Effects of breakpoint changes on carbapenem susceptibility rates of Enterobacteriaceae: Results from the SENTRY Antimicrobial Surveillance Program, United States, 2008 to 2012.

In the absence of clinical resistance, breakpoints for many antimicrobial agents are often set high. Clinical failures following use of the agents over time requires re-evaluation of breakpoints. This is based on patient response, pharmacokinetic/pharmacodynamic information and in vitro minimal inhibitory concentration data. Data from the SENTRY Antimicrobial Surveillance Program has shown that Clinical and Laboratory Standards Institute breakpoint changes for carbapenems that occurred between 2008 and 2012 in North America have resulted in decreased levels of susceptibility for some species. In particular, reduced susceptibility to imipenem was observed for Proteus mirabilis (35%) and Morganella morganii (80%). Minor decreases in susceptibility were also noted for Enterobacter species with ertapenem (5%) and imipenem (4.3%), and Serratia species with imipenem (6.4%). No significant decreases in susceptibility were observed for meropenem following the breakpoint changes. There were no earlier breakpoints established for doripenem. Very few of these Enterobacteriaceae produce carbapenamase enzymes; therefore, the clinical significance of these changes has not yet been clearly determined. In conclusion, ongoing surveillance studies with in vitro minimum inhibitory concentration data are essential in predicting the need for breakpoint changes and in identifying the impact of such changes on the percent susceptibility of different species.

Antimicrobial susceptibility breakpoints are initially determined under statutes by regulatory agencies (United States Food and Drug Administration and European Medicines Agency) at the time of clinical approval based on accumulated microbiology, pharmacokinetic (PK)/pharmacodynamic (PD) and clinical trial outcome information. On their release, resistance to antimicrobials is often uncommon. This is especially true for broad-spectrum β-lactams (third- and fourth-generation cephems and carbapenems), leading to elevated breakpoints and the subsequent risk of false-susceptible in vitro testing results when testing Enterobacteriaceae. Reports of clinical failures among cases caused by strains having minimum inhibitory concentration (MIC) values in the high susceptible range (1,2), and improved/ updated PK/PD analyses (3) have forced re-evaluations of clinical susceptibility breakpoints established for several antimicrobials approved from 1980 to 2000. These processes were initially addressed by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (4) and later by the Clinical and Laboratory Standards Institute (CLSI) (5–7).

Responses to these lowered CLSI breakpoints have varied widely, from “there was no perceived adverse clinical signal and in fact the change would lead to unneeded applications of potentially toxic broader spectrum agents” to “the new lowered breakpoints without companion resistance enzyme screening would place patients at risk, or these recent changes were based on flawed science” (8–12). Regardless of the ongoing debate, the CLSI breakpoint changes (6,7) have resulted in significantly decreased susceptibility rates for some β-lactams, particularly the carbapenems. In the present article, we document the extent of spectrum/coverage impact for the four most commonly used carbapenems (doripenem, ertapenem, imipenem and meropenem) in North America following CLSI document breakpoint modification (5–7).

These analyses used data from the SENTRY Antimicrobial Surveillance Program, an international resistance monitoring platform that reviews antimicrobial susceptibility data for a large number of agents and organisms each year since 1997. The strains, which come from many laboratories, are all tested using the same CLSI methodology (13) at JMI Laboratories (North Liberty, Iowa, USA). In this way, methodological and organism identification differences that may occur at primary testing laboratories are minimized or eliminated. It is also possible to temporally review changes to MIC values. This evaluation was performed to determine the effect of changing the breakpoints of four carbapenem agents on the perceived in vitro susceptibility of 19,382 strains of Enterobacteriaceae (seven species) isolated between 2008 and 2012. The determination was made by comparing MIC values using the 2010 and 2013 CLSI-defined breakpoints for these agents (5–7). The applied/compared breakpoints are presented in Table 1.

TABLE 1

Clinical Laboratory Standards Institute (CLSI) clinical breakpoint concentration (μg/mL) criteria for Enterobacteriaceae in 2010 and 2013 for carbapenems

Susceptibility breakpoints	Carbapenem and CLSI year*
	Doripenem		Ertapenem		Imipenem		Meropenem
	2010	2013	2010	2013	2010	2013	2010	2013
Susceptible	NC	≤1	≤2	≤0 5	≤4	≤1	≤4	≤1
Intermediate	NC	2	4	1	8	2	8	2
Resistant	NC	≥4	≥8	≥2	≥16	≥4	≥16	≥4

Criteria from CLSI, references 5–7. NC No criteria published

More than 19,000 strains representing seven species or genus groups of Enterobacteriaceae were included. These were strains isolated from participating laboratories in North America (predominantly from the USA). In all, there were 6882 Escherichia coli, 5467 Klebsiella species, 2662 Enterobacter species, 746 Citrobacter species, 1119 Serratia species, 1244 Proteus mirabilis and 490 Morganella morganii, ie, 96.0% of all enteric bacilli processed. Each strain was submitted to the monitor for storage and were then retested to confirm identity and perform susceptibility testing (6,11). Each carbapenem was tested in concentrations ranging from 0.06 μg/mL to 8 μg/mL using validated CLSI reference panels.

The results of the changes in breakpoints from 2010 to current criteria (6) are shown in Tables 1 and 2. Significant decreases or decline in susceptibility rates (defined as lowering of susceptibility of >4%) due to the reductions in breakpoints occurred for the following species – antimicrobial agent combinations: Enterobacter species for ertapenem (−5.0%) and imipenem (−4.3%), Serratia species for imipenem (−6.4%), P mirabilis for imipenem (−35.3%) and M morganii for imipenem (−80.4%). There were no notable changes for meropenem (all <1.0% reduction in susceptibility rates). No breakpoints for doripenem were published in 2010 (Table 1). For all species, susceptibility to doripenem was ≥98% using current breakpoint criteria. These revised breakpoints (6,7) were founded on solid PK/PD calculations for the most commonly used and indicated dosing regimens for doripenem (500 mg every 8 h), ertapenem (1 g every 24 h), imipenem (500 mg every 8 h or 1 g every 8 h) and meropenem (1 g every 8 h). These modified clinical breakpoints also efficiently separate carbapenemase-producing Enterobacteriaceae from wild-type susceptible populations (4,7,8) and more accurately predict clinical outcomes (2).

TABLE 2

Spectrum effects of Clinical Laboratory Standards Institute (CLSI) 2012 breakpoint criteria changes on carbapenems (results from the North America SENTRY Antimicrobial Surveillance Program, 2008–2012)

Enteric group (n tested)	% Susceptible (2012 criteria/2010 criteria)
	Ertapenem	Imipenem	Meropenem	Doripenem
Enterobacteriaceae (19,382)	97.1/98.1	92.4/98.6	98.3/98.6	98.3/−*
Escherichia coli (6882)	99.6/99.8	99.8/100	99.9/99.9	99.9/−
Klebsiella species (5467)	94.7/95.1	95.3/95.9	95.3/95.9	95.3/−
Enterobacter species (2662)	92.9[†]/97.9	94.7[†]/99.0	98.7/99.2	98.7/−
Proteus mirabilis (1244)	99.9/100	64.5/99.8	99.9/100	99.8/−
Serratia species (1119)	98.0/98.8	92.9[†]/99.3	98.8/99.2	98.8/−
Citrobacter species (746)	97.7/98.8	97.1/99.3	98.8/99.3	98.9/−
Morganella morganii (490)	100/100	19.6[†]/100	100/100	100/−

No earlier breakpoints were published by CLSI;

Significant (lowering of susceptibility rate of >4%) decline in susceptibility rate

EUCAST carbapenem breakpoints are similar to those of the CLSI (4,6), and the European group also publishes a warning that “low-level resistance is common in Morganella spp., Proteus spp. and Providencia spp.” when tested against imipenem. This phenomenon appears to be detected more credibly (Table 2) using the revised CLSI criteria (6,7). Furthermore, review of the initial imipenem clinical trial results from 1985 demonstrated suboptimal outcomes (≤60% eradications) for multiple types of infections caused by these indole-positive and -negative Proteae (14–19). Thus, one must conclude that these recent breakpoint modifications were appropriate, but also long overdue. Furthermore, the emergence of carbapenamase-mediated resistances, such as the KPC and NDM genes, in North America requires breakpoint changes to optimize choices of therapy among β-lactam agents (20,21), as well as initiating control interventions (22).

The lowering of breakpoints for the carbapenems has not had a profound negative effect on overall susceptibility for most species of Enterobacteriaceae when tested against the four carbapenem agents under surveillance. It is noteworthy that reduced susceptibility was observed for ertapenem and imipenem, but only for certain species. There has been no significant rate change for meropenem by reducing the breakpoints, and there has not been sufficient time or use of doripenem to identify whether breakpoints at this level will effectively identify strains that may fail therapy. Major reductions in breakpoint change-related susceptibility to imipenem have occurred in P mirabilis (35%) and M morganii; however, the rank order of carbapenem antimicrobial coverage remained the same in North America (doripenem = meropenem [98.3% to 98.3%] > ertapenem [97.1%] > imipenem [92.4%]) between 2010 and 2012.

It is still uncertain what these changes (6,7) will mean clinically over time. The vast majority of these Enterobacteriaceae tested against the carbapenems do not produce clinically significant carbapenemases; otherwise, reduced susceptibility to meropenem and possibly doripenem would also be observed (Table 2). The current study was based only on MICs to the carbapenems to reflect the changes made to breakpoints. It will be important, however, to continue to identify changes in susceptibility of the commonly prescribed broad-spectrum β-lactam agents and antimicrobial combinations in a global setting through ongoing surveillance networks (the SENTRY Program and the European Antimicrobial Resistance Surveillance Network).