Summary trends for the Meropenem Yearly Susceptibility Test Information Collection Program: a 10-year experience in the United States (1999–2008)

1. Introduction 

The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program was a longitudinal antimicrobial resistance surveillance study initiated in 1997; the program expanded to include other geographic regions and, for its final year (2008), had greater than 100 participant medical centers worldwide, located in Europe, North America, South America, and Asia, to monitor for changes in the in vitro activity of meropenem and other broad-spectrum antimicrobial agents (Jones et al., 2005, Turner, 2000, Turner, 2004, Turner, 2005, Turner, 2009, Turner et al., 1999). The United States (USA) portion of the MYSTIC Program (Jones et al., 2005, Pfaller and Jones, 2000, Pfaller et al., 2001, Rhomberg et al., 2004a, Rhomberg et al., 2004b, Rhomberg et al., 2005, Rhomberg et al., 2006a, Rhomberg et al., 2006b, Rhomberg and Jones, 2007, Rhomberg et al., 2007) began in 1999 with 10 selected medical centers where meropenem was the primary treatment carbapenem on the formulary (Edwards, 1995, Package Insert, 2007, Pfaller and Jones, 1997, Roberts et al., 2009, Wisemann et al., 1995). The program was expanded to 15 sites participating annually from 2000 through 2008 using a central processing laboratory design (JMI Laboratories, North Liberty, IA), also employed in Brazil (Pfaller and Jones, 2000) and special samplings in India (Jones et al., 2002, Mathai et al., 2002). Reference quality broth microdilution susceptibility testing was performed according to Clinical and Laboratory Standards Institute (CLSI, 2009b) (formerly National Committee for Clinical Laboratory Standards) methods to detect antimicrobial resistance rates and resistance trends for the carbapenems (meropenem and imipenem) and other comparator broad-spectrum agents.

Antimicrobial agents in the β-lactam class, especially meropenem (Wisemann et al., 1995), were initially very effective therapeutic agents in the treatment of serious infections caused by Gram-negative pathogens. The development and spread of β-lactamase resistance mechanisms within Gram-negative bacilli have significantly reduced the value of early β-lactam agents and required newer more potent and enzyme inhibitor protected extended-spectrum agents to be developed (Jones, 1996, Landman et al., 2002, Spellberg et al., 2008). To address the detection of emerging resistances, we have developed surveillance programs at all levels (local, regional, and global), stimulated by discussions in the United States and elsewhere (EARSS, 2007, Jones, 1996). These programs vary widely in design, scope, applied methods, and monitored compound, thus, requiring careful examination of method/design to assure the value of results (Jones, 2000, Jones and Masterton, 2001, Masterton, 2000). Notable surveillance networks include EARSS (2007), Alexander Project (Felmingham et al., 2005), Intensive Care Antimicrobial Resistance Epidemiology (Fridkin et al., 1999), PROTEKT (Harding and Felmingham, 2004), SENTRY Antimicrobial Surveillance Program (Jones, 2003), and the MYSTIC Program (Turner et al., 1999). These programs, some with excellent molecular support for determining mechanisms of β-lactam resistance, have discovered emerging high rates of enzyme-mediated resistances.

The genes encoding most β-lactamases are on plasmids or transposons, which can be easily transferred to other strains and often carry additional genetic elements encoding resistances to other antimicrobial classes (Castanheira et al., 2008). The most prevalent extended-spectrum β-lactamases (ESBLs) worldwide are the CTX-M type, found in the community and hospital settings (Castanheira et al., 2008). Another β-lactam resistance mechanism that is on the rise is plasmid-mediated AmpC enzymes. Chromosomal AmpC enzymes have become mobilized on plasmids and transferred to commonly isolated Enterobacteriaceae, such as Escherichia coli and Klebsiella spp. (Castanheira et al., 2008). Fortunately, meropenem and other carbapenems retain excellent antimicrobial activity against these ESBL- and AmpC-producing Enterobacteriaceae.

Historically, resistance to the carbapenems among Gram-negative bacilli has been secondary to hyperproduction of AmpC β-lactamase associated with a loss of outer membrane proteins and/or overexpression of efflux pumps (Bradford et al., 1997, Cao et al., 2000) or the presence of an intrinsic metallo-β-lactamase (MβL) in some rarer nonfermentative Gram-negative species (Chryseobacterium spp., Stenotrophomonas spp.). Recently, Enterobacteriaceae, Acinetobacter spp., and Pseudomonas spp. isolates have acquired carbapenemases (MβLs, oxacillinases, and serine carbapenemases). Initially, IMP- and VIM-producing MβL isolates were observed in Japan, Greece, and Italy, but MβLs remain rare in USA isolates. However, the USA MYSTIC and SENTRY Programs have documented MβL-producing Pseudomonas aeruginosa strains (Aboufaycal et al., 2007, Deshpande et al., 2006, Toleman et al., 2004). Also, very infrequent in USA Enterobacteriaceae are the presence of the serine carbapenemase SME types with a handful of isolates observed (Deshpande et al., 2006, Gales et al., 2001, Queenan et al., 2000) during the entire monitored period (1999–2008). Of greater concern in the United States is the detection and rapid spread of the KPC-type serine carbapenemases. KPC-type enzymes were first detected in Klebsiella pneumoniae from North Carolina (Yigit et al., 2001), with KPC-2 and KPC-3 soon appearing in Maryland, Massachusetts, New York, and Europe (Hossain et al., 2004, Miriagou et al., 2003, Woodford et al., 2004, Woodford et al., 2007). The swift spread of the KPC-type carbapenemase among K. pneumoniae isolates in New York medical centers prompted the Department of Health to issue an advisory for the detection and control of this pathogen. The KPC-type carbapenemases have now spread to medical centers within and outside the New York geographic area and also have been reported among other Enterobacteriaceae species (Bradford et al., 2004, Bratu et al., 2005, Castanheira et al., 2008, Deshpande et al., 2006).

This report summarizes the in vitro activity of meropenem and that of other broad-spectrum comparator agents tested against Enterobacteriaceae, Gram-negative nonfermentative bacilli, and Gram-positive cocci submitted from the MYSTIC Program (USA) medical centers in 2008 and the 9 prior years. We observed the continued potent activity of the carbapenem class against Enterobacteriaceae except for the known KPC-producing Enterobacteriaceae as part of an expanding epidemic (Deshpande et al., 2006, Rhomberg and Jones, 2007, Rhomberg et al., 2007). Increasing resistance rates for all agents against Acinetobacter spp. isolates has been pronounced, and annual resistance rates have been documented for carbapenems, β-lactams, aminoglycosides, and fluoroquinolones against major pathogen groups, to establish trends/changes and relationships to drug use (Mutnick et al., 2004) for organisms submitted for the MYSTIC Program (1999 and 2008). This is the summary report of the entire MYSTIC Program (USA) and related pharmacokinetic investigations (Kuti et al., 2004).

2. Materials and methods 

The MYSTIC Program in the United States was initiated in 1999 with 10 medical centers geographically dispersed across the United States; the program later expanded to 15 medical centers (2000–2008). The annual study protocols differed slightly over the testing years but, in general, dictated specific quotas of isolates among Gram-negative and Gram-positive pathogens to be submitted, up to a total of 200 isolates per medical center all originating from serious clinical infections in hospitalized patients. Due to intrinsic or enzyme-mediated resistances against carbapenems (Stenotrophomonas maltophilia, Chryseobacterium spp., oxacillin-resistant staphylococci, and Enterococcus faecium), some species were excluded from study sampling. All isolates were submitted to a central monitoring laboratory (JMI Laboratories) on provided transport devices with accompanying demographic information for each strain, allowing further analyses.

In 2008, a total of 2851 isolates (95.0% protocol compliance) were processed, and over the 10-year period of the USA MYSTIC Program, 27 289 isolates (94.1% compliance) were collected and tested. Bacterial strain identifications were performed at the local laboratory, and identifications were confirmed, as necessary, at the central monitoring laboratory using colony morphology, biochemical tests (Remel, Lenexa, KS), and/or the Vitek 2 System identification cards (bioMerieux, Hazelwood, MO). All isolates were stored at −70 °C.

Broth microdilution susceptibility testing was utilized on all bacterial strains by applying CLSI (2009b) reference methods published in M07-A8 to determine MICs. The antimicrobial agents tested in 2008 were meropenem, imipenem, ertapenem, cefepime, ceftazidime, ceftriaxone, piperacillin/tazobactam, tobramycin, ciprofloxacin, levofloxacin, and penicillin. Additionally, oxacillin and cefoxitin disk susceptibility testing was performed on staphylococcal isolates using the CLSI (2009a) M02-A10 method to confirm methicillin (oxacillin)-resistant strains. CLSI (2009c) interpretive breakpoint criteria published in M100-S19 were applied for determination of susceptibility rates. Concurrent testing with American Type Culture Collection (ATCC) strains E. coli ATCC 25922, P. aeruginosa ATCC 27853, Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 29213, and ATCC 25923 and Streptococcus pneumoniae ATCC 49619 assured the quality control (QC) of the susceptibility test methods (Clinical and Laboratory Standards Institute (CLSI), 2009b, Clinical and Laboratory Standards Institute (CLSI), 2009c) . All QC results were within published ranges (CLSI, 2009c).

The CLSI ESBL screening criteria (MIC, ≥2 μg/mL) for ceftazidime or ceftriaxone were applied to the E. coli, Klebsiella spp., and Proteus mirabilis with isolates further tested by a disk approximation or the Etest ESBL method (AB BIODISK, Solna, Sweden) to demonstrate an enhanced ceftazidime or cefotaxime activity in the presence of clavulanate. The CLSI (2009c) screening criteria of ≥2 μg/mL for both meropenem and imipenem was also utilized to detect possible KPC-type serine carbapenemase enzymes in Enterobacteriaceae isolates followed by multiplex polymerase chain reaction (PCR) confirmatory methods. Finally, all Gram-negative bacilli matching the Senda et al., 1996a, Senda et al., 1996b criteria of resistance to meropenem (≥16 μg/mL), imipenem (≥16 μg/mL), and ceftazidime (≥32 μg/mL) were tested by PCR methods to determine the presence of a MβL.

Multidrug-resistant (MDR) isolates within a bacterial species or genus group were analyzed by antimicrobial resistance antibiogram patterns to screen for the presence of local epidemic clonality. Selected strains were then typed for genotypic relatedness using automated ribotyping (RiboPrinter™ Microbial Characterization System; Qualicon, Wilmington, DE) of genomic DNA after digestion using appropriate restriction enzymes. The DNA fragments were separated by agarose gel electrophoresis resulting in banding patterns, which were then captured by image analysis software and compared to all previously tested isolates in the riboprint library network (the United States, Brazil, United Kingdom, and Australia) to assign a ribogroup. When necessary, further discrimination of a ribogroup was performed using CHEF-DRII pulsed-field gel electrophoresis (BioRad Laboratories, Hercules, CA) on restriction digested DNA. Gels were stained with ethidium bromide to visually identify the banding patterns and determine clonal relatedness (Tenover et al., 1995).

3. Results 

3.1. Activity of meropenem in the 2008 MYSTIC Program 

The susceptibility testing results for the sampled year 2008 isolates, including the MIC50, MIC90, and percentage susceptible and resistant, are summarized in Table 1 for 6 Enterobacteriaceae species or genus groups, as well as for all Enterobacteriaceae isolates combined. The carbapenems (meropenem, imipenem, and ertapenem) all demonstrated a high level of antimicrobial activity against the Enterobacteriaceae (1537 strains), with ≥96.6% susceptible rates. When comparing MIC50 and MIC90 results for all Enterobacteriaceae isolates combined, meropenem was 8- to 16-fold more potent than imipenem equal to or 2-fold more potent than ertapenem. Modest levels of carbapenem resistance was observed among E. coli (1.6%, 8 strains), Serratia spp. (2.8%, 4 strains), and Enterobacter spp. (4.2%, 9 strains) and was most prevalent among Klebsiella spp. (6.3%; 26 strains). Only cefepime, among the comparator agents, had a similar overall susceptibility rate (95.3%) against Enterobacteriaceae with all other broad-spectrum agents having susceptibility rates ranging from 80.5% to 89.3% (Table 1). Lowest susceptibility rates were observed for the fluoroquinolones (80.5–81.8%), especially prevalent among E. coli and P. mirabilis (14.0–31.8% resistant) isolates.

Table 1. Activity of meropenem and 9 comparator broad-spectrum antimicrobial agents tested against Enterobacteriaceae isolates collected from USA medical centers participating in the MYSTIC Program in 2008

	Organism (no. tested)/antimicrobial agent	MIC (μg/mL)			% Susceptible/resistanta
		50%	90%	Range
	Citrobacter spp. (103)
	Meropenem	0.03	0.06	≤0.015 to 4	100.0/0.0 (1.0)b
	Imipenem	0.5	1	0.12 to 2	100.0/0.0
	Ertapenem	≤0.03	0.12	≤0.03 to 4	99.0/0.0
	Ceftriaxone	≤0.25	32	≤0.25 to >32	81.6/7.8
	Ceftazidime	0.25	>16	≤0.12 to >16	80.6/18.4
	Cefepime	≤0.12	1	≤0.12 to >16	99.0/1.0 (1.0)c
	Piperacillin/tazobactam	≤8	32	≤8 to >64	87.4/2.9
	Ciprofloxacin	≤0.25	0.5	≤0.25 to >2	94.2/2.9
	Levofloxacin	≤0.5	1	≤0.5 to >4	95.1/2.9
	Tobramycin	≤2	≤2	≤2 to >8	96.1/3.9
	Enterobacter spp. (215)
	Meropenem	0.03	0.12	≤0.015 to 32	96.7/2.3 (4.2)b
	Imipenem	0.5	1	0.03 to 32	97.2/1.9
	Ertapenem	≤0.03	0.5	≤0.03 to >4	94.9/4.2
	Ceftriaxone	≤0.25	>32	≤0.25 to >32	74.9/17.2
	Ceftazidime	0.25	>16	≤0.12 to >16	74.0/21.9
	Cefepime	≤0.12	4	≤0.12 to >16	94.4/3.7 (6.5)c
	Piperacillin/tazobactam	≤8	>64	≤8 to >64	75.8/11.2
	Ciprofloxacin	≤0.25	2	≤0.25 to >2	89.8/8.4
	Levofloxacin	≤0.5	2	≤0.5 to >4	91.2/7.4
	Tobramycin	≤2	≤2	≤2 to >8	91.2/7.9
	E. coli (487)
	Meropenem	≤0.015	0.03	≤0.015 to 16	98.6/0.8 (1.6)b
	Imipenem	0.12	0.25	0.06 to 16	98.6/0.2
	Ertapenem	≤0.03	≤0.03	≤0.03 to >4	98.2/1.6
	Ceftriaxone	≤0.25	16	≤0.25 to >32	89.3/7.8 (11.5)d
	Ceftazidime	0.25	2	≤0.12 to >16	92.6/3.7 (10.9)d
	Cefepime	≤0.12	0.5	≤0.12 to >16	94.5/5.1
	Piperacillin/tazobactam	≤8	≤8	≤8 to >64	93.6/3.1
	Ciprofloxacin	≤0.25	>2	≤0.25 to >2	68.2/31.8
	Levofloxacin	≤0.5	>4	≤0.5 to >4	68.0/31.4
	Tobramycin	≤2	>8	≤2 to >8	84.8/10.3
	Klebsiella spp. (416)
	Meropenem	0.03	0.06	≤0.015 to >32	94.2/4.3 (6.5)b
	Imipenem	0.12	0.5	0.06 to >32	94.5/4.3
	Ertapenem	≤0.03	0.12	≤0.03 to >4	93.5/6.3
	Ceftriaxone	≤0.25	>32	≤0.25 to >32	87.3/10.3 (16.3)d
	Ceftazidime	≤0.12	>16	≤0.12 to >16	86.3/13.0 (15.9)d
	Cefepime	≤0.12	4	≤0.12 to >16	93.0/5.3
	Piperacillin/tazobactam	≤8	>64	≤8 to >64	85.6/11.3
	Ciprofloxacin	≤0.25	>2	≤0.25 to >2	84.1/14.7
	Levofloxacin	≤0.5	>4	≤0.5 to >4	85.6/13.7
	Tobramycin	≤2	>8	≤2 to >8	85.1/12.5
	P. mirabilis (171)
	Meropenem	0.06	0.06	0.03 to 0.12	100.0/0.0 (0.0)b
	Imipenem	1	2	0.06 to 2	100.0/0.0
	Ertapenem	≤0.03	≤0.03	≤0.03	100.0/0.0
	Ceftriaxone	≤0.25	≤0.25	≤0.25 to >32	99.4/0.6 (1.8)d
	Ceftazidime	≤0.12	≤0.12	≤0.12 to 4	100.0/0.0 (1.2)d
	Cefepime	≤0.12	≤0.12	≤0.12 to >16	99.4/0.6
	Piperacillin/tazobactam	≤8	≤8	≤8	100.0/0.0
	Ciprofloxacin	≤0.25	>2	≤0.25 to >2	77.2/17.5
	Levofloxacin	≤0.5	>4	≤0.5 to >4	80.1/14.0
	Tobramycin	≤2	≤2	≤2 to >8	95.9/2.3
	Serratia spp. (145)
	Meropenem	0.06	0.06	≤0.015 to >32	97.2/2.1 (2.8)b
	Imipenem	0.5	1	0.06 to >32	97.2/2.8
	Ertapenem	≤0.03	0.06	≤0.03 to >4	96.6/2.8
	Ceftriaxone	≤0.25	2	≤0.25 to >32	95.9/3.4
	Ceftazidime	≤0.12	0.5	≤0.12 to >16	98.6/0.7
	Cefepime	≤0.12	0.25	≤0.12 to >16	97.9/0.7 (2.0)c
	Piperacillin/tazobactam	≤8	≤8	≤8 to >64	93.8/2.1
	Ciprofloxacin	≤0.25	1	≤0.25 to >2	91.7/4.8
	Levofloxacin	≤0.5	2	≤0.5 to >4	95.9/3.4
	Tobramycin	≤2	4	≤2 to >8	91.7/6.2
	Enterobacteriaceae (1537)e
	Meropenem	0.03	0.06	≤0.015 to >32	97.3/2.0 (3.2)b
	Imipenem	0.25	1	0.03 to >32	97.4/1.8
	Ertapenem	≤0.03	0.12	≤0.03 to >4	96.6/3.1
	Ceftriaxone	≤0.25	32	≤0.25 to >32	88.0/8.6
	Ceftazidime	0.25	16	≤0.12 to >16	88.9/9.0
	Cefepime	≤0.12	1	≤0.12 to >16	95.3/3.8
	Piperacillin/tazobactam	≤8	32	≤8 to >64	89.3/6.0
	Ciprofloxacin	≤0.25	>2	≤0.25 to >2	80.5/17.8
	Levofloxacin	≤0.5	>4	≤0.5 to >4	81.8/16.8
	Tobramycin	≤2	8	≤2 to >8	88.4/8.8

a Criteria as published by the Clinical and Laboratory Standards Institute (CLSI), 2009a, Clinical and Laboratory Standards Institute (CLSI), 2009b, Clinical and Laboratory Standards Institute (CLSI), 2009c. b Bush group 2f carbapenemase screening concentration of ≥2 μg/mL for both meropenem and imipenem. c Percentage ESBL phenotypes using a screening concentration of ≥8 μg/mL. ESBL percentage includes strains with possible serine carbapenemase. (MYSTIC Program screening criteria). d Percentage ESBL phenotypes using Clinical and Laboratory Standards Institute (CLSI), 2009a, Clinical and Laboratory Standards Institute (CLSI), 2009b, Clinical and Laboratory Standards Institute (CLSI), 2009c screening concentration of ≥2 μg/mL. ESBL percentage includes strains with possible serine carbapenemases. e Includes Citrobacter amalonaticus (3 strains), Citrobacter braakii (3 strains), Citrobacter freundii (53 strains), Citrobacter koseri (27 strains), Citrobacter sedlakii (1 strain), Enterobacter aerogenes (39 strains), Enterobacter asburiae (2 strains), Enterobacter cloacae (141 strains), Enterobacter gergoviae (2 strains), Enterobacter hormaechei (1 strain), Enterobacter sakazakii (2 strains), E. coli (487 strains), Klebsiella oxytoca (79 strains), K. pneumoniae (321 strains), P. mirabilis (171 strains), Serratia liquefaciens (5 strains), S. marcescens (119 strains), unspeciated Citrobacter (16 strains), unspeciated Enterobacter (28 strains), unspeciated Klebsiella (16 strains), and unspeciated Serratia (21 strains).

The MYSTIC Program (2008) results for the nonfermentative Gram-negative bacilli, P. aeruginosa and Acinetobacter spp., are found in Table 2. Against P. aeruginosa, piperacillin/tazobactam (90.2% at ≤64 μg/mL [CLSI]) and tobramycin (89.1%) had the highest coverage rates (% susceptible) followed by cefepime (86.6%), ceftazidime (85.6%), and meropenem (85.4%). The fluoroquinolones again had the lowest susceptibility rates (72.7–77.0%) among the agents recommended for antipseudomonal therapy. Among carbapenem agents, meropenem was 2-fold more potent than imipenem (MIC90, 8 versus 16 μg/mL). Against Acinetobacter spp. isolates, tobramycin had the highest susceptibility rate (only 59.1%), and the carbapenems were next at 52.0% (imipenem) and 45.7% (meropenem). All other so-called “broad-spectrum agents” had susceptible rates at less than 34.6%, confirming this pathogen group as the most difficult to treat using currently marketed agents.

Table 2. Activity of meropenem and 9 comparator broad-spectrum antimicrobial agents tested against nonfermentative Gram-negative bacilli isolates collected from USA medical centers participating in the MYSTIC Program in 2008

	Organism (no. tested)/antimicrobial agent	MIC (μg/mL)			% Susceptible/resistanta
		50%	90%	Range
	P. aeruginosa (439)
	Meropenem	0.5	8	0.03 to >32	85.4/7.5
	Imipenem	1	16	0.06 to 32	79.5/15.5
	Ertapenem	>4	>4	≤0.03 to 4
	Ceftriaxone	>32	>32	0.5 to >32	8.9/70.8
	Ceftazidime	4	16	≤0.12 to >16	85.6/9.8
	Cefepime	4	16	≤0.12 to >16	86.6/6.4
	Piperacillin/tazobactam	≤8	64	≤8 to >64	90.2/9.8
	Ciprofloxacin	≤0.25	>2	≤0.25 to >2	77.0/17.3
	Levofloxacin	≤0.5	>4	≤0.5 to >4	72.7/19.1
	Tobramycin	≤2	8	≤2 to >8	89.1/9.1
	Acinetobacter spp. (127)b
	Meropenem	8	>32	0.06 to >32	45.7/47.2
	Imipenem	4	>32	0.06 to >32	52.0/38.6
	Ertapenem	>4	>4	0.5 to >4
	Ceftriaxone	>32	>32	4 to >32	11.8/62.2
	Ceftazidime	>16	>16	1 to >16	31.5/60.6
	Cefepime	>16	>16	0.5 to >16	31.5/55.1
	Piperacillin/tazobactam	>64	>64	≤8 to >64	34.6/60.6
	Ciprofloxacin	>2	>2	≤0.25 to >2	32.3/66.9
	Levofloxacin	>4	>4	≤0.5 to >4	33.9/59.1
	Tobramycin	≤2	>8	≤2 to >8	59.1/33.9

a Criteria as published by the Clinical and Laboratory Standards Institute (CLSI), 2009a, Clinical and Laboratory Standards Institute (CLSI), 2009b, Clinical and Laboratory Standards Institute (CLSI), 2009c. b Includes Acinetobacter baumannii (94 strains), Acinetobacter calcoaceticus (1 strain), Acinetobacter lwoffii (12 strains), and unspeciated Acinetobacter (20 strains).

Table 3 lists the susceptibility testing results for the Gram-positive cocci collected as part of the 2008 MYSTIC Program. The oxacillin-susceptible staphylococci were completely susceptible (100.0%) to the carbapenems and cefepime, in contrast to methicillin-resistant S. aureus isolates that are considered resistant to all currently available β-lactams (Clinical and Laboratory Standards Institute (CLSI), 2008, Clinical and Laboratory Standards Institute (CLSI), 2009b). Reduced susceptibility rates were observed only for the fluoroquinolones, 77.6% to 78.3% against coagulase-negative staphylococci and 87.7% to 89.6% against S. aureus. The β-hemolytic streptococci were very susceptible to all agents tested, except tobramycin (MIC50, >8 μg/mL,) and susceptibility rates were 100.0% for all agents using published CLSI (2009c) breakpoints. The viridans group streptococci and S. pneumoniae isolates were less susceptible to the carbapenems than the β-hemolytic streptococci, with meropenem susceptibility rates of 90.0% and 80.0%, respectively. The meropenem MIC90 values for viridans group streptococci (0.5 μg/mL) and S. pneumoniae (1 μg/mL) were greater than for the β-hemolytic streptococci (0.06 μg/mL).

Table 3. Activity of meropenem and 9 comparator broad-spectrum antimicrobial agents tested against Gram-positive cocci isolates collected from USA medical centers participating in the MYSTIC Surveillance Program in 2008

	Organism (no. tested)/antimicrobial agent	MIC (μg/mL)			% Susceptible/resistanta
		50%	90%	Range
	S. aureus (317)
	Meropenem	0.12	0.12	0.03 to 0.25	100.0/0.0
	Imipenem	0.03	0.03	≤0.015 to 0.06	100.0/0.0
	Ertapenem	0.12	0.25	0.06 to 0.5	100.0/0.0
	Ceftriaxone	4	4	0.5 to 16	99.7/0.0
	Ceftazidime	8	8	2 to 16	95.3/0.0
	Cefepime	2	4	0.5 to 8	100.0/0.0
	Piperacillin/tazobactam	≤8	≤8	≤8 to 16	99.7/0.3
	Ciprofloxacin	0.5	>2	≤0.25 to >2	87.7/11.0
	Levofloxacin	≤0.5	4	≤0.5 to >4	89.6/10.1
	Tobramycin	≤2	≤2	≤2 to >8	96.8/2.5
	Coagulase-negative staphylococci (143)b
	Meropenem	0.12	0.25	0.03 to 0.5	100.0/0.0
	Imipenem	0.03	0.03	≤0.015 to 0.12	100.0/0.0
	Ertapenem	0.12	0.5	0.06 to 1	100.0/0.0
	Ceftriaxone	2	4	≤0.25 to 16	99.3/0.0
	Ceftazidime	4	8	1 to 16	93.7/0.0
	Cefepime	0.5	2	≤0.12 to 4	100.0/0.0
	Piperacillin/tazobactam	≤8	≤8	≤8	100.0/0.0
	Ciprofloxacin	≤0.25	>2	≤0.25 to >2	77.6/21.7
	Levofloxacin	≤0.5	>4	≤0.5 to >4	78.3/21.0
	Tobramycin	≤2	≤2	≤2 to >8	93.7/2.1
	S. pneumoniae (125)
	Meropenem	≤0.015	1	≤0.015 to 2	80.0/14.4
	Imipenem	≤0.015	1	≤0.015 to 1	81.6/11.2
	Ertapenem	≤0.03	1	≤0.03 to 2	94.4/0.0
	Ceftriaxone	≤0.25	1	≤0.25 to 4	90.4/0.8
	Ceftazidime	0.25	16	≤0.12 to >16
	Cefepime	≤0.12	1	≤0.12 to 2	92.8/0.0
	Penicillin	≤0.06	4	≤0.06 to 8	85.6/4.8 (60.0/20.0)c
	Piperacillin/tazobactam	≤8	≤8	≤8 to 16
	Ciprofloxacin	1	2	0.5 to >2
	Levofloxacin	1	1	≤0.5 to >4	99.2/0.8
	Tobramycin	>8	>8	≤2 to >8
	β-Hemolytic streptococci (119)d
	Meropenem	≤0.015	0.06	≤0.015 to 0.12	100.0/–
	Imipenem	≤0.015	0.03	≤0.015 to 0.06
	Ertapenem	≤0.03	0.06	≤0.03 to 0.5	100.0/–
	Ceftriaxone	≤0.25	≤0.25	≤0.25	100.0/–
	Ceftazidime	0.25	1	≤0.12 to 4
	Cefepime	≤0.12	≤0.12	≤0.12 to 0.5	100.0/–
	Penicillin	≤0.06	≤0.06	≤0.06 to 0.12	100.0/–
	Piperacillin/tazobactam	≤8	≤8	≤8
	Ciprofloxacin	0.5	1	0.5 to 2
	Levofloxacin	≤0.5	1	≤0.5 to 2	100.0/0.0
	Tobramycin	>8	>8	4 to >8
	Viridans group streptococci (40)e
	Meropenem	0.06	0.5	≤0.015 to 4	90.0/–
	Imipenem	0.03	0.25	≤0.015 to 4
	Ertapenem	0.12	1	≤0.03 to 4
	Ceftriaxone	≤0.25	2	≤0.25 to 8	87.5/7.5
	Ceftazidime	2	8	≤0.12 to >16
	Cefepime	0.25	1	≤0.12 to 8	90.0/5.0
	Penicillin	≤0.06	2	≤0.06 to >8	67.5/7.5
	Piperacillin/tazobactam	≤8	≤8	≤8 to >64
	Ciprofloxacin	1	>2	≤0.25 to >2
	Levofloxacin	1	>4	≤0.5 to >4	85.0/15.0
	Tobramycin	8	>8	≤2 to >8

a Criteria as published by the Clinical and Laboratory Standards Institute (CLSI), 2009a, Clinical and Laboratory Standards Institute (CLSI), 2009b, Clinical and Laboratory Standards Institute (CLSI), 2009c, β-lactam susceptibility should be directed by the oxacillin test results. b Includes Staphylococcus capitis (6 strains), Staphylococcus epidermidis (26 strains), Staphylococcus haemolyticus (1 strain), Staphylococcus hominis (3 strains), Staphylococcus lugdunensis (6 strains), Staphylococcus simulans (1 strain), Staphylococcus warneri (1 strain), and unspeciated coagulase-negative staphylococci (99 strains). c Both parenteral and oral (in parenthesis) breakpoints provided. d Includes group A Streptococcus (45 strains), group B Streptococcus (54 strains), group C Streptococcus (2 strains), group F Streptococcus (2 strains), and group G Streptococcus (16 strains). e Includes Streptococcus anginosus (4 strains), Streptococcus constellatus (1 strain), Streptococcus milleri (2 strains), Streptococcus mitis (4 strains), Streptococcus oralis (4 strains), Streptococcus sanguinis (1 strain), unspeciated α-hemolytic streptococci (1 strain), and unspeciated viridians group streptococci (23 strains).

3.2. Susceptibility rate trends in MYSTIC Program (1999–2008) 

Table 4 shows the longitudinal resistance trends in the USA MYSTIC Program for up to 10 monitored broad-spectrum antimicrobial agents over the 10-year study interval. Not all species groups were monitored in all years; among Gram-negative bacilli, only E. coli and Klebsiella sp. isolates were collected in 2006, and no Gram-positive cocci were collected in 2004.

Table 4. Resistance rates for meropenem and comparator broad-spectrum antimicrobial agents tested by year against Gram-negative bacilli and Gram-positive cocci isolates collected from USA medical centers participating in the MYSTIC Program between 1999 and 2008

	Organism (no. tested)/antimicrobial agent	% Resistancea
		1999	2000	2001	2002	2003	2004	2005	2006	2007	2008
	Citrobacter spp. (no. tested)	(46)	(68)	(80)	(80)	(141)	(141)	(146)		(115)	(103)
	Meropenem	0.0	0.0	0.0	0.0	0.0	0.0	0.0		0.0	0.0
	Imipenem	0.0	0.0	0.0	0.0	0.0	0.0	0.0		1.7	0.0
	Ceftriaxone	4.3	8.8	1.3	3.8	6.4	5.0	6.8		3.5	7.8
	Ceftazidime	6.5	23.5	8.8	10.0	14.2	10.6	19.2		13.0	18.4
	Cefepime	2.2	0.0	0.0	0.0	0.7	0.0	0.0		0.0	1.0
	Piperacillin/tazobactam	2.2	10.3	1.3	3.8	5.0	2.8	6.8		4.3	2.9
	Gentamicin	2.2	7.4	6.3	8.8	8.5	7.8	6.2		4.3
	Tobramycin	2.2	4.4	2.5	7.5	5.7	5.7	6.2		3.5	3.9
	Ciprofloxacin	6.5	4.4	2.5	6.3	7.1	4.3	6.2		1.7	2.9
	Levofloxacin					4.3	2.8	4.8		1.7	2.9
	Enterobacter spp. (no. tested)	(97)	(158)	(145)	(143)	(158)	(160)	(159)		(172)	(215)
	Meropenem	0.0	0.6	0.7	0.7	0.0	0.0	0.0		1.2	2.3
	Imipenem	0.0	0.6	0.7	0.7	0.0	0.0	0.0		1.7	1.9
	Ceftriaxone	7.2	8.2	13.1	9.8	8.9	9.4	13.8		8.7	17.2
	Ceftazidime	13.4	11.4	19.3	15.4	15.2	16.3	21.4		18.0	21.9
	Cefepime	0.0	0.6	0.7	2.1	1.3	0.6	0.0		4.7	3.7
	Piperacillin/tazobactam	6.2	5.1	11.0	7.0	6.3	5.6	6.9		10.5	11.2
	Gentamicin	2.1	1.3	4.1	4.2	7.6	9.4	6.9		3.5
	Tobramycin	1.0	1.3	5.5	4.9	5.1	8.8	7.5		7.0	7.9
	Ciprofloxacin	0.0	1.9	9.7	7.0	9.5	8.8	3.8		9.9	8.4
	Levofloxacin					5.7	7.5	3.1		8.7	7.4
	E. coli (no. tested)	(197)	(312)	(306)	(303)	(469)	(724)	(491)	(640)	(465)	(487)
	Meropenem	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.8
	Imipenem	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.2
	Ceftriaxone	1.0	0.6	0.7	0.3	0.2	1.1	2.6	3.4	5.4	7.8
	Ceftazidime	2.5	1.6	2.3	0.3	0.4	1.5	3.1	3.3	1.5	3.7
	Cefepime	0.5	0.0	0.0	0.0	0.0	0.4	1.4	1.6	3.0	5.1
	Piperacillin/tazobactam	1.5	1.3	1.3	1.7	1.3	1.1	2.4	1.7	4.9	3.1
	Gentamicin	3.0	1.9	4.2	4.0	2.8	9.4	10.2	11.4	12.9
	Tobramycin	1.5	2.3	1.6	3.0	1.3	2.2	5.9	9.1	6.2	10.3
	Ciprofloxacin	4.1	2.9	9.2	7.3	10.9	20.7	21.6	27.5	29.0	31.8
	Levofloxacin					10.2	20.2	20.4	26.4	28.4	31.4
	K. pneumoniae (no. tested)	(118)	(195)	(176)	(194)	(235)	(337)	(367)	(529)	(222)	(321)
	Meropenem	0.0	2.6	0.0	0.0	0.0	0.6	4.6	9.6	10.8	5.6
	Imipenem	0.0	2.1	0.0	0.0	0.0	0.6	1.9	7.9	12.2	5.3
	Ceftriaxone	0.0	2.6	1.1	1.5	0.9	2.7	10.4	12.1	15.3	11.8
	Ceftazidime	2.5	5.6	4.5	3.1	4.7	4.5	15.0	15.1	22.5	15.0
	Cefepime	0.0	3.6	0.6	0.0	0.4	0.9	4.4	10.8	10.8	6.2
	Piperacillin/tazobactam	4.2	3.1	1.1	2.6	2.1	3.6	10.9	14.7	21.6	11.5
	Gentamicin	2.5	5.1	3.4	2.6	4.7	4.5	6.8	7.2	8.1
	Tobramycin	2.5	5.2	2.3	2.1	5.1	4.7	13.4	15.5	22.5	14.3
	Ciprofloxacin	4.2	5.1	4.5	1.0	4.7	5.0	15.8	19.3	26.1	16.5
	Levofloxacin					4.3	4.5	14.2	18.9	25.7	16.2
	P. mirabilis (no. tested)	(95)	(143)	(142)	(138)	(154)	(128)	(147)		(118)	(171)
	Meropenem	0.0	0.0	0.0	0.0	0.0	0.0	0.0		0.0	0.0
	Imipenem	0.0	1.4	0.0	0.0	0.0	0.0	0.0		0.8	0.0
	Ceftriaxone	0.0	0.0	0.0	0.0	0.0	0.0	0.0		0.0	0.6
	Ceftazidime	1.1	2.1	1.4	0.0	0.0	0.0	0.0		0.0	0.0
	Cefepime	1.1	0.7	0.0	0.0	0.0	0.0	0.0		0.0	0.6
	Piperacillin/tazobactam	0.0	0.7	0.0	0.0	0.0	0.0	0.0		0.0	0.0
	Gentamicin	1.1	7.7	4.2	5.8	5.8	0.8	3.4		5.1
	Tobramycin	0.0	4.9	3.5	4.3	1.3	0.0	0.7		4.2	2.3
	Ciprofloxacin	2.1	7.0	7.0	7.2	10.4	7.0	15.6		20.3	17.5
	Levofloxacin					7.8	6.3	11.6		16.9	14.0
	Serratia spp. (no. tested)	(53)	(74)	(74)	(77)	(133)	(149)	(134)		(138)	(145)
	Meropenem	3.8	0.0	0.0	0.0	0.0	0.0	0.7		0.0	2.1
	Imipenem	3.8	0.0	0.0	1.3	0.0	0.0	0.7		0.0	2.8
	Ceftriaxone	0.0	2.7	1.4	0.0	0.8	1.3	1.5		0.7	3.4
	Ceftazidime	0.0	2.7	1.4	2.6	0.8	2.7	2.2		0.7	0.7
	Cefepime	0.0	1.4	0.0	1.3	0.0	0.0	0.7		0.7	0.7
	Piperacillin/tazobactam	0.0	0.0	0.0	1.3	0.0	0.0	0.0		2.2	2.1
	Gentamicin	1.9	2.7	1.4	3.9	0.8	4.7	3.7		2.2
	Tobramycin	3.8	5.4	6.8	5.2	2.3	7.4	6.0		3.6	6.2
	Ciprofloxacin	3.8	8.1	8.1	1.3	3.8	1.3	1.5		4.3	4.8
	Levofloxacin					3.0	0.0	0.7		2.2	3.4
	All Enterobacteriaceae (no. tested)	(708)	(1048)	(1037)	(1057)	(1439)	(1865)	(1657)	(1259)	(1393)	(1538)
	Meropenem	0.3	0.6	0.1	0.1	0.0	0.1	1.1	4.1	1.9	2.0
	Imipenem	0.3	0.7	0.1	0.2	0.1	0.1	0.5	3.3	2.4	1.8
	Ceftriaxone	1.7	2.9	2.6	2.1	1.9	2.4	5.2	6.8	5.7	8.6
	Ceftazidime	4.0	5.6	5.5	3.9	4.1	4.3	8.4	8.0	7.7	9.0
	Cefepime	0.4	1.0	0.3	0.4	0.3	0.4	1.4	5.3	3.4	3.8
	Piperacillin/tazobactam	2.3	2.7	2.5	2.8	2.2	2.0	5.0	7.8	8.0	6.0
	Gentamicin	2.7	4.0	3.8	4.6	4.6	6.8	7.4	8.9	7.5
	Tobramycin	1.7	3.3	2.9	4.2	3.1	4.0	6.9	11.2	7.8	8.8
	Ciprofloxacin	3.7	4.4	6.8	6.9	8.6	12.9	14.8	22.5	18.3	17.8
	Levofloxacin					7.0	11.7	13.2	21.7	17.3	16.8
	A. baumannii (no. tested)	(20)	(34)	(56)	(55)	(73)	(111)	(88)		(86)	(94)
	Meropenem	35.0	17.6	17.9	16.4	11.0	20.7	11.4		48.8	57.4
	Imipenem	10.0	8.8	10.7	14.5	2.7	10.8	4.5		37.2	47.9
	Ceftriaxone	40.0	32.4	35.7	40.0	39.7	45.9	48.9		68.6	68.1
	Ceftazidime	30.0	26.5	32.1	38.2	38.4	46.8	46.6		64.0	68.1
	Cefepime	20.0	23.5	30.4	32.7	26.0	38.7	31.8		59.3	62.8
	Piperacillin/tazobactam	30.0	20.6	21.4	21.8	24.7	46.8	39.8		66.3	69.1
	Gentamicin	50.0	32.4	33.9	34.5	34.2	39.6	36.4		55.8
	Tobramycin	30.0	17.6	26.8	21.8	9.6	13.5	8.0		43.0	40.4
	Ciprofloxacin	40.0	35.3	41.1	47.3	46.6	53.2	56.8		74.4	73.4
	Levofloxacin					41.1	46.8	42.0		73.3	64.9
	P. aeruginosa (no. tested)	(193)	(299)	(298)	(301)	(454)	(689)	(589)	(606)	(454)	(439)
	Meropenem	16.1	10.0	8.4	4.7	7.3	6.0	6.8	6.4	8.6	7.5
	Imipenem	18.7	13.4	9.7	8.0	9.5	5.1	7.3	10.7	18.3	15.5
	Ceftriaxone	77.2	77.9	68.5	59.1	63.0	78.8	53.5	68.6	75.1	70.8
	Ceftazidime	10.9	13.0	10.1	10.3	10.8	13.4	9.8	12.9	10.8	9.8
	Cefepime	7.3	9.7	5.4	5.6	6.2	5.8	4.8	5.6	6.6	6.4
	Piperacillin/tazobactam	10.9	13.7	9.1	9.0	9.7	12.0	9.0	11.4	11.0	9.8
	Gentamicin	8.8	9.0	10.1	8.6	11.0	9.9	12.1	11.7	9.9
	Tobramycin	5.7	7.0	7.7	7.0	9.5	7.7	10.4	7.9	7.3	9.1
	Ciprofloxacin	11.9	20.4	22.1	23.9	25.3	21.2	22.4	20.6	19.6	17.3
	Levofloxacin					26.0	23.2	22.4	21.8	22.0	19.1

a Criteria as published by the CLSI (2008).

Against the Citrobacter spp. isolates tested over the last decade, most agents showed stable resistance rates with only small variations ±5% changes annually. Ceftazidime showed a dramatic increase in 2000 compared to the baseline year (1999) and a slight increasing trend over the 10-year period, mainly due to the spread of stably depressed AmpC enzyme-producing strains in this species group. Carbapenem resistance was rarely observed among Enterobacter spp. during the first 7 years; however, an increasing trend toward resistance was noted in the final 2 years studied due to the spread of KPC carbapenemase from the Klebsiella spp. into Enterobacter spp. strains and secondary spread of this resistance mechanism beyond the New York City geographic area, where it has become endemic in MYSTIC Program monitored hospitals.

The most interesting pathogen group with multiple antimicrobial agents showing increased resistance rates is the E. coli (Table 4 and Fig. 1). Ciprofloxacin resistance was only 4.1% in the baseline year and has steadily increased to 31.8% after 10 years (Table 4). The aminoglycosides also exhibited a slower, but still consistent, increase in resistance from 1999 (tobramycin, resistance at 1.5%) to 2007 (10.3%). Cefepime resistance in the E. coli strains first emerged in 2004 (0.4%) and rapidly climbed to 5.1% in only 5 years (CTX-M ESBL- and KPC-producing isolates). Carbapenem resistance among E. coli isolates was first observed in the 2008 sample, again, most likely due to the spread of KPC genes from Klebsiella spp. Among the Klebsiella spp. isolates, carbapenem resistance was rarely observed prior to 2003, but after the emergence, the resistance rates quickly increased to nearly 8% in 2007 before falling back to 4.3% in 2008 associated with local infection control interventions. Concurrent with the spread of KPC enzymes in these Klebsiella spp. isolates was the rise in resistance among the other β-lactam and β-lactam/β-lactamase inhibitor combination agents tested (Table 4 and Fig. 2). A rapid rise in fluoroquinolone and aminoglycoside resistance was noted in 2005 compared to the stable rates observed in 1999 through 2004. This was due to coresistances carried on KPC-harboring plasmids.

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Fig. 1. Annual rate of antimicrobial resistance among E. coli isolates (4394 strains) tested against selected agents from the MYSTIC Program (1999–2008).

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Fig. 2. Annual rate of antimicrobial resistance among K. pneumoniae isolates (2694 strains) tested against selected agents from the MYSTIC Program (1999–2008).

Most broad-spectrum agents showed stable resistance rates against the indole-positive Proteus spp. and P. mirabilis isolates except for the fluoroquinolones tested against P. mirabilis, which showed a dramatic 10-fold increase from 2.1% (ciprofloxacin) in 1999 to nearly 20% in 2007 to 2008 (target mutations and plasmidic qnr genes). Serratia spp. isolates also exhibited highly stable resistance rates over the 10-year study period except for some clonally related SME carbapenemase-producing isolates in 1999 and KPC-producing Serratia marcescens in 2008.

Against the Acinetobacter spp. isolates, resistance rates ranged from 10.0% (imipenem) to 50.0% (gentamicin) in the 1999 baseline year. Most agents showed increasing resistance rates over the 10-year study period with the highest rates in 2008 for ciprofloxacin (73.4%), piperacillin/tazobactam (69.1%), and ceftriaxone and ceftazidime (68.1%). Lowest resistance rates observed were for tobramycin (40.4%), imipenem (47.9%), and meropenem (57.4%). Resistance rates varied up to ±7% annually among these agents tested against P. aeruginosa isolates tested between 1999 and 2008; however, the overall resistance rates generally remained stable or decreasing slightly for some agents (Table 4 and Fig. 3).

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Fig. 3. Annual rate of antimicrobial resistance among P. aeruginosa isolates (4322 strains) tested against selected agents from the MYSTIC Program (1999–2008).

Among the methicillin-susceptible S. aureus and coagulase-negative Staphylococcus, resistance rates remained very stable for most agents tested, except for the fluoroquinolones where the 1999 baseline rates of 4.2% and 9.2% increased to 11.0% and 21.7% for ciprofloxacin against S. aureus and coagulase-negative staphylococci, respectively (data not shown). Levofloxacin showed a rapidly increasing resistance rate from 0.0% in 2003 to 15.0% in 2008 for viridians group streptococci due to clonal spread of QRDR mutant strains in several institutions.

4. Discussion 

Serious bacterial infections require prompt, appropriate treatment to minimize the risk of morbidity and mortality, and carbapenems have been strongly recommended as an initial empiric treatment followed by more directed therapy after follow-up susceptibility results are known from culture of the causative pathogen. Meropenem is a very broad-spectrum carbapenem approved by the USA Food and Drug Administration for the treatment of complicated skin and skin structure infections in adults and children, complicated intra-abdominal infections in adults and children, and pediatric bacterial meningitis infections in children ≥3 years old. (Package Insert, 2007, Wisemann et al., 1995). Unlike imipenem, meropenem does not require the coadministration of the renal dehydropeptidase inhibitor cilastatin to prevent rapid inactivation and toxicity. These risks are minimized with meropenem treatment, and it has been shown to be well tolerated in many clinical trials and at alternative dosing regimens to optimized PK/PD target attainments (Kuti et al., 2004, Package Insert, 2007, Roberts et al., 2009). Meropenem is approved for meningitis because it penetrates well into most body fluids and tissue, including the cerebral spinal fluid. Bacterial meningitis infections caused by S. pneumoniae, Haemophilus influenzae, and Neisseria meningitidis are all within the spectrum of meropenem treatment.

In the USA meropenem is not approved for antimicrobial treatment of nosocomial pneumonia (including hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, and health-care–associated bacterial pneumoniae); however, it has demonstrated efficacy for these indications in numerous clinical trials and is recommended in the American Thoracic Society and Infectious Disease Society of America guidelines (American Thoracic Society and Infectious Disease Society of America, 2005) as initial empiric therapy for patients suspected of being infected with MDR pathogens or with significant risk factors (Spellberg et al., 2008). With a near-complete wide spectrum of activity, meropenem does not cover methicillin-resistant staphylococci, E. faecium, S. maltophilia, and Chryseobacterium spp. due to intrinsic or acquired resistance mechanisms.

Antimicrobial surveillance on a local, regional, or national level can be a valuable tool to assist clinicians in using accurate contemporary information to establish or modify existing treatment guidelines, especially in the choice of appropriate empiric antimicrobial therapy (Jones, 2000, Jones and Masterton, 2001, Masterton, 2000). Many antimicrobial resistance surveillance programs have been initiated to address these needs, each designed to monitor specific pathogens causing infections or antimicrobial agents (EARSS, 2007, Felmingham et al., 2005, Fridkin et al., 1999, Harding and Felmingham, 2004, Jones, 2000, Jones and Masterton, 2001, Turner, 2000). Earlier reports have documented the value and outline the fundamental differences between some of these surveillance programs and the vital constituents that make up a quality surveillance program (Harding and Felmingham, 2004, Jones, 1996, Jones and Masterton, 2001, Masterton, 2000, Turner, 2000, Turner, 2005).

The MYSTIC antimicrobial resistance surveillance program has documented the continued high potency and wide spectrum of activity of meropenem worldwide against Enterobacteriaceae species isolates, including those with ESBL- and AmpC-producing resistance mechanisms (Castanheira et al., 2008, Jones et al., 2002, Jones et al., 2008, Mathai et al., 2002, Pfaller and Jones, 2000, Rhomberg and Jones, 2007, Turner, 2004). Recently, there has been a significant spread of the Ambler class A serine carbapenemase KPC-type endemic within the geographically distinct areas, primarily among K. pneumoniae isolates, but transmission to other Enterobacteriaceae species has also been observed via mobile genetic elements (Hussein et al., 2009, Jones et al., 2008, Rhomberg et al., 2007). This KPC-type resistance mechanism has not yet been observed within the European portion of the MYSTIC surveillance program through the 2008 bacterial collection (Turner, 2009). The presence of the SME-type serine carbapenemase, identified in only 3 S. marcescens isolates in the USA MYSTIC Program over 10 years, remains rare and does not seem to be as transmissible or virulent as the KPC type (Deshpande et al., 2006, Gales et al., 2001, Queenan et al., 2000). Other clonal occurrences of carbapenem resistances have also compromised therapy among nonfermentative Gram-negative bacilli throughout the interval of the MYSTIC Program (USA) in some institutions (Jones et al., 2004).

The current CLSI MIC susceptibility breakpoints for the carbapenems listed in the M100-S19 standard (e.g. ≤4, 8, ≥16 meropenem against Enterobacteriaceae) are higher than those in use by EUCAST for Europe (≤2, 4, ≥8), which has necessitated re-evaluation of breakpoints by the CLSI to achieve international harmonization. These to be lowered CLSI carbapenem breakpoints will cause a shift toward elevated resistance rates for some bacterial species with low level carbapenem resistance mechanisms (MIC values 0.5–4 μg/ml).

While the carbapenem resistance rates have not varied significantly during the monitored interval of 1999 to 2008 for the MYSTIC Program, other comparator broad-spectrum agents have shown increasing resistance rates, most notably the fluoroquinolone class (Adam et al., 2009, Jones, 2003, Jones and Pfaller, 2002, Rhomberg et al., 2003). The presence of endemic and epidemic dissemination of fluoroquinolone-resistant clones among Enterobacteriaceae species isolates has been observed with a resulting effect to drive up the overall fluoroquinolone resistance rates. Increasing fluoroquinolone resistance rates have been reported among many bacterial species where surveillance is performed (Fig. 1, Fig. 2, Fig. 3, Fig. 4) and evidence of a relationship to use has been suggested (Adam et al., 2009, Mutnick et al., 2004). The genus groups showing the greatest increases in fluoroquinolone resistance in the MYSTIC program are the indole-positive Proteae, E. coli, and Acinetobacter spp.

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Fig. 4. Annual rate of antimicrobial resistance among all Enterobacteriaceae isolates (13 001 strains) tested against selected agents from the MYSTIC Program (1999–2008).

Clearly, the USA MYSTIC Program (1999–2008) has contributed to the monitoring of antimicrobial resistances via use of molecular techniques to identify resistance mechanisms, clonal spread, relationships to local hospital use statistics, and ranking of the most broad-spectrum agents currently available for empiric treatment of serious hospital-associated infections. As documented initially in 1999, the MYSTIC Program for 2008 again confirms that carbapenems (meropenem) have the widest coverage of nosocomial pathogens, and they remain excellent choices to apply in various monotherapeutic or combination regimens to maximize clinical outcomes. As newer and investigational carbapenems (doripenem, razopenem, etc.) become established in the antimicrobial market place, the class must be followed by well-structured resistance surveillance studies to assure continued value across the United States (Edwards, 1995, Paterson, 2000, Wisemann et al., 1995) and to establish the advantages of alternative dosing and drug delivery (Crandon et al., 2009, Kuti et al., 2003, Kuti et al., 2004, Li et al., 2006, Roberts et al., 2009).