MYSTIC (Meropenem Yearly Susceptibility Test Information Collection

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... the selective pressure of antimicrobial use.2,4–8 The establishment of several ... bial Resistance Epidemiology (ICARE) project,1,5 The. Surveillance Network ...
Journal of Antimicrobial Chemotherapy (2000) 46, Topic T2, 25–37

JAC

MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) results from the Americas: resistance implications in the treatment of serious infections Michael A. Pfaller*, Ronald N. Jones for the MYSTIC Study Group (Americas)† CAST Laboratories and the Division of Medical Microbiology, Department of Pathology, University of Iowa College of Medicine, Iowa City, IA 52242, USA The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) programme aims to provide in vitro surveillance data for geographically diverse institutions where meropenem is available for use. The in vitro activity of meropenem and eight comparator antimicrobial agents against 2340 significant pathogens obtained in 1999 was assessed and compared in 14 study centres in Brazil, Mexico and the USA. Isolates were further characterized for production of extended-spectrum β-lactamases (ESBLs), AmpC β-lactamases and carbapenemases. Carbapenems demonstrated their broad spectrum and potency, inhibiting > 95% of all isolates irrespective of the geographical region or centre type. The overall order of activity of the nine agents tested against all pathogens in 1999 was meropenem (96%) > imipenem (95%) > cefepime (92%) > gentamicin (89%) > piperacillin/tazobactam (88%) > ceftazidime  tobramycin (86%) > cefotaxime (84%) > ciprofloxacin (83%). Thus far, the results from the Americas indicate that meropenem has excellent potency and spectrum of activity despite being prescribed for the treatment of seriously ill patients. In contrast, other ESBLs, fluoroquinolones and aminoglycosides have lost activity in many institutions as a result of the selection of strains producing ESBLs or having AmpC and other resistance determinants. Carbapenem resistance was observed rarely and at a prevalence similar to those reported in earlier studies. Carbapenems appear to be a continuing reliable option for the treatment of serious nosocomial infection.

and Control of Pathogens of Epidemiologic Importance (SCOPE) programme,11–14 the Intensive Care Antimicrobial Resistance Epidemiology (ICARE) project,1,5 The Surveillance Network (TSN) and the SENTRY antimicrobial surveillance programme, have provided important information about changes in the spectrum of microbial pathogens and trends in antimicrobial resistance patterns in nosocomial and community-acquired infections.15–19 This information has proved useful in the development of empirical approaches to the treatment of serious infection,

Introduction The importance of antimicrobial resistance among nosocomial and community-acquired pathogens is now appreciated worldwide.1–3 Numerous classes of antimicrobial agents have become less effective as a result of the emergence of resistance, often following the selective pressure of antimicrobial use.2,4–8 The establishment of several surveillance programmes, such as the National Nosocomial Infection Surveillance (NNIS) system,9,10 the Surveillance

*Correspondence address. Medical Microbiology Division, C606 GH, Department of Pathology, University of Iowa College of Medicine, Iowa City, IA 52242, USA. Tel: 1-319-384-9566; Fax: 1-319-356-4916; E-mail: [email protected] †USA: M. D. Anderson Cancer Center (K. Ralston), Houston, TX; Columbia Presbyterian Medical Center (P. Della-Latta), New York, NY; Arkansas Children’s Hospital (T. Beavers-May, R. Jacobs), Little Rock, AR; Winthorp University Hospital (P. Shoch), Mineola, NY; Spectrum Health (R. Fader), Grand Rapids, MI; New York University Medical Center (P. Tierno), New York, NY; Children’s Hospital (J. Bradley), San Diego, CA; University Hospitals of Cleveland (M. Jacobs), Cleveland, OH; Penrose Hospital (M. Reynolds), Colorado Springs, CO; and Northwestern Memorial Hospital (L. Peterson), Chicago, IL. Brazil: HCFMUSP/Laboratório Fleury (C. Mendes), São Paulo; FAC Medicina–UFSC (C. Zocolli) Florianópolis; FAC Medicina (I. Mimica) São Paulo. Mexico: Centro Medico ‘La Raza’ (G. Barriga), Mexico City.

25 © 2000 The British Society for Antimicrobial Chemotherapy

M. A. Pfaller and R. N. Jones and may be of use in the prevention and control of infections caused by resistant organisms.1,3,16–18,20,21 Furthermore, surveillance has provided evidence of important differences in antimicrobial resistance patterns that may occur in various geographical regions.1,16–19 In addition to identifying the emergence of resistance to established antimicrobial agents, surveillance efforts may also be useful in documenting continued efficacy among newly introduced agents.2,20 The comparison of in vitro activity against isolates obtained before and after the introduction of a new antimicrobial agent into clinical use is an important aspect of post-marketing surveillance. A diverse collection of geographical regions must be represented in these surveillance programmes, because of variations in drug utilization and the resistance mechanisms prevalent among clinical isolates.16–18 The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) programme was established to monitor the performance of meropenem and comparator broad-spectrum agents against significant pathogens isolated from infected patients hospitalized in institutions where meropenem is prescribed.22 Although the MYSTIC programme has been active in Europe since 1997, it was not implemented in the USA or Latin America until 1999, apart from one centre in Mexico. The present report summarizes the in vitro activity of meropenem and eight comparators tested against significant pathogens obtained from study centres in the USA (10 centres), Mexico (one centre) and Brazil (three centres) during the 1999 calendar year. Although these data will serve as the benchmark for the Americas MYSTIC programme in these 14 centres, it is instructive to compare them with data obtained from in vitro susceptibility studies performed before the introduction of meropenem. Likewise, data from the SENTRY antimicrobial surveillance programme in 1998 may serve as a useful comparator for the MYSTIC results from the USA and Brazil, by comparing meropenem activity against isolates obtained from institutions where meropenem is not used routinely.17 Thus we will provide some measure of the resistance implications of carbapenem use in the Americas.

Brazil (three centres) and Mexico (one centre) performed susceptibility testing on-site, whereas isolates from the 10 US centres were sent to a central reference laboratory (CAST Laboratories, Iowa City, IA, USA) for identification confirmation and MIC determination.23 The three centres in Brazil were all intensive care units (ICUs) and all remaining centres were general wards. Possible extended-spectrum β-lactamase (ESBL)producing isolates of Escherichia coli and Klebsiella pneumoniae were defined as those with ceftazidime MICs of 2 mg/L.23 ESBL production was confirmed by in vitro synergy between ceftazidime and clavulanate (4 mg/L).23 Although in the USA and Brazil, data for only 1 year have been collated, we have compared them with data from the SENTRY study to investigate possible trends. Threeyear data have been reported for Mexico.

Results During 1999 a total of 2430 isolates from 14 MYSTIC centres (1800 from the USA, 471 from Brazil and 159 from Mexico) were tested against meropenem and the eight comparator antimicrobial agents. Table I gives details of the isolates contributed from each region. The staphylococci included methicillin-susceptible strains of Staphylococcus aureus (362 isolates) and coagulase-negative staphylococci (CNS; 155 isolates). The enterococci were either Enterococcus faecalis (164 isolates) or Enterococcus spp. not otherwise identified. The streptococci included both β-haemolytic and viridans-group isolates.

Antimicrobial susceptibility of Gram-positive pathogens The MICs of meropenem and eight comparator agents against staphylococci, streptococci and enterococci from the USA, Brazil and Mexico are shown in Tables II–IV. Meropenem and all comparative agents were active against methicillin-susceptible staphylococci from all three geographical regions. No differences in susceptibility were observed between S. aureus and CNS strains (data not shown). All of the staphylococcal isolates were susceptible to meropenem and imipenem, 99% to cefotaxime, cefepime and piperacillin/tazobactam, and 96% to gentamicin. Tobramycin (74% susceptible) was the least active agent against staphylococci in Brazil, whereas ciprofloxacin (37% susceptible) was the least active agent in Mexico. Streptococci from all centres were highly susceptible to meropenem and other β-lactams (95–100% susceptible), but were generally resistant to aminoglycosides. None of the agents tested was particularly active against enterococci as defined by NCCLS breakpoints.23 The order of activity of the nine agents tested against all Gram-positive cocci was meropenem  piperacillin/tazobactam (99% susceptible)  imipenem  cefotaxime 

Materials and methods Study design The study design and in vitro susceptibility testing methods used throughout the MYSTIC programme are described by Turner22 and will not be repeated in detail herein. Each centre examined up to 100 aerobic Gram-negative isolates and 100 Gram-positive isolates. MICs of meropenem, imipenem, cefotaxime, ceftazidime, cefepime, piperacillin/tazobactam, ciprofloxacin, gentamicin and tobramycin were determined using the broth microdilution method recommended by the National Committee for Clinical Laboratory Standards (NCCLS).23 The centres in 26

MYSTIC Americas results Table I. Aerobic bacteria tested in the MYSTIC–Americas antimicrobial surveillance programme, 1999 No. of isolates from Organism

Mexico

Staphylococci Streptococci Enterococci Other Gram-positive cocci Enteric bacilli Citrobacter spp. E. coli Enterobacter spp. Klebsiella spp. P. mirabilis Serratia spp. other Non-fermentative Gram-negative bacilli P. aeruginosa Acinetobacter spp. other Total

35 49 0 0 62 12 15 9 19 0 7 0 13 13 0 0 159

cefepime (98%)  gentamicin (96%)  tobramycin (91%)  ceftazidime (90%)  ciprofloxacin (77%). The order of activity against strains from each study region was similar.

USA 406 180 222 35 711 46 197 100 152 95 53 68 246 193 32 21 1800

Brazil

Total

76 43 35 0 196 5 51 46 58 8 15 13 121 63 51 7 471

517 272 257 35 969 63 263 155 229 103 75 81 380 269 83 28 2430

susceptible to meropenem. None of the 15 E. coli isolates from Mexico produced ESBLs. Meropenem and imipenem (98% susceptible) were the most active agents tested against Klebsiella spp. Ciprofloxacin (94% susceptible) and cefepime (92%) were also active agents. None of the remaining β-lactams (65–88% susceptible) or aminoglycosides (75–85%) tested inhibited 90% of the Klebsiella spp. at accepted MIC breakpoints. Compared with isolates from the USA and Mexico, Klebsiella spp. isolates from Brazil were less susceptible to every antimicrobial tested, although the carbapenems still inhibited 90% of these strains. These differences were most pronounced for cefotaxime (97–100% susceptible for isolates from the USA and Mexico, compared with 46% susceptible for isolates from Brazil), ceftazidime (96–100% and 62%, respectively), cefepime (100% and 69%, respectively), piperacillin/tazobactam (93–100% and 76%, respectively), and gentamicin (96–100% and 52%, respectively). Of the 229 Klebsiella spp. collected in 1999, 36/58 (62%) isolates from Brazil and nine of 152 (5.9%) isolates from the USA demonstrated a phenotype consistent with ESBL production.23 Meropenem was active against all but three of these strains. The three meropenem-resistant strains were all from Brazil and probably had altered porin proteins in addition to producing ESBLs.24 Citrobacter spp. isolates were uniformly susceptible to the carbapenems, cefepime, piperacillin/tazobactam, ciprofloxacin and the aminoglycosides. Only cefotaxime

Antimicrobial susceptibility of Gram-negative pathogens Tables II–IV list the MICs of the nine antimicrobial agents tested against isolates of Enterobacteriaceae, Acinetobacter spp. and Pseudomonas aeruginosa from the USA, Brazil and Mexico. Meropenem was the most active agent against E. coli (100% susceptible), while cefepime and piperacillin/ tazobactam (98%) were the next most active antimicrobials. There were no major differences in susceptibility between E. coli from the USA and those from Mexico. Isolates from these countries were highly susceptible to all agents tested. However, apart from meropenem (100%), each of these antimicrobials and antimicrobial classes (imipenem, 94% susceptible; cephalosporins, 88– 92%; piperacillin/tazobactam, 96%; ciprofloxacin, 82%; aminoglycosides, 68–86%) was less active against isolates from Brazil. Of the 263 E. coli isolates collected in 1999, 10/51 (19.6%) isolates from Brazil and 10/197 (5.0%) isolates from the USA had a phenotype consistent with ESBL production (MIC of ceftazidime 2 mg/L and enzyme inhibition with clavulanate). All of these isolates were 27

M. A. Pfaller and R. N. Jones Table II. Antimicrobial activity of meropenem and eight other broad-spectrum antimicrobial agents tested against Gram-negative and Gram-positive isolates from Brazil (MYSTIC programme, 1999; three ICUs) Cumulative percentage inhibition at MIC (mg/L) Organism (no. tested)/ antimicrobial agent Staphylococci (76)a meropenem imipenem cefotaxime cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin Streptococci (43) meropenem imipenem cefotaxime cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin Enterococcus spp. (35) meropenem imipenem cefotaxime cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin E. coli (51) meropenem imipenem cefotaxime cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin Klebsiella spp. (58) meropenem imipenem cefotaxime cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin

0.016

0.03 0.06

0.12 0.25 80 95 0 0 0 9 49 24 17

88 97 0 1 0 18 79 34 25

0.5

0 17 0 0 0 0 0 1 0

7 58 0 0 0 0 0 12 1

50 89 0 0 0 4 13 21 11

93 99 8 9 0 37 87 58 46

76 65 58 7 2 51 0 0 0

79 93 70 42 2 58 0 0 0

98 98 79 65 9 65 0 0 0

0 0 3 0 0 0 3 0 6

0 0 3 0 0 0 3 0 6

0 0 3 0 0 0 3 0 6

0 0 3 0 0 0 6 0 6

3 0 3 3 0 0 6 0 6

3 9 3 3 0 3 37 0 6

55 0 6 6 2 0 59 0 0

88 0 29 33 6 0 71 0 0

94 2 65 69 14 0 75 0 0

96 14 73 73 49 0 75 0 0

96 67 84 82 67 0 77 2 0

96 92 82 84 75 4 77 2 4

26 0 0 0 0 0 24 0 0

62 0 3 3 0 0 60 0 0

84 0 22 24 2 0 69 0 0

86 5 24 24 24 0 71 0 0

88 60 26 31 28 0 83 0 0

89 86 26 34 29 2 90 12 5

100 100b 100 98b 100 100 98 98 100b 81 98 98b 23 60 72 72 81 95 5 9 63 0 0 0 0 0 0

28

32

64

128

96 97 100 100 26 53 26 70 0 8 67 93 92b 95 86 91 71 72

97b 99 99 99 100b 100 100 100 79 93b 99 99 97 99b 99 100 38 88b 97 99 99 99 100b 100 97 99 99 99 93b 96 99 99 74b 74 74 75

100 100 99 100 99 100 100 99 78

100 100 100 100 100 100 100 100 100

100 100 100 100 95 100 84 7 0

100 100 100 100 98 100 100 26 5

1

9 40 3 3 3 14 60b 3 6

2

100 100 100 100 95 100 98 19 2 17 71 6 6 11 48 69 3 6

100 100 94 94 82 86 84 90 80 86 31 77 82b 82 45 80 24 61 89 91 31 40 33 7 91b 31 22

91 91 34 50 41 48 97 47 28

4

8

16

100 100 100 100 98 100 100 42 21

100 100 100 100 98 100 100 63 27

100 100 100 100 100 100 100 86 47

100 100 100 100 100 100 100 98 70

100 100 100 100 100 100 100 100 100

57 83 11 11 14 74 74 43 29

57 83 11 17 17 80 74 57 37

63 83 17 31 17 83 74 71 57

91 100 20 57 17 89 94 71 74

100 100 100 100 100 100 100 100 100

100b 100 100 100 98 98 94b 98 86 88b 88 88 94 92 92b 92 90 90b 90 96 84 94 96b 96 86 86 88 88 86b 90 94 96 69b 78 84 90

100 100 94 100 96 96 100 98 96

100 100 100 100 100 100 100 100 100

100 100 64 93 79 78 100 83 83

100 100 100 100 100 100 100 100 100

40b 83b 9 9 14 71 74 14 6

95b 91b 43 60 52 60 97 52b 29b

95 91 47b 69b 62b 71 98 53 33

95 91 53 79 71 76b 98 59 45

95 91 59 89 74 78 98 66 59

MYSTIC Americas results Table II. (Continued) Cumulative percentage inhibition at MIC (mg/L) Organism (no. tested)/ antimicrobial agent Enterobacter spp. (46) meropenem imipenem cefotaxime cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin Serratia spp. (15) meropenem imipenem cefotaxime cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin Acinetobacter spp. (51) meropenem imipenem cefotaxime cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin P. aeruginosa (63) meropenem imipenem cefotaxime cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin

0.016

0.03 0.06

0.12 0.25

0.5

1

2

32

64

128

100b 100 100 100 93b 93 100 100 50 54b 61 65 76 87b 93 98 54 59b 67 76 57 63 65b 70 89 93 93 93 65b 70 74 80 48b 52 59 72

100 100 78 100 78 72 100 85 83

100 100 100 100 100 100 100 100 100

100b 100 100 100b 100 100 73 87b 87 100 100b 100 93 93b 93 60 60 73b 93 93 93 60b 60 60 47b 47 47

100 100 93 100 93 80 100 67 60

100 100 100 100 100 100 100 67 73

100 100 100 100 100 100 100 100 100

4

8

16

22 0 0 11 0 0 41 0 0

43 0 13 26 0 0 59 0 0

57 0 17 37 9 2 63 0 0

70 4 28 46 28 2 72 2 2

85 37 39 46 39 2 76 7 2

89 70 39 50 41 4 78 20 11

97 100 80 93 39 43 52 72 48 50 24 39 85b 85 37 57 28 43

0 0 0 0 0 0 7 0 0

20 0 7 7 0 0 7 0 0

67 0 13 27 13 0 27 0 0

100 0 13 47 47 0 53 0 0

100 7 27 60 47 0 60 7 0

100 33 60 67 67 0 73 7 0

100 100 100 100 67 67 93 100 87 93 7 40 73b 80 20 47 7 33

0 0 0 0 0 6 0 0 0

0 0 0 0 0 6 0 0 0

2 0 0 0 0 8 6 0 2

4 2 0 0 0 8 12 0 2

18 14 0 2 0 8 22 4 6

35 31 0 4 0 8 27 6 8

69 61 2 10 2 10 29b 10 12

84 84 6 16 6 14 29 20 25

92b 90b 8 22 16 16 33 41b 39b

94 90 16b 25b 20b 22 37 47 45

94 92 22 45 25 22b 43 47 51

94 92 24 49 43 24 47 47 57

98 100 25 80 57 33 98 47 59

100 100 100 100 100 100 100 100 100

0 0 0 0 0 0 0 0 0

2 0 0 0 0 0 3 0 0

13 0 0 0 0 0 16 0 0

32 0 0 0 0 0 41 0 0

40 0 0 0 0 0 52 0 3

52 6 0 0 0 0 57 0 3

59 24 0 11 30 2 59b 0 18

65 52 0 38 46 16 60 21 38

70b 64b 2 49 56 30 60 44b 54b

70 67 14b 60b 62b 43 60 56 56

71 68 32 71 68 51 62 57 57

73 70 38 78 75 65 64 57 62

100 100 60 86 78 71b 98 59 67

100 100 100 100 100 100 100 100 100

a

Includes methicillin-susceptible strains of S. aureus (56 strains) and coagulase-negative species (20 strains). Percentage inhibited at NCCLS (2000) susceptible breakpoint, if published or applicable.23

b

and ceftazidime inhibited 90% of isolates (USA) at 8 mg/L.23 Meropenem (99% susceptible), imipenem (98%), cefepime (94%) and ciprofloxacin (94%) were the most active agents tested against Enterobacter spp. Similar to the other Gram-negative enteric bacilli, a trend in susceptibility by region (Mexico  USA  Brazil) was noted for

Enterobacter spp. For example, cefepime (97–100% susceptible) and ciprofloxacin (98–100%) were highly active against Enterobacter spp. from the USA and Mexico, but were less active (87% and 85%, respectively) against strains from Brazil. The aminoglycosides showed even less activity (48–65%) against isolates from Brazil, as did cefotaxime and ceftazidime (54% and 58%, respectively). Of 29

M. A. Pfaller and R. N. Jones Table III. Antimicrobial activity of meropenem and eight other broad-spectrum antimicrobial agents tested against Gram-negative and Gram-positive isolates from Mexico (MYSTIC programme, 1999; one medical centre) Cumulative percentage inhibition at MIC (mg/L) Organism (no. tested)/ antimicrobial agent Staphylococci (35)a meropenem imipenem cefotaxime ceftazidime cefepime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin Streptococci (49) meropenem imipenem cefotaxime cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin E. coli (15) meropenem imipenem cefotaxime cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin Citrobacter spp. (12) meropenem imipenem cefotaxime cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin Klebsiella spp. (19) meropenem imipenem cefotaxime cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin

0.016

2

4

8

16

32

100 100 11 0 11 83 40b 20 34

100 100 46 26 43 94 49 51 83

100b 100b 86 51 80 100 91 100b 100b

100 100 100b 80b 100b 100 100 100 100

100 100 100 94 100 100 100 100 100

100 100 100 100 100 100 100 100 100

100 100 100b 98b 100 61 53 63 82

100 100 100 100 100 71 89 65 100

100 100 100 100 100 86 100 67 100

100 100 100 100 100 96 100 84 100

100 100 100 100 100 100 100 98 100

100 100 100 100 100 100 100 100 100

100 100 100 100 100 100 100 100 100

100 73 60 100 40 0 100 33 0

100 100 100 100 93 20 100 93 0

100 100 100 100 100 60 100b 100 33

100 100 100 100 100 93 100 100 80

100b 100b 100 100 100 100 100 100b 100b

100 100 100b 100b 100b 100 100 100 100

100 100 100 100 100 100b 100 100 100

100 100 100 100 100 100 100 100 100

100 0 0 8 0 33 42 0 0

100 50 8 8 0 75 64 0 0

100 100 50 67 8 100 100 0 0

100 100 92 92 33 100 100b 8 58

100 100 100 100 75 100 100 58 75

100b 100b 100 100 100 100 100 100b 100b

100 100 100b 100b 100b 100 100 100 100

100 100 100 100 100 100b 100 100 100

100 100 100 100 100 100 100 100 100

100 37 0 26 21 0 95 0 0

100 79 42 47 21 0 100 11 0

100 100 100 100 89 0 100 63 0

100 100 100 100 100 5 100b 79 5

100 100 100 100 100 47 100 95 26

100b 100b 100 100 100 89 100 100b 58b

100 100 100b 100b 100b 100 100 100 79

100 100 100 100 100 100b 100 100 100

100 100 100 100 100 100 100 100 100

0.03

0.06

0.12

0.25

0.5

0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0

20 3 0 0 0 0 0 0 0

54 69 0 0 0 3 6 0 0

83 100 0 0 0 43 17 0 11

16 4 0 0 0 0 0 0 0

33 8 0 0 0 0 0 0 0

78 42 10 6 8 0 0 0 0

98 92b 37 26 24 0 0 0 6

100b 100 65 65 73 18 16 32 24

0 0 0 0 0 0 0 0 0

33 0 0 0 0 0 27 0 0

80 0 0 40 0 0 93 0 0

100 47 20 100 0 0 100 0 0

0 0 0 0 0 0 0 0 0

50 0 0 0 0 0 0 0 0

100 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0

37 0 0 0 0 0 0 0 0

100 0 0 0 0 0 37 0 0

30

1

MYSTIC Americas results Table III. (Continued) Cumulative percentage inhibition at MIC (mg/L) Organism (no. tested)/ antimicrobial agent Enterobacter spp. (9) meropenem imipenem cefotaxime cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin Serratia spp. (7) meropenem imipenem cefotaxime cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin P. aeruginosa (13) meropenem imipenem cefotaxime cefepime ceftazidime piperacillin/tazobactamc ciprofloxacin gentamicin tobramycin

0.016

2

4

8

16

32

100 100 100 100 78 100 100b 100 67

100 100 100 100 100 100 100 100 100

100b 100b 100 100 100 100 100 100b 100b

100 100 100b 100b 100b 100 100 100 100

100 100 100 100 100 100b 100 100 100

100 100 100 100 100 100 100 100 100

100 100 100 100 100 0 100 100 0

100 100 100 100 100 57 100b 100 29

100 100 100 100 100 100 100 100 71

100b 100b 100 100 100 100 100 100b 100b

100 100 100b 100b 100b 100 100 100 100

100 100 100 100 100 100b 100 100 100

100 100 100 100 100 100 100 100 100

77 0 0 0 8 0 0 0 0

100 39 0 39 39 0 8b 23 3

100 84 31 77 69 31 54 54 8

100b 100b 100 100 100 92 100 100b 69b

100 100 100b 100b 100b 100 100 100 92

100 100 100 100 100 100 100 100 100

100 100 100 100 100 100 100 100 100

0.03

0.06

0.12

0.25

0.5

0 0 0 0 0 0 0 0 0

33 0 0 0 0 0 0 0 0

78 11 33 0 0 0 0 0 0

100 56 56 44 0 22 44 0 0

100 100 89 67 0 22 89 56 0

100 100 100 100 44 89 100 100 0

0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0

29 0 0 0 0 0 0 0 0

71 43 0 14 0 0 43 0 0

100 86 43 100 14 0 71 29 0

0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0

15 0 0 0 0 0 0 0 0

46 0 0 0 0 0 0 0 0

1

a

Includes methicillin-susceptible strains of S. aureus (19 strains) and coagulase-negative species (16 strains). Percentage inhibited at NCCLS (2000) susceptible breakpoint, if published or applicable.23 c NCCLS breakpoint is 64/4 mg/L (100% susceptible).

b

the 155 Enterobacter spp. collected in 1999, 14/46 (30%) isolates from Brazil and 10/100 (10%) isolates from the USA demonstrated a phenotype consistent with a stably derepressed AmpC β-lactamase-producing strain (highlevel resistance to cefotaxime, ceftazidime and piperacillin/ tazobactam but susceptible to cefepime). These isolates were all susceptible to meropenem. Cefepime and ceftazidime were the most active agents against Serratia spp. (99–100% susceptible), followed by cefotaxime (97%), meropenem and imipenem (96%) and piperacillin/tazobactam (95%). Again, isolates from the USA and Mexico were highly susceptible to all agents tested, whereas greater resistance was observed among isolates from Brazil. The latter isolates were especially resistant to piperacillin/tazobactam (73% susceptible),

ciprofloxacin (73%) and the aminoglycosides (47–60%). Two Serratia marcescens isolates from one US centre were resistant (MIC  32 mg/L) to meropenem, imipenem and aztreonam but susceptible to cefotaxime, ceftazidime, cefepime and piperacillin/tazobactam. These isolates were indistinguishable by ribotyping and pulsed-field gel electrophoresis and contained a non-metallo-carbapenemhydrolysing β-lactamase, SmeI (Bush group 2f) (Gales, A. C., Winokur, P. L., Pfaller, M. A. & Jones, R. N., unpublished data). Proteus mirabilis isolates were only submitted from the USA and Brazilian centres and were highly susceptible to all agents tested (97–100%). Piperacillin/tazobactam (85% susceptible) was the most active agent against all P. aeruginosa isolates, followed by tobramycin (81%), ceftazidime (79%), meropenem (77%) 31

M. A. Pfaller and R. N. Jones Table IV. Antimicrobial activity of meropenem and eight other broad-spectrum antimicrobial agents tested against Gram-negative and Gram-positive isolates from the USA (MYSTIC programme, 1999; 10 medical centres) Cumulative percentage inhibition at MIC (mg/L) Organism (no. tested)/ antimicrobial agent Staphylococci (406)a meropenem imipenem ceftriaxone cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin Streptococci (180) meropenem imipenem ceftriaxone cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin Enterococcus spp. (222) meropenem imipenem ceftriaxone cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin E. coli (197) meropenem imipenem ceftriaxone cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin Citrobacter spp. (46) meropenem imipenem ceftriaxone cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin

0.016

0.03 0.06

0.12 0.25

0.5

1

2

4

8

16

32

64

128

0 18 0 –c – – – – –

3 90 0 – – – – – –

29 99 0 – – – – – –

86 99 0 1 0 – – – –

95 99 0 3 0 17 73 – –

99 99 2 10 0 37 92 – –

99 100 99 100 10 41 25 22 0 1 80 99 96b 97 – 95 93 94

100b 100b 95 99 26 100 – 96b 95b

100 100 100b 99b 92b 100 – 98 97

100 100 100 100 99 100b – – –

100 100 100 – – 100 – – –

– – 100 – – 100 – – –

– – 100 – – 100 – – –

32 69 4 – – – – – –

46 85 29 – – – – – –

84 89 47 – – – – – –

89 91b 82 80 13 – – – –

92b 93 87 85 30 63 3 – –

96 96 89b 90b 52 88 19 – –

98 99 98 98 81 89 73 – 2

99 99 98 99 84 95 90 18 4

100 100 99 99 90 97 – 45 12

100 100 100 100 96 99 – 86 36

100 100 100 100 99 100 – – –

100 100 100 – – 100 – – –

– – 100 – – 100 – – –

– – 100 – – 100 – – –

0 0 0 – – – – – –

1 0 0 – – – – – –

1 1 0 – – – – – –

1 1 0 0 0 – – – –

1 3 0 0 0 0 1 – –

5 5 1 1 0 0 5 – –

6 29 1 1 0 1 5b – 1

7 80 1 1 0 32 68 3 3

80 99 1 1 1 99 – 56 46

98 97 2 9 1 99 – – –

100 100 100 – – 99 – – –

– – 100 – – 99 – – –

– – 100 – – 100 – – –

29 0 6 – – – – – –

94 0 38 – – – – – –

99 1 84 – – – – – –

100 39 92 91 51 – – – –

100 84 94 95 85 0 95 – –

100 99 95 98 92 8 96 – –

100 100 99 100 95 97 99 99 95 95 42 85 96b 96 – 94 78 96

100b 100 100 100 100b 100 100 100 99 97 98b 99 99 99b 99 – – 96 97b 98 94 96 98b 98 – – – – 96b 96 – – 96b 99 – –

– – 100 – – 99 – – –

– – 100 – – 100 – – –

9 0 2 – – – – – –

85 0 13 – – – – – –

96 2 28 – – – – – –

98 22 46 74 26 – – – –

99 50 70 80 46 – 89 – –

100 61 74 91 61 2 91 – –

100 100 96 98 79 80 94 96 72 78 11 67 94b 94 – 96 94 98

100b 100 100 100 100b 100 100 100 85 85b 91 96 98 98b 98 – 80 85b 94 – 83 89 98b 98 – – – – – – 98b 98 98b 98 – –

– – 100 – – 98 – – –

– – 100 – – 100 – – –

32

30b 98b 1 1 1 93 – 15 14

MYSTIC Americas results Table IV. (Continued) Cumulative percentage inhibition at MIC (mg/L) Organism (no. tested)/ antimicrobial agent Klebsiella spp. (152) meropenem imipenem ceftriaxone cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin Enterobacter spp. (100) meropenem imipenem ceftriaxone cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin P. mirabilis (95) meropenem imipenem ceftriaxone cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin Serratia spp. (53) meropenem imipenem ceftriaxone cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin Acinetobacter spp. (32) meropenem imipenem ceftriaxone cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin

0.016

0.03 0.06

0.12 0.25

0.5

1

2

4

8

16

32

64

128

2 0 1 – – – – – –

78 0 22 – – – – – –

99 0 70 – – – – – –

99 8 91 86 30 – – – –

99 47 93 92 78 1 83 – –

99 87 94 95 90 3 90 – –

99 100 97 99 94 94 95 97 93 93 11 45 95b 97 – 95 94 95

100b 100 100 100 100b 100 100 100 95 97b 98 99 99 100b 100 – 95 96b 97 – 81 90 93b 95 – – – – 96b 97 – – 95b 97 – –

– – 100 – – 96 – – –

– – 100 – – 100 – – –

0 0 1 – – – – – –

35 0 2 – – – – – –

70 0 14 – – – – – –

88 1 36 73 6 – – – –

95 2 56 77 36 0 90 – –

97 27 65 83 63 0 93 – –

97 76 71 90 74 8 98b – 90

99b 100 100 100 100b 100 100 100 79 83b 84 90 96 97b 97 – 81 81b 84 – 73 79 86b 88 – – – – 96b 96 – – 96b 96 – –

– – 100 – – 94 – – –

– – 100 – – 100 – – –

1 0 95 – – – – – –

23 0 98 – – – – – –

88 0 99 – – – – – –

99 0 99 96 96 – – – –

100 1 99 98 97 54 97 – –

100 8 99 99 98 99 97 – –

100 100 41 80 100 100 99 98 98 98 100 100 97b 98 – 96 80 96

100b 99b 100 99 99 100 – 99b 99b

100 100 100 – – 100 – – –

– – 100 – – 100 – – –

– – 100 – – 100 – – –

0 0 0 – – – – – –

6 0 0 – – – – – –

83 0 8 – – – – – –

93 0 32 77 38 – – – –

94 0 68 87 83 2 83 – –

96 8 89 96 93 15 87 – –

96 96 49 93 89 94 100 100 98 98 42 87 93b 96 – 96 38 72

96b 96 96 96 96b 96 96 96 94 98b 100 100 100 100b 100 – 100 100b 100 – 94 98 98b 98 – – – – 98b 98 – – 94b 96 – –

– – 100 – – 100 – – –

– – 100 – – 100 – – –

0 0 0 – – – – – –

3 0 0 – – – – – –

6 0 3 – – – – – –

16 19 6 9 0 – – – –

31 50 9 9 9 25 59 – –

50 69 9 13 9 41 66 – –

– – 100 – – 78 – – –

– – 100 – – 100 – – –

33

69 72 9 22 13 44 72b – 63

97 97 77 92 77 54 98 93 93

72 78 13 38 25 50 75 66 69

78b 81b 22 63 53 56 – 66b 72b

100 100 100b 99b 99b 100 – 99 100

100 100 100 99 99 100b – – –

78 88 97 94 100 100 34b 72 75 69b 88 – 69b 81 – 63 72b 75 – – – 66 – – 75 – –

M. A. Pfaller and R. N. Jones Table IV. (Continued) Cumulative percentage inhibition at MIC (mg/L) Organism (no. tested)/ antimicrobial agent P. aeruginosa (193) meropenem imipenem ceftriaxone cefepime ceftazidime piperacillin/tazobactam ciprofloxacin gentamicin tobramycin

0.016 0 0 0 – – – – – –

0.03 0.06 0 0 0 – – – – – –

1 0 0 – – – – – –

0.12 0.25 5 0 0 0 0 – – – –

12 1 0 0 1 1 51 – –

0.5

1

2

4

8

16

32

64

128

32 3 0 1 1 2 72 – –

53 28 0 3 4 3 83b – 87

73 62 1 26 37 6 88 64 92

78b 78b 1 60 67 24 – 87b 93b

84 81 5b 79b 83b 60 – 91 94

92 93 12 93 89 74 – – –

98 98 23 – – 83 – – –

– – 100 – – 89b – – –

– – 100 – – 100 – – –

a

Includes methicillin-susceptible strains of S. aureus (287 strains) and coagulase-negative species (119 strains). Percentage inhibited at NCCLS (2000) susceptible breakpoint, if published or applicable.23 c An untested MIC value.

b

pathogens tested was meropenem (96%)  imipenem (95%)  cefepime (92%)  gentamicin (89%)  piperacillin/tazobactam (88%)  ceftazidime  tobramycin (86%)  cefotaxime (84%)  ciprofloxacin (83%). Susceptibility to meropenem remained universal among E. coli isolates from Brazil and Enterobacter spp. from 1998 and 1999, and decreased slightly (from 100% to 93%) among Klebsiella spp. (Table V). Likewise, the activity of ciprofloxacin and imipenem against the Enterobacteriaceae remained stable or decreased only slightly between 1998 and 1999. Rates of susceptibility to piperacillin/ tazobactam increased among E. coli and Klebsiella spp. and decreased among Enterobacter spp. over the 2 year period. In contrast, the susceptibility to cefotaxime, ceftazidime and cefepime decreased considerably in all three genera, reflecting the high prevalence of ESBLs and AmpC β-lactamases in these isolates. A considerable degree of resistance to all agents tested was observed in P. aeruginosa isolates and appeared to increase between 1998 and 1999. Meropenem and imipenem activity decreased by 17% and 20%, respectively, during this period (Table V), and the MIC90s of both agents increased from 8 to 64 mg/L. However, similar changes were also observed for the other agents. A total of 491 aerobic bacterial isolates from a single centre in Mexico between 1997 and 1999 (159–167 isolates each year) were tested against the nine antimicrobial agents (data not shown). The isolates remained highly susceptible to all agents tested except ciprofloxacin against P. aeruginosa (susceptibility decreased from 45% to 8% between 1997 and 1999). Notably, meropenem was active against all isolates in each year, indicating no decrease in activity despite meropenem being prescribed in the hospital.

and gentamicin (77%). Ciprofloxacin, cefepime and imipenem inhibited 75% of the isolates at their assigned breakpoint concentrations. The isolates from Mexico were highly susceptible to all compounds tested (92–100%), except tobramycin (46%) and ciprofloxacin (8%). Over 75% of isolates from the USA were inhibited by meropenem (78%), imipenem (78%), ceftazidime (83%), cefepime (79%), piperacillin/tazobactam (89%), ciprofloxacin (85%), gentamicin (87%) and tobramycin (93%). Almost all drugs tested were less active against P. aeruginosa isolates from Brazil than against those from the USA and Mexico. Piperacillin/tazobactam (71% susceptible) and meropenem (70% susceptible) were the most active agents against P. aeruginosa strains from Brazil, and cefotaxime (14%) and the aminoglycosides (44–54%) were the least active. Only meropenem (87% susceptible), imipenem (87%) and tobramycin (52%) inhibited 50% of all Acinetobacter spp. at clinically relevant concentrations. Isolates of Acinetobacter spp. from Brazil were more susceptible to meropenem (92% susceptible) than isolates from the USA (78% susceptible) but were considerably less susceptible to the cephalosporins (15–25% for isolates from Brazil and 34–69% for isolates from the USA), piperacillin/tazobactam (21% and 72%, respectively) ciprofloxacin (29% and 72%, respectively) and aminoglycosides (39–41% and 66–72%, respectively). The order of activity of the nine agents tested against all Gram-negative bacilli from the Americas was meropenem  imipenem (93% susceptible)  cefepime (88%)  ciprofloxacin (86%)  gentamicin (85%)  ceftazidime (84%)  piperacillin/tazobactam  tobramycin (83%)  cefotaxime (75%). Meropenem was the only agent tested that was active against 90% of Gram-negative bacilli in all three geographical regions. The order of activity against all 34

Table V. Activity of meropenem and comparators against selected Gram-negative pathogens from SENTRY (Latin America, 1998) and MYSTIC (Brazil, 1999)a SENTRY (Latin America, 1998)b

MYSTIC (Brazil, 1999)

Antimicrobial agent

no.

MIC90

percentage susceptible

no.

MIC90

E. coli

meropenem imipenem ceftriaxone ceftazidime cefepime piperacillin/tazobactam ciprofloxacin meropenem imipenem ceftriaxone ceftazidime cefepime piperacillin/tazobactam ciprofloxacin meropenem imipenem ceftriaxone ceftazidime cefepime piperacillin/tazobactam ciprofloxacin meropenem imipenem ceftriaxone ceftazidime cefepime piperacillin/tazobactam ciprofloxacin

192

0.06 0.25 0.25 0.5 0.25 32 >2 0.06 0.5 >32 >16 4 >64 1 0.12 2 >32 >16 4 >64 2 8 8 >32 >16 16 >64 >2

100 100 93 96 99 88 85 100 100 85 82 97 69 91 100 98 70 68 100 70 88 87 84 7 75 79 84 63

51

0.06 0.5 64 4 2 8 64 0.5 1 >128 >128 32 >128 1 0.5 1 >128 >128 16 >128 4 64 64 >128 >128 >128 >128 64

Klebsiella spp.

35 Enterobacter spp.

P. aeruginosa

a

66

44

75

58

46

63

Comparison is between hospital-wide strains as characterized by SENTRY and intensive care unit strains as characterized by MYSTIC. Adapted from reference 17.

b

percentage susceptible 100 100 88 90 92 96 82 93 91 46 62 69 76 91 100 93 54 58 87 65 85 70 64 14 62 60 71 59

MYSTIC Americas results

Organism

M. A. Pfaller and R. N. Jones Enterobacter spp. comparing MYSTIC 1999 results for the USA (Table IV) with data obtained before the introduction of meropenem25 or with data from the SENTRY programme in 1998.17 This reflects the continued low prevalence of ESBL-producing strains and the low levels of fluoroquinolone resistance among US isolates.17 Although rates of resistance of Enterobacter spp. to cefotaxime, ceftazidime and piperacillin/tazobactam remain higher than that observed for carbapenems, they do not appear to have increased. Susceptibility to carbapenems, ceftriaxone and cefepime was 8–13% lower in MYSTIC 1999 US isolates of P. aeruginosa than in pre-1994 isolates25 and isolates from SENTRY, 1998.17 Increased carbapenem resistance among P. aeruginosa isolates has been described previously; the mechanisms of resistance include altered porin proteins and, rarely, metallo-enzymes or carbapenemases.22,26,27 In summary, the comparison with MIC data obtained before the introduction of meropenem in the USA proved useful in establishing the continued low rates of resistance to meropenem among the Gram-negative bacilli, and no differences have been detected in the 3 year MYSTIC data from Mexico. Hence, the 1998 SENTRY data for the USA and Latin America data provide another useful comparison and demonstrate the complementary nature of the various surveillance programmes.16–21 It should be noted, however, that all three of the Brazilian centres in the MYSTIC study are ICUs, whereas in the SENTRY study, the Brazilian centres were general wards. It is expected that rates of resistance would be higher in an ICU environment and this may account for any decreased susceptibilities. Further surveillance of these agents in Brazil appears prudent. Surveillance and data gathering studies such as the MYSTIC programme are essential to further the efficient use of clinical practice healthcare resources. Identifying changes in the spectrum of pathogenic disease and the development of resistance patterns in nosocomial and community-acquired infections is a vital part of the development of new treatment strategies. Such information not only is useful in studying the mechanisms of resistance but also provides empirical data for preventing the development of resistance and for controlling resistant organisms. In summary, the results presented here indicate the potency and spectrum of activity of meropenem over a broad geographical range despite being prescribed for the treatment of seriously ill patients. Carbapenems appear to be a reliable option for the initial empirical treatment of serious infection.

Discussion The MYSTIC surveillance programme for the Americas provides documentation of the broad spectrum and potency of meropenem, despite its use even in centres with high rates of resistance to other extended-spectrum β-lactam agents. These initial, baseline data illustrate the importance of examining bacterial isolates from a broad geographical distribution. The types of resistance mechanisms being expressed differ from country to country and may reflect differences in prescribing practices within the countries and within the different types of unit. In the Americas, strains producing ESBLs and/or stably derepressed AmpC β-lactamases were most common in Brazil and were detected more rarely or not at all in the USA and Mexico. The carbapenems, meropenem and imipenem, had consistent activity against ESBL-producing strains, whereas ceftazidime and gentamicin appeared to be the least active. Similar observations were made regarding resistance to fluoroquinolones and aminoglycosides. Isolates from Brazil were often resistant to multiple classes of antimicrobial agents and susceptible only to the carbapenems. This observation must be tempered by the fact that all of the Brazilian centres were ICUs and would be expected to have higher rates of resistance than those observed in general wards. Clonal transmission of resistant strains and transfer of resistance genes between organisms have been well documented in Brazil and in some centres in the USA.17,21 The MYSTIC programme data presented herein should be considered as baseline information for the 14 institutions included in this longitudinal study. However, it is important not only to establish the prevalence of antimicrobial resistance at a single point in time, but also to provide longitudinal data to track changes over time.17 This longitudinal approach is particularly useful when coupled with antimicrobial usage data or when the in vitro activity of a specific agent for isolates can be compared before and after the introduction of the agent into clinical use on a local or national scale. Although meropenem usage in MYSTIC centres remains to be defined, we have MIC data for 3 years (1997–1999) for a single meropenem-using centre in Mexico and have a large body of MIC data obtained from the USA before the introduction of meropenem that can be compared with the 1999 MYSTIC data from the USA.25 The SENTRY programme provides MIC data on the prevalent pathogens in the USA and Brazil from 1998, and represents meropenem activity against isolates obtained from centres generally not using meropenem routinely.16–21 We believe that it is of value to compare SENTRY data with the first-year MYSTIC data from Brazil and the USA. No increase in resistance to the carbapenems, cephalosporins, piperacillin/tazobactam or ciprofloxacin was observed among isolates of E. coli, Klebsiella spp. or

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