Consultation on the Revision of Carbapenem Breakpoints

Transcription

1 Consultation on the Revision of Carbapenem Breakpoints July 2018 Please send comments to the EUCAST Scientific Secretary at by September 15. EUCAST revision of carbapenem breakpoints July 2018 Page 1 of 22

2 Summary of Proposed Breakpoint Changes Changes are highlighted in yellow PK-PD Breakpoints Carbapenem Current Breakpoint Proposed Breakpoint S R > S R > Doripenem Ertapenem Imipenem Meropenem Enterobacterales Carbapenem Current Breakpoint Proposed Breakpoint S R > S R > Doripenem Ertapenem Imipenem (except Proteus spp., Providencia spp. and M. morganii) Imipenem (Proteus spp., Providencia spp. and M. morganii) Meropenem Applies to high-dose treatment Acinetobacter spp. Carbapenem Current Breakpoint Proposed Breakpoint S R > S R > Doripenem Ertapenem Imipenem Meropenem Pseudomonas spp. Carbapenem Current Breakpoint Proposed Breakpoint S R > S R > Doripenem Ertapenem Imipenem Meropenem Applies to high-dose treatment EUCAST revision of carbapenem breakpoints July 2018 Page 2 of 22

3 Anaerobes Carbapenem Current Breakpoint Proposed Breakpoint S R > S R > Doripenem Ertapenem Imipenem Meropenem Haemophilus influenzae Carbapenem Current Breakpoint Proposed Breakpoint S R > S R > Meropenem meningitis Applies to high-dose treatment Streptococcus pneumoniae Carbapenem Current Breakpoint Proposed Breakpoint S R > S R > Meropenem meningitis Applies to high-dose treatment EUCAST revision of carbapenem breakpoints July 2018 Page 3 of 22

4 1 Background Carbapenem clinical breakpoints were established in 2008 and rationale documents were released in 2009 for meropenem, imipenem and ertapenem. These documents are available on the EUCAST website ( Since then, the pharmacodynamics targets have been revisited, new mechanisms of resistance have been described and a new carbapenem, doripenem, was given marketing authorisation in 2008 (withdrawn in Europe in 2014) and highlighted the need for consistency in comparison with imipenem and meropenem. These events have led to a critical re-evaluation of all carbapenem clinical breakpoints during which the relationship between PK-PD breakpoints and ECOFFs were reassessed as well as available data on carbapenem MIC values in carbapenemase-producing Enterobacterales and clinical outcomes when using carbapenems alone or in combination with other antimicrobial agents. Moreover, new clinical intermediate category definition as susceptible, increased exposure has been proposed. 2 Current breakpoints Current PK-PD breakpoints are listed in table 1 and clinical breakpoints for Enterobacterales, Acinetobacter spp. and Pseudomonas spp. in tables 2-4. The general procedure followed for setting PK-PD breakpoints is described by Mouton et al (2012). Table 1: Current PK-PD breakpoints for carbapenems Carbapenem Breakpoint PK-PD (non-species related) breakpoints are based on the indicated dosages S R > (See section 8 in rationale documents) Doripenem 1 2 Breakpoints apply to doripenem 500 mg x 3 daily administered intravenously over 1 hour as the lowest dose. 500 (1000 in augmented renal clearance) mg x 3 daily administered over 4 hours was taken into consideration for severe infections and in setting the I/R breakpoint. Ertapenem Breakpoints apply to ertapenem 1000 mg x 1 daily administered intravenously over 30 minutes as the only dose. Imipenem 2 8 Breakpoints apply to imipenem 500 mg x 4 daily administered intravenously over 30 minutes as the lowest dose. 1 g x 4 daily was taken into consideration for severe infections and in setting the I/R breakpoint. Meropenem 2 8 Breakpoints apply to meropenem 1000 mg x 3 daily administered intravenously over 30 minutes as the lowest dose. 2 g x 3 daily was taken into consideration for severe infections and in setting the I/R breakpoint. EUCAST revision of carbapenem breakpoints July 2018 Page 4 of 22

5 Table 2: Current clinical breakpoints for Enterobacterales Carbapenem 1 Breakpoint S R > Notes 1. The carbapenem breakpoints for Enterobacterales will detect all clinically important resistance mechanisms (including the majority of carbapenemases). Some isolates that produce carbapenemase are categorised as susceptible with these breakpoints and should be reported as tested, i.e. the presence or absence of a carbapenemase does not in itself influence the categorisation of susceptibility. Carbapenemase detection and characterisation are recommended for public health and infection control purposes. Doripenem Low-level resistance is common in Morganella Ertapenem morganii., Proteus spp. and Providencia spp. Imipenem Meropenem 2 8 Table 3: Current clinical breakpoints for Acinetobacter spp. Carbapenem Breakpoint Notes S R > Doripenem Breakpoints relate to high dose therapy. Ertapenem - - Imipenem Meropenem 2 8 Table 4: Current clinical breakpoints for Pseudomonas spp. Carbapenem MIC breakpoint S R > Doripenem Breakpoints relate to high dose therapy. Ertapenem - - Imipenem Meropenem 2 8 EUCAST revision of carbapenem breakpoints July 2018 Page 5 of 22

6 Table 5: Current clinical breakpoints for Gram-positive and Gram-negative anaerobes. Carbapenem MIC breakpoint S R > Doripenem 1 1 Ertapenem 1 1 Imipenem 4 8 Meropenem 2 8 Table 6: Current clinical breakpoints for Haemophilus influenzae. Carbapenem MIC breakpoint S R > Meropenem (meningitis) Meropenem is the only carbapenem used for meningitis Table 7: Current clinical breakpoints for Streptococcus pneumoniae. Carbapenem MIC breakpoint S R > Meropenem (meningitis) Meropenem is the only carbapenem used for meningitis EUCAST revision of carbapenem breakpoints July 2018 Page 6 of 22

7 3 Proposed revised breakpoints Proposed revised breakpoints are listed in Table 8. Revision of the meningitis breakpoints for H. influenzae and S. pneumoniae due to single high-dose regimen used for this condition Table 8: Proposed revised breakpoints for carbapenems Organism group Agent PK-PD a Breakpoint S R > Comments Doripenem mg x 3 by 60 min iv infusion 500 mg x 3 by 4 h iv infusion Ertapenem mg x 1 by 30 min iv infusion Imipenem mg x 3 by 30 min iv infusion 1000 mg x 4 by 30 min iv infusion Meropenem mg x 3 by 30 min iv infusion 2000 mg x 3 by 3h iv infusion Enterobacterales Doripenem Applies to high-dose treatment Ertapenem Imipenem (species excluding Proteus, Providencia and Morganella morganii) Imipenem (Proteus spp., Providencia spp. and Morganella morganii.) Meropenem 2 8 Acinetobacter spp. Doripenem 1 2 Ertapenem - - Imipenem 2 4 Meropenem 2 8 Pseudomonas spp. Doripenem Applies to high-dose treatment. Ertapenem - - Imipenem Meropenem 2 8 Anaerobes Doripenem 1 2 Ertapenem Imipenem 2 4 Meropenem 2 8 EUCAST revision of carbapenem breakpoints July 2018 Page 7 of 22

8 Haemophilus influenzae Meropenem (meningitis) 2,3 Streptococcus pneumoniae Meropenem (meningitis) 2,3 2. Meropenem is the only carbapenem used for meningitis 3. Applies to high-dose treatment 2. Meropenem is the only carbapenem used for meningitis 3. Applies to high-dose treatment a. The PK-PD susceptible and resistant breakpoints relate to the lowest and highest exposure dosing regimen stated in the comments table, respectively. 4 Rationale for the revised carbapenem breakpoints 4.1 MIC distribution data and ECOFFs MIC distributions and ECOFFs for the carbapenems have been reviewed according to the newly developed procedures described in SOP These are displayed in Tables EUCAST revision of carbapenem breakpoints July 2018 Page 8 of 22

9 Total ECOFF 99% Table 9: Doripenem MIC distributions and ECOFFs Species (No. of distributions) Enterobacter cloacae (5) Enterococcus faecalis (11) Morganella morganii (10) Proteus mirabilis (26) Proteus vulgaris (9) Pseudomonas aeruginosa (15) * Staphylococcus aureus (5) Acinetobacter baumannii (3) Alcaligenes xylosoxidans (2) Bacteroides fragilis (2) Enterobacter aerogenes Escherichia coli (4) Haemophilus influenzae (4) Klebsiella oxytoca (3) Klebsiella pneumoniae (4) Serratia marcescens (3) Staphylococcus epidermidis MSSE (2) Streptococcus agalactiae (3) Streptococcus anginosus (3) Streptococcus group G (2) Streptococcus oralis (2) Enterobacter cloacae (5) * Excessively wide distribution. Further investigation required Too few distributions to establish an ECOFF EUCAST revision of carbapenem breakpoints July 2018 Page 9 of 22

10 Total ECOFF 99% Table 10: Ertapenem MIC distributions and ECOFFs Species (No. of distributions) Haemophilus influenzae (10) Morganella morganii (6) Proteus mirabilis (6) Staphylococcus aureus (5) Streptococcus agalactiae (7) Streptococcus pneumoniae (7) Acinetobacter baumannii (3) Bacteroides fragilis (2) Enterobacter cloacae (4) Enterococcus faecalis (4) Escherichia coli (4) Haemophilus parainfluenzae (2) Klebsiella pneumoniae (4) Moraxella catarrhalis (4) Proteus vulgaris (3) Klebsiella oxytoca (2) Streptococcus anginosus (3) Streptococcus group G (2) Streptococcus oralis (2) * Excessively wide distribution. Further investigation required Too few distributions to establish an ECOFF EUCAST revision of carbapenem breakpoints July 2018 Page 10 of 22

11 Total ECOFF 99% Table 11: Imipenem MIC distributions and ECOFFs Species (No. of distributions) Bacteroides fragilis (5) * Bacteroides thetaiotaomicron (5) * Citrobacter freundii (6) Enterobacter aerogenes (24) * Enterococcus faecalis (14) Escherichia coli (54) Haemophilus influenzae (10) * Klebsiella pneumoniae (39) Morganella morganii (16) Proteus mirabilis (11) Pseudomonas aeruginosa (60) * Klebsiella oxytoca (25) Staphylococcus aureus (27) Streptococcus agalactiae (5) Clostridium difficile (4) Haemophilus parainfluenzae (3) Moraxella catarrhalis (4) Neisseria gonorrhoeae (2) Serratia marcescens (4) Stenotrophomonas maltophilia (3) Streptococcus anginosus (2) Streptococcus oralis (2) Yersinia enterocolitica (2) * Excessively wide distribution. Further investigation required Too few distributions to establish an ECOFF EUCAST revision of carbapenem breakpoints July 2018 Page 11 of 22

12 Total ECOFF 99% Table 12: Meropenem MIC distributions and ECOFFs Species (No. of distributions) Bacteroides fragilis (23) Bacteroides thetaiotaomicron (9) Enterobacter aerogenes (15) Enterobacter cloacae (29) * Enterococcus faecalis (14) Escherichia coli (34) Klebsiella pneumoniae (33) Proteus mirabilis (6) Proteus vulgaris (5) Pseudomonas aeruginosa (42) * Klebsiella oxytoca (11) Staphylococcus aureus (5) Streptococcus pneumoniae (5) Bacteroides ovatus (3) Bacteroides vulgatus (2) Listeria monocytogenes (3) Moraxella catarrhalis (2) Morganella morganii (4) Proteus mirabilis (4) Providencia stuartii (2) Serratia marcescens (2) Staphylococcus capitis (3) Stenotrophomonas maltophilia (2) Streptococcus anginosus (3) Streptococcus group G (2) Streptococcus mitis (2) Streptococcus oralis (3) * Excessively wide distribution. Further investigation required Too few distributions to establish an ECOFF EUCAST revision of carbapenem breakpoints July 2018 Page 12 of 22

13 4.2 Pharmacodynamic data Pharmacodynamic data for carbapenems are presented in table 13. These data are slightly changed from those in the current rationale documents. Table 13: Summary of pharmacodynamic data for carbapenems % ft>mic for bacteriostasis (experimental) % ft>/mic for 1-log reduction (experimental) % ft>/mic for 2-log reduction (experimental) %ft>mic from clinical data Comments Enterobacterales, Pseudomonas aeruginosa Streptococcus pneumoniae Staphylococcus aureus PK-PD data for carbapenems are presented as class effects. There are no indications that the PK-PD properties differ between carbapenem agents. Cells are left empty when data are not readily available. References DeRyke CA, et al. Antimicrob Agents Chemother 2007; 51:1481. Li C, et al. Antimicrob Agents Chemother 2007; 51:1725 Maglio D, et al. Antimicrob Agents Chemother 2005; 49:276 Xuan D, et al. Antimicrob Agents Chemother 2002; 46:2990 Andes D, et al. ICAAC 2003 abstr. A308 Takata T, et al. J Infect Chemother 2004; 10:76 Sugihara K, et al. ICAAC 2008 abstr. A027 MacGowan AP et al. Antimicrob. Agents Chemother. 2008, 52: Mavridou et al. Antimicrob. Agents Chemother. 2015; 59: EUCAST revision of carbapenem breakpoints July 2018 Page 13 of 22

14 A 1-log drop in viable Gram-negative organisms in animal model infections requires 40% ft> MIC and a 2-log drop requires 40-50% ft >MIC. For carbapenems a PD target of 40% ft> MIC is usually regarded as sufficient. 4.2 Pharmacokinetic data In general, the pharmacokinetic profiles of imipenem, meropenem and doripenem are very similar, with a half-life of close to one hour. The protein binding of imipenem is higher (around 20%) than that of meropenem and doripenem (both < 10%), but this does not significantly affect the %ft>mic. The pharmacokinetics of ertapenem differ from the other carbapenems and protein binding is much higher (95%). Consequently, the half-life (approximately 4 h) is much longer. As the pharmacokinetic profiles of meropenem, imipenem and doripenem are similar, the pharmacodynamic profiles of these agents are primarily determined by the dose and dosing regimen and the activity of each carbapenem against the various bacterial species. Since the publication of the previous rationale documents, new data and population models have become available. These models have been used in the simulations below. 4.3 Monte Carlo simulations and PK-PD breakpoints Monte Carlo simulations (MCS) were performed for each carbapenem for different dosing regimens. Pharmacokinetic population models were used if available and specified below for each carbapenem. For the estimation of PK-PD breakpoints EUCAST normally use the 95 and 99% percentile (here-under sometimes referred to as confidence interval) to assess target attainment at different MIC values. For doripenem the standard dose is 500 mg x 3 administered by 60 min infusion with 500 mg x 3 infusion over 4-hours for severe infections. A dose of 1 g x 3 as a 4 h infusion may be considered in patients with augmented renal clearance, particularly those with creatinine clearance (CrCl) 150 ml/min, and/or in infections due to nonfermenting Gram-negative pathogens such as Pseudomonas spp. and Acinetobacter spp. The 99% confidence interval for the 500 mg dose administered by 60 min infusion results in an S breakpoint of 1 mg/l (Figure 1). The R breakpoint of 2 mg/l is based on a 500 mg x 3 dose administered by i.v. infusion over 4 h. Figure 1: Monte Carlo simulations for doripenem 2 dosing regimens EUCAST revision of carbapenem breakpoints July 2018 Page 14 of 22

15 For ertapenem the standard dose is 1000 mg x 1 administered by 30 min i.v. infusion and there is no higher dose. The 99% confidence interval for the 1000 mg dose administered by 30 min i.v. infusion results in an S breakpoint of 0.5 mg/l (Figure 2). There is no higher approved dose so the R breakpoint is >0.5 mg/l Figure 2: Monte Carlo simulations for ertapenem For imipenem the common dose is 1000 mg x 3 and the high dose 1000 mg x 4, both administered by 30 min i.v. infusion. The 99% confidence interval for the 1000 mg dose administered by 30 min i.v. infusion results in an S breakpoint of 2 mg/l (Figure 3). The R breakpoint of 4 mg/l is based on a 1000 mg x 4 dose. EUCAST revision of carbapenem breakpoints July 2018 Page 15 of 22

16 Figure 3: Monte Carlo simulations for imipenem 4 dosing regimens EUCAST revision of carbapenem breakpoints July 2018 Page 16 of 22

17 For meropenem the common dose is 1000 mg x 3 and the high dose 2000 mg x 3, both administered by 30 min i.v. infusion. In addition, meropenem is now also given as a 3 h infusion. It should be noted that there is a dearth of population PK models of meropenem in the literature. However, none of these models were suitable to use for MCS, either because they were from special populations or did not provide enough information. Therefore, the data as provided by Krueger et al (2005) were remodelled using Nonmem. In addition, the data from Mouton and Michel (1991) were also remodelled as a validation check. The 99% confidence interval for the 1000 mg dose administered by 30 min i.v. infusion results in an S breakpoint of 2 mg/l (Figure 4). The R breakpoint of 8 mg/l is based on a 2g dose given as a 3h infusion. Figure 5 provides a comparison between simulations based on two different models. The conclusions from both both models are the same. In addition, the tables for PTA are provided for both models. Figure 4: Monte Carlo simulation for meropenem 4 dosing regimens EUCAST revision of carbapenem breakpoints July 2018 Page 17 of 22

18 Figure 5 (including table): Monte Carlo simulations of a 1 g meropenem dose as a 0.5h infusion for the model based on the data of Krueger et al (left) and Mouton and Michel (right). The tables below the figure provide the PTA s. EUCAST revision of carbapenem breakpoints July 2018 Page 18 of 22

19 A summary of PK-PD breakpoints indicated by different doses is given in table 14. There is some variation in the doses for imipenem and meropenem and in this case the S breakpoint is based on the most common dose. EUCAST revision of carbapenem breakpoints July 2018 Page 19 of 22

20 Table 14: Summary of PK-PD breakpoints based on %ft>mic of 40 and 99% CI for various carbapenem dosing regimens Agent Dose (mg x daily frequency) Breakpoint Comments Doripenem 500 x 3 1 EUCAST S breakpoint 1 mg/l 500 x 3 1,2 2 EUCAST R breakpoint >2 mg/l 1. 4 h infusion 2. In patients with augmented renal clearance the dosing is 1000 mg x 3 with 4 h infusion Ertapenem 1000 x EUCAST S breakpoint 1 mg/l EUCAST R breakpoint >1 mg/l Imipenem 500 x x 4 2 EUCAST S breakpoint 2 mg/l Meropenem 1000 x x 4 4 EUCAST R breakpoint >4 mg/l 500 x x 3 2 EUCAST S breakpoint 2 mg/l 2000 x x EUCAST R breakpoint > 8 mg/l 3. 3 h infusion 5. Clinical data A prospective observational study of patients with bloodstream infections caused by VIM carbapenemase-producing K. pneumoniae showed that MICs of imipenem and meropenem >4 mg/l had a significant impact on 14-day mortality (p=0.044) (Daikos et al., 2009). Moreover, in a review, Tzouvelekis et al. (2012) compiled data for 50 patients receiving a carbapenem in monotherapy for treatment of infection with KPCor MBL-producing K. pneumoniae isolates (most from bloodstream infections). Percentage failure of treatment was 29.4% (5/17), 25.0% (3/12), 28.6% (2/7), and 33.3% (2/6) when the K. pneumoniae isolates exhibited MIC values of 1, 2, 4 and 8 mg/l, respectively. The percentage failure of treatment increased to 75% for K. pneumoniae isolates displaying carbapenem MICs of >8 mg/l. In two more recent studies, a significantly higher mortality rate was observed in patients treated with monotherapy than in those treated with combination therapy (Tumbarello et al., 2012; Daikos et al., 2014). The lowest mortality rate was observed in patients treated with combination therapy including a carbapenem. Nevertheless, mortality was increased when carbapenem MICs for carbapenemase-producing K. pneumoniae isolates were higher than 8 mg/l. Interestingly, in the study by Tumbarello et al, mortality was absent when combination therapy included EUCAST revision of carbapenem breakpoints July 2018 Page 20 of 22

21 meropenem and an active agent against infections due to isolates displaying meropenem MICs 2 mg/l. However, only a low number of patients could be evaluated, At least with KPC- and VIM-producing K. pneumoniae isolates, these data support proposed breakpoints. Although some clinical data might support a resistant breakpoint of >8 mg/l, the number of isolates with carbapenem MICs of 8 mg/l in the available clinical studies are low and MCS data (section 4.3) do not support an R breakpoint of than >8 mg/l, even if a 3h infusion is applied. EUCAST revision of carbapenem breakpoints July 2018 Page 21 of 22

22 6. References for PK-PD analyses and clinical data Mouton, J. W. et al. (2012). The role of pharmacokinetics/pharmacodynamics in setting clinical MIC breakpoints: the EUCAST approach. Clin Microbiol Infect 18(3): E37-E45. Mouton JW, Michel MF. Pharmacokinetics of meropenem in serum and suction blister fluid during continuous and intermittent infusion. J Antimicrob Chemother Dec;28(6): Daikos GL, Petrikkos P, Psichogiou M, Kosmidis C, Vryonis E, Skoutelis A, Georgousi K, Tzouvelekis LS, Tassios PT, Bamia C, Petrikkos G. Prospective observational study of the impact of VIM-1 metallo-beta-lactamase on the outcome of patients with Klebsiella pneumoniae bloodstream infections. Antimicrob Agents Chemother. 2009; 53: Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou A, Stefanou I, Sypsa V, Miriagou V, Nepka M, Georgiadou S, Markogiannakis A, Goukos D, Skoutelis A. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother. 2014; 58: Krueger WA, Bulitta J, Kinzig-Schippers M, Landersdorfer C, Holzgrabe U, Naber KG, Drusano GL, Sörgel F. Evaluation by monte carlo simulation of the pharmacokinetics of two doses of meropenem administered intermittently or as a continuous infusion in healthy volunteers. Antimicrob Agents Chemother May;49(5): Tumbarello M, Viale P, Viscoli C,Trecarichi EM, Tumietto F, Marchese A, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis 2012; 55: Tzouvelekis LS, Markogiannakis A, Psichogiou M, Tassios PT, Daikos GL. Carbapenemases in Klebsiella pneumoniae and other Enterobacterales: an evolving crisis of global dimensions. Clin Microbiol Rev. 2012; 25: EUCAST revision of carbapenem breakpoints July 2018 Page 22 of 22