrease erythromycin resistance. The increasing use of azithromycin (frequently combined with use of a β-lactam antibiotic) for the treatment of lower respiratory tract infection, as well as the loose restrictions imposed by the NHI against its use, are alarming. Previous reports have indicated that azithromycin, an agent with a long half-life and longer selective window, is more likely to select resistance [5]. Although our study does not support this finding at this time, it is possible that consumption levels need to exceed a certain threshold to trigger the emergence of resistance [5]. The adoption of reimbursement restrictions to limit the unnecessary use of antimicrobial agents in countries with national health insurance programs may be an effective method for controlling erythromycin resistance in S. pyogenes. Potential conflicts of interest. All authors: no conflicts.