Consultation on the Revision of Carbapenem Breakpoints

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

Summary of Proposed Breakpoint Changes Changes are highlighted in yellow PK-PD Breakpoints Carbapenem Current Breakpoint Proposed Breakpoint S R > S R > Doripenem 1 2 1 2 Ertapenem 0.5 1 0.5 0.5 Imipenem 2 8 2 4 Meropenem 2 8 2 8 Enterobacterales Carbapenem Current Breakpoint Proposed Breakpoint S R > S R > Doripenem 1 4 1 2 Ertapenem 0.5 1 0.5 0.5 Imipenem (except Proteus spp., Providencia spp. and M. morganii) Imipenem (Proteus spp., Providencia spp. and M. morganii) 2 8 2 4 -- -- 4 1 4 Meropenem 2 8 2 8 1. Applies to high-dose treatment Acinetobacter spp. Carbapenem Current Breakpoint Proposed Breakpoint S R > S R > Doripenem 1 2 1 2 Ertapenem -- -- Imipenem 2 8 2 4 Meropenem 2 8 2 8 Pseudomonas spp. Carbapenem Current Breakpoint Proposed Breakpoint S R > S R > Doripenem 1 2 1 2 Ertapenem -- -- Imipenem 2 8 4 1 4 Meropenem 2 8 2 8 1. Applies to high-dose treatment EUCAST revision of carbapenem breakpoints July 2018 Page 2 of 22

Anaerobes Carbapenem Current Breakpoint Proposed Breakpoint S R > S R > Doripenem 1 1 1 2 Ertapenem 1 1 0.5 0.5 Imipenem 4 8 2 4 Meropenem 2 8 2 8 Haemophilus influenzae Carbapenem Current Breakpoint Proposed Breakpoint S R > S R > Meropenem meningitis 1 0.25 1 0.25 0.25 1. Applies to high-dose treatment Streptococcus pneumoniae Carbapenem Current Breakpoint Proposed Breakpoint S R > S R > Meropenem meningitis 1 0.25 1 0.25 0.25 1. Applies to high-dose treatment EUCAST revision of carbapenem breakpoints July 2018 Page 3 of 22

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 (http://www.eucast.org/documents/rd). 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of resistance have been described and a new carbapenem, doripenem, was given marketing authorisation in 2008 (withdrawn in Europe in 2014) and highlighted the need for consistency in comparison with imipenem and meropenem.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 0.5 1 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

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 1 4 2. Low-level resistance is common in Morganella Ertapenem 0.5 1 morganii., Proteus spp. and Providencia spp. Imipenem 2 2 8 Meropenem 2 8 Table 3: Current clinical breakpoints for Acinetobacter spp. Carbapenem Breakpoint Notes S R > Doripenem 1 1 2 1. Breakpoints relate to high dose therapy. Ertapenem - - Imipenem 1 2 8 Meropenem 2 8 Table 4: Current clinical breakpoints for Pseudomonas spp. Carbapenem MIC breakpoint S R > Doripenem 1 1 2 1. Breakpoints relate to high dose therapy. Ertapenem - - Imipenem 1 4 8 Meropenem 2 8 EUCAST revision of carbapenem breakpoints July 2018 Page 5 of 22

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) 2 0.25 1 2. Meropenem is the only carbapenem used for meningitis Table 7: Current clinical breakpoints for Streptococcus pneumoniae. Carbapenem MIC breakpoint S R > Meropenem (meningitis) 2 0.25 1 2. Meropenem is the only carbapenem used for meningitis EUCAST revision of carbapenem breakpoints July 2018 Page 6 of 22

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 1 2 500 mg x 3 by 60 min iv infusion 500 mg x 3 by 4 h iv infusion Ertapenem 0.5 0.5 1000 mg x 1 by 30 min iv infusion Imipenem 2 4 1000 mg x 3 by 30 min iv infusion 1000 mg x 4 by 30 min iv infusion Meropenem 2 8 1000 mg x 3 by 30 min iv infusion 2000 mg x 3 by 3h iv infusion Enterobacterales Doripenem 1 2 1. Applies to high-dose treatment Ertapenem 0.5 0.5 Imipenem (species excluding Proteus, Providencia and Morganella morganii) Imipenem (Proteus spp., Providencia spp. and Morganella morganii.) 2 4 4 1 4 Meropenem 2 8 Acinetobacter spp. Doripenem 1 2 Ertapenem - - Imipenem 2 4 Meropenem 2 8 Pseudomonas spp. Doripenem 1 2 1. Applies to high-dose treatment. Ertapenem - - Imipenem 4 1 4 Meropenem 2 8 Anaerobes Doripenem 1 2 Ertapenem 0.5 0.5 Imipenem 2 4 Meropenem 2 8 EUCAST revision of carbapenem breakpoints July 2018 Page 7 of 22

Haemophilus influenzae Meropenem 0.25 0.25 (meningitis) 2,3 Streptococcus pneumoniae Meropenem 0.25 0.25 (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 10.0. These are displayed in Tables 9-12. EUCAST revision of carbapenem breakpoints July 2018 Page 8 of 22

0.002 0.004 0.008 0.016 0.032 0.064 0.125 0.25 0.5 1 2 4 8 16 32 64 128 256 512 Total ECOFF 99% Table 9: Doripenem MIC distributions and ECOFFs Species (No. of distributions) Enterobacter cloacae (5) 0 0 1 149 606 322 201 71 20 4 1 1 0 0 0 0 0 0 0 1376 0.125 Enterococcus faecalis (11) 0 0 0 0 1 12 1 13 56 127 1559 4172 1319 337 2 0 1 0 0 7600 16 Morganella morganii (10) 0 0 0 0 2 43 175 225 88 9 0 0 0 0 0 0 0 0 0 542 1 Proteus mirabilis (26) 0 0 0 2 87 1140 2176 1344 196 26 9 0 0 3 0 0 0 0 0 4983 0.5 Proteus vulgaris (9) 0 0 0 0 0 45 119 58 5 0 0 0 0 0 0 0 0 0 0 227 0.5 Pseudomonas aeruginosa (15) 0 0 0 7 68 524 1601 2133 2149 1422 785 865 651 575 45 7 0 0 0 10832 * Staphylococcus aureus (5) 0 0 0 133 1597 1318 74 18 8 4 3 0 0 0 0 0 0 0 0 3155 0.125 Acinetobacter baumannii (3) 0 0 0 0 0 3 19 34 44 41 26 40 69 49 0 0 0 0 0 325 Alcaligenes xylosoxidans (2) 0 0 0 0 0 0 2 3 15 5 4 5 1 1 0 0 0 0 0 36 Bacteroides fragilis (2) 0 0 0 0 3 4 33 131 35 11 11 9 4 4 1 0 0 0 0 246 Enterobacter aerogenes 0 0 0 3 22 27 11 2 0 0 0 0 0 0 0 0 0 0 0 65 Escherichia coli (4) 0 0 6 407 1850 95 13 4 0 0 0 1 0 0 0 0 0 0 0 2376 Haemophilus influenzae (4) 0 0 14 22 97 454 411 156 130 44 21 9 0 0 0 0 0 0 0 1358 Klebsiella oxytoca (3) 0 0 0 10 88 47 5 2 1 0 0 0 0 0 0 0 0 0 0 153 Klebsiella pneumoniae (4) 0 0 1 81 939 583 150 11 3 0 1 2 1 0 1 0 0 0 0 1773 Serratia marcescens (3) 0 0 0 4 33 207 363 115 11 2 0 0 0 0 0 3 0 0 0 738 Staphylococcus epidermidis MSSE 0 0 1 37 22 15 4 4 1 0 0 0 0 0 0 0 0 0 0 84 (2) Streptococcus agalactiae (3) 0 3 26 194 18 0 0 0 0 0 0 0 0 0 0 0 0 0 0 241 Streptococcus anginosus (3) 0 0 2 20 36 9 1 1 0 1 0 0 0 0 0 0 0 0 0 70 Streptococcus group G (2) 5 72 8 8 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 94 Streptococcus oralis (2) 0 7 27 38 20 6 7 3 3 1 0 0 0 0 0 0 0 0 0 112 Enterobacter cloacae (5) 0 0 1 149 606 322 201 71 20 4 1 1 0 0 0 0 0 0 0 1376 0.125 * Excessively wide distribution. Further investigation required Too few distributions to establish an ECOFF EUCAST revision of carbapenem breakpoints July 2018 Page 9 of 22

0.002 0.004 0.008 0.016 0.032 0.064 0.125 0.25 0.5 1 2 4 8 16 32 64 128 256 512 Total ECOFF 99% Table 10: Ertapenem MIC distributions and ECOFFs Species (No. of distributions) Haemophilus influenzae (10) 1 7 67 371 1334 1258 423 154 38 7 0 0 0 0 0 0 0 0 0 3660 0.125 Morganella morganii (6) 0 4 47 75 93 41 6 1 0 0 0 2 0 0 0 0 0 0 0 269 0.125 Proteus mirabilis (6) 1 63 581 242 7 1 1 0 0 0 0 0 0 0 0 0 0 0 0 896 0.03 Staphylococcus aureus (5) 0 0 5 2 7 64 572 262 41 14 7 16 17 16 16 7 11 10 0 1067 0.5 Streptococcus agalactiae (7) 0 0 31 56 261 189 37 3 1 0 0 0 2 2 0 0 0 0 0 582 0.125 Streptococcus pneumoniae (7) 99 590 1109 712 106 50 41 98 90 23 2 0 0 1 0 0 0 0 0 2921 0.03 Acinetobacter baumannii (3) 0 0 0 2 0 1 4 5 9 49 90 67 39 14 9 7 0 0 6 302 Bacteroides fragilis (2) 0 0 1 2 5 41 55 58 28 3 13 4 0 0 0 0 0 0 0 210 Enterobacter cloacae (4) 0 0 41 160 110 64 49 39 30 72 46 18 1 0 0 0 0 0 0 630 Enterococcus faecalis (4) 0 0 0 0 0 0 0 0 2 3 25 174 204 55 17 0 0 0 0 480 Escherichia coli (4) 0 40 691 178 42 23 10 2 0 0 0 0 2 0 0 0 0 0 0 988 Haemophilus parainfluenzae (2) 0 0 20 34 123 61 17 4 2 0 0 0 0 0 0 0 0 0 0 261 Klebsiella pneumoniae (4) 0 2 251 314 61 40 37 12 5 5 3 1 1 0 0 0 0 0 0 732 Moraxella catarrhalis (4) 4 107 304 578 185 137 28 0 0 0 0 0 0 0 0 0 0 0 0 1343 Proteus vulgaris (3) 0 0 18 137 70 16 20 9 7 1 0 0 2 0 0 0 0 0 0 280 Klebsiella oxytoca (2) 0 4 38 49 10 3 0 0 0 0 0 1 0 0 0 0 0 0 0 105 Streptococcus anginosus (3) 0 0 0 0 2 15 35 10 5 0 0 0 0 0 0 0 0 0 0 67 Streptococcus group G (2) 0 7 31 40 14 1 1 0 0 0 0 0 0 0 0 0 0 0 0 94 Streptococcus oralis (2) 0 0 4 24 30 18 8 7 3 3 0 1 0 0 0 0 0 0 0 98 * Excessively wide distribution. Further investigation required Too few distributions to establish an ECOFF EUCAST revision of carbapenem breakpoints July 2018 Page 10 of 22

0.002 0.004 0.008 0.016 0.032 0.064 0.125 0.25 0.5 1 2 4 8 16 32 64 128 256 512 Total ECOFF 99% Table 11: Imipenem MIC distributions and ECOFFs Species (No. of distributions) Bacteroides fragilis (5) 0 0 0 28 211 358 663 450 155 93 42 12 12 4 4 4 7 0 0 2043 * Bacteroides thetaiotaomicron (5) 0 0 0 1 23 61 82 100 85 43 10 3 3 0 0 0 0 0 0 411 * Citrobacter freundii (6) 0 0 0 2 6 20 163 389 675 356 47 16 0 4 1 0 0 0 0 1679 2 Enterobacter aerogenes (24) 0 0 1 4 1 27 194 629 1011 919 329 52 29 18 10 14 2 1 0 3241 * Enterococcus faecalis (14) 0 0 0 5 8 27 128 306 1885 5801 4091 993 232 113 18 5 0 0 0 13612 4 Escherichia coli (54) 0 0 7 25 148 1192 4723 3821 910 188 110 27 8 5 3 4 1 0 0 11172 0.5 Haemophilus influenzae (10) 0 0 1 3 13 155 248 779 1262 556 219 78 22 7 2 0 0 0 0 3345 * Klebsiella pneumoniae (39) 0 0 12 16 40 583 7061 4793 3451 494 138 29 15 20 6 5 1 0 0 16664 1 Morganella morganii (16) 0 0 0 1 1 3 4 28 92 330 985 470 59 10 5 1 0 0 0 1989 8 Proteus mirabilis (11) 0 0 1 2 2 38 245 1005 1874 2860 2559 602 57 6 7 0 0 0 0 9258 8 Pseudomonas aeruginosa (60) 0 0 1 3 6 21 68 507 3087 9079 5312 1735 1538 2462 339 371 20 37 0 24586 * Klebsiella oxytoca (25) 0 0 1 6 8 88 435 785 280 44 17 6 2 2 2 0 0 0 0 1676 1 Staphylococcus aureus (27) 0 0 110 514 916 352 54 28 13 12 4 4 4 0 2 1 0 1 0 2015 0.125 Streptococcus agalactiae (5) 0 2 85 151 94 24 1 0 1 3 0 0 0 0 0 0 0 0 0 361 0.06 Clostridium difficile (4) 0 0 0 0 0 0 5 3 4 32 548 1594 825 127 52 2056 2 0 0 5248 Haemophilus parainfluenzae (3) 0 0 0 0 7 8 36 107 90 51 23 8 1 0 0 0 0 0 0 331 Moraxella catarrhalis (4) 0 0 5 11 77 132 163 26 19 2 0 0 0 0 0 0 0 0 0 435 Neisseria gonorrhoeae (2) 0 0 0 6 18 13 33 8 0 1 0 0 0 0 0 0 0 0 0 79 Serratia marcescens (4) 0 0 1 8 1 4 29 193 326 195 78 13 0 2 0 0 0 1 0 851 Stenotrophomonas maltophilia (3) 0 0 0 0 0 0 0 0 0 0 0 0 1 3 0 1 47 25 1 78 Streptococcus anginosus (2) 0 0 2 19 17 5 1 0 0 0 0 0 0 0 0 0 0 0 0 44 Streptococcus oralis (2) 0 2 12 29 28 9 6 4 2 2 2 0 0 0 0 0 0 0 0 96 Yersinia enterocolitica (2) 0 0 0 0 0 14 88 76 92 2 0 0 0 0 0 0 0 0 0 272 * Excessively wide distribution. Further investigation required Too few distributions to establish an ECOFF EUCAST revision of carbapenem breakpoints July 2018 Page 11 of 22

0.002 0.004 0.008 0.016 0.032 0.064 0.125 0.25 0.5 1 2 4 8 16 32 64 128 256 512 Total ECOFF 99% Table 12: Meropenem MIC distributions and ECOFFs Species (No. of distributions) Bacteroides fragilis (23) 2 4 32 211 573 408 147 49 37 19 21 5 3 3 0 3 0 0 0 1517 0.125 Bacteroides thetaiotaomicron (9) 4 2 10 15 85 284 118 29 7 5 2 0 0 0 0 0 0 0 0 561 0.25 Enterobacter aerogenes (15) 0 0 14 88 361 1721 313 72 29 13 28 25 15 6 2 6 1 1 0 2695 0.25 Enterobacter cloacae (29) 45 196 424 346 165 78 38 5 3 5 1 0 0 2 0 0 0 0 0 1308 * Enterococcus faecalis (14) 0 0 0 5 5 12 66 64 172 643 3004 4208 2873 944 168 17 1 0 187 12369 16 Escherichia coli (34) 0 0 432 2167 2013 165 42 24 8 2 0 0 1 1 0 0 0 0 0 4855 0.06 Klebsiella pneumoniae (33) 0 0 211 878 2242 11127 409 148 98 56 42 26 18 16 4 1 0 0 0 15276 0.125 Proteus mirabilis (6) 0 0 11 109 693 3510 482 128 75 17 3 4 0 2 0 0 0 0 0 5034 0.125 Proteus vulgaris (5) 0 0 2 16 87 321 55 11 7 5 1 0 0 0 0 0 0 0 0 505 0.125 Pseudomonas aeruginosa (42) 0 0 3 35 130 1863 4279 7709 8403 6149 3647 2708 2342 2256 373 421 31 13 0 40362 * Klebsiella oxytoca (11) 0 0 31 126 100 25 4 2 1 2 0 0 0 0 0 1 0 0 0 292 0.06 Staphylococcus aureus (5) 0 0 0 98 582 1398 1670 656 156 74 25 40 26 8 8 6 0 1 0 4748 0.25 Streptococcus pneumoniae (5) 18 275 205 50 20 18 17 39 28 4 0 0 1 0 0 0 0 0 0 675 0.016 Bacteroides ovatus (3) 0 0 0 1 3 42 58 28 6 2 0 0 0 0 0 0 0 0 0 140 Bacteroides vulgatus (2) 0 0 3 12 15 8 5 2 2 0 0 0 0 0 0 0 0 0 0 47 Listeria monocytogenes (3) 0 0 0 0 1 6 237 45 0 0 0 0 0 0 0 0 0 0 0 289 Moraxella catarrhalis (2) 10 25 7 8 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 50 Morganella morganii (4) 0 0 7 16 87 660 457 139 32 12 1 1 1 0 0 0 0 0 0 1413 Proteus mirabilis (4) 0 0 10 78 485 3422 474 128 75 17 3 4 0 2 0 0 0 0 0 4698 Providencia stuartii (2) 0 0 1 2 12 135 36 14 3 5 4 1 0 1 0 0 0 0 0 214 Serratia marcescens (2) 0 0 13 36 269 2778 349 86 43 25 12 2 4 11 0 1 0 0 0 3629 Staphylococcus capitis (3) 0 0 1 2 14 31 38 13 2 7 4 6 5 1 0 0 0 0 0 124 Stenotrophomonas maltophilia (2) 0 0 0 0 0 0 0 1 1 2 8 8 13 5 2 2 2 0 0 44 Streptococcus anginosus (3) 0 0 0 4 22 37 6 1 2 0 0 0 0 0 0 0 0 0 0 72 Streptococcus group G (2) 6 44 34 8 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 94 Streptococcus mitis (2) 0 0 1 9 32 30 17 7 14 8 6 3 0 1 0 0 0 0 0 128 Streptococcus oralis (3) 0 0 9 38 27 24 9 9 3 3 4 0 0 0 0 0 0 0 0 126 * Excessively wide distribution. Further investigation required Too few distributions to establish an ECOFF EUCAST revision of carbapenem breakpoints July 2018 Page 12 of 22

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 25-45 15-20 10-30 30-50 20-30 15-30 35-55 25-40 15-40 54 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: 1401-06 Mavridou et al. Antimicrob. Agents Chemother. 2015; 59: 790-6 EUCAST revision of carbapenem breakpoints July 2018 Page 13 of 22

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

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

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

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

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

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

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 1 0.5 EUCAST S breakpoint 1 mg/l EUCAST R breakpoint >1 mg/l Imipenem 500 x 3 1 500 x 4 2 EUCAST S breakpoint 2 mg/l Meropenem 1000 x 3 2 1000 x 4 4 EUCAST R breakpoint >4 mg/l 500 x 3 1 1000 x 3 2 EUCAST S breakpoint 2 mg/l 2000 x 3 2000 x 3 3 4 8 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

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

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. 1991 Dec;28(6):911-8. 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: 1868-73 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: 2322-8. 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. 2005 May;49(5):1881-9. 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: 943-50. 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; 25:682-707. EUCAST revision of carbapenem breakpoints July 2018 Page 22 of 22