Infection Control & Hospital Epidemiology
Table 2. Rate Ratiosa (RRs) and Associated 95% Confidence Intervals (CIs) to Compare Annual Trends in Fluoroquinolone Susceptibility Rates Before (1998–2005) and After (2006–2016) the Implementation of an Antimicrobial Stewardship Program Requiring Preauthorization for Fluoroquinolone Use
Organism Overall
Acinetobacter spp. Enterobacter cloacae Escherichia coli
Klebsiella pneumoniae Pseudomonas aeruginosa
1998–2005 RR (95% CI) 0.935 (0.918–0.954) 0.871 (0.833–0.912) 0.898 (0.870–0.926) 0.952 (0.941–0.964) 0.976 (0.964–0.989) 0.937 (0.923–0.951)
aEstimated from Poisson regression. bP value for the comparison of annual trends between periods.
susceptibility may be due to the use of FQ in the community; thus, to achieve a sustained increase in FQ susceptibility among E. coli isolates, community prescribing practices must be targeted. Similar studies have demonstrated that hospital E. coli resistance correlates to community FQ use and not to hospital FQ use.14–17 In a study of 9 hospitals and several long-term care facilities, an FQ restriction program was associated with a decline in FQ prescriptions at their facilities, a decrease in the FQ resistance rate in E. coli urinary isolates, and a concomitant decrease in FQ use in the community.18 Other stewardship programs that only restricted FQ use in hospitals have failed to demonstrate any improvement in E. coli FQ resistance.19–21 Thus, community FQ use, as opposed to hospital use, appears to be driving the devel- opment of E. coli resistance and its persistence, and stewardship efforts focusing on community restriction are essential. In terms of the classic healthcare-associated pathogens, there
are data demonstrating limited success in improving P. aerugi- nosa susceptibility in the context of FQ restriction, but suscept- ibility data pertaining to E. cloacae, Acinectobacter spp. and K. pneumoniae susceptibility have not shown significant improve- ment with similar restriction programs.20,21,26,27 Interestingly, a 1997 study showed that while E. cloacae, Acinetobacter spp. and K. pneumoniae did not improve their susceptibility rates to ciprofloxacin with restricted use, susceptibility rates for non- restricted antibiotics, including β-lactams, demonstrated improvement.26 Other studies have shown similar improvements in susceptibility to other antibiotic classes, including decreasing rates of extended spectrum β-lactamases (ESBL)–producing urinary isolates with FQ restriction.18 Fluoroquinolones, β-lac- tams, and aminoglycosides are known to co-select for resistance, even with chemically unrelated drug exposure due to multiple plasmid-mediated mechanisms that carry resistance genes to multiple drug classes, such as the E. coli ST131 clone.28 Fluor- oquinolone exposure is a risk factor for development of ESBL E. coli urinary tract infections, and globally, 35%–65% of ESBL- producing Enterobacteriaceae are also FQ resistant.28 ESBL pro- ducing bacteria continue to be an escalating problem, especially in the southeastern United States,29 and adoption of FQ restriction in stewardship programs is a useful tool available to fight this trend. Despite the continued decrease in FQ susceptibility in E. coli in our study, our overall ESBL rates are low for all isolates, which indicates less likely clonal expansion of multidrug-resistant bacteria in our institution. Given the dual approach that our stewardship program has taken not only in restricting empiric FQ use but also in
streamlining the choices of FQs through a restricted formulary, we cannot definitively conclude which aspect had the largest effect on our observed susceptibility results. Interestingly, some in vitro data show that gram-negative resistance to levofloxacin occurs faster and reaches higher MICs than for ciprofloxacin.30 Not surprisingly, a survey of US hospital data found that increasing levofloxacin and ofloxacin expenditures were corre- lated with decreasing P. aeruginosa susceptibility to cipro- floxacin.31 In contrast, increased ciprofloxacin use has not been associated with FQ resistance, suggesting that levofloxacin is playing a more significant role in driving FQ class resistance. Thus, the removal of levofloxacin from our formulary may have had a significant impact on our susceptibility profile. Our study had several limitations. Our data were compiled
from a single academic medical center. The stewardship initiative was broadly applied; thus, no control units or hospitals were available for comparison. We did not collect data on the indica- tions for FQ use to evaluate the quality of our restricted use policy; instead, they used FQ DOT per 1,000 patient days as a surrogate measure. Based on this measure alone, our program was highly successful. We witnessed a 60% decline in use between the pre- and postimplementation data. Furthermore, these data focus on clinical isolates gathered in the microbiology laboratory; thus, they do not distinguish between colonizing isolates versus true pathogens. More detailed data on the influence of restricted-use policies on prescribing practices may help elucidate areas of focus for programmatic improvement and may better explain the lack of susceptibility improvement in certain species. For example, it is not clear to us why Acinetobacter spp. FQ susceptibility initially improved, then plateaued, and has started to decline over the last few years despite continued low FQ use. This may be the result of cluster outbreaks of Acinetobacter, but this trend will require further study. This study occurred over a long period; thus, infection prevention efforts may have also played a role in improving FQ susceptibility. Finally, our data demonstrate the feasibility and the critical importance of long-term tracking to re- evaluate the influence of stewardship programs. As hospitals and health systems attempt to combat growing
resistance rates to antibacterial agents, FQ resistance in gram- negative organisms remains a serious challenge. Our data demonstrate that decreasing overall FQ use, possibly through limiting routine access to levofloxacin specifically, can result in improvement overall in susceptibility of several gram-negative bacteria. For certain organisms, such as E. coli, decreasing hospital use alone appears to be insufficient to reverse the FQ resistance
2006–2016 RR (95% CI) 1.000 (0.990–1.009) 1.038 (1.005–1.072) 1.028 (1.013–1.044) 0.981 (0.975–0.987) 1.002 (0.996–1.008) 1.013 (1.006–1.020)
P Valueb <.0001 <.0001 <.0001 <.0001 .0002
<.0001
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