Bacterial Resistance: A Worldwide Problem

Bacterial Resistance: A Worldwide Problem Ronald N. Jones and Michael A. Pfaller

The therapeutic crisis produced by emerging antimicrobial resistances has compromised the chemotherapy of hospitalized patients with serious infections. For the most prevalent resistance problems, meropenem, a new carbapenem, appears to provide a potency and spectrum for: 1) extended-spectrum b-lactamase-producing Enterobacteriaceae; 2) Bush-JacobyMerdeiros group 1 enzyme-producing ceftazidime-resistant Enterobacter spp., Citrobacter freundii, and some Serratia spp.; 3) ceftazidime- and imipenem-resistant Pseudomonas aeruginosa; and 4) some Streptococcus spp. with elevated penicillin MICs. Documented in vitro study results using 1997 Gram-negative blood stream infection isolates indicate a wider spectrum and a two- to fourfold greater potency for

meropenem compared with imipenem. This was especially true for P. aeruginosa where 93.4% of strains were susceptible to meropenem (84.1% for imipenem). Also among over 30,000 reported in vitro meropenem results from the United States and Europe, 90.6% of Gram-positive cocci and 99.1% of anaerobes were inhibited at #4 mg/ml. Over 90% of ceftazidime-resistant blood stream infection strains were meropenem susceptible, a rate greater than those of imipenem, ciprofloxacin, and gentamicin. As the clinical utility of many contemporary antimicrobial agents is challenged by emerging resistance, the carbapenems (meropenem, imipenem) appear positioned for a greater role in the treatment of infections in hospitalized patients. © 1998 Elsevier Science Inc.

INTRODUCTION

interventions; 2) education of health care professionals and the public as to effective prescribing habits or expectations; and 3) basic research for developing new modes of therapy or infection prevention.

A wide variety of microbes have acquired antimicrobial resistances in the last two decades (Jones 1996a). This has been associated with changing patterns of pathogen occurrences e.g., the emergence of Grampositive organisms as the dominant species causing blood stream infections in neutropenic patients (Jones 1996a; Etling et al. 1997). The most recent discussions of these negative events have focused on the misuse of antimicrobials in the outpatient setting (Gonzales et al. 1997) and elsewhere (Kunin, 1997). Actions necessary to limit the selection of resistance have been summarized in the comprehensive report by the American Society for Microbiology Task Force on Antibiotic Resistance in 1995 (Jones 1996b). That report emphasized the need for: 1) surveillance networks to recognize emerging resistance and direct From the Medical Microbiology Division, University of Iowa College of Medicine, Iowa City, Iowa. Address reprint requests to Professor Ronald N. Jones, M.D., Medical Microbiology Division, Department of Pathology, C606 GH, University of Iowa College of Medicine, Iowa City, IA 52242. Received 10 January 1998; accepted 9 March 1998.

DIAGN MICROBIOL INFECT DIS 1998;31:379 –388 © 1998 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010

EMERGING ANTIMICROBIAL RESISTANCES Those antimicrobial resistances currently presenting the greatest threat to favorable therapeutic outcomes are listed in Table 1. The most serious are oxacillinresistant Staphylococcus aureus, vancomycin-resistant enterococci, and penicillin-non-susceptible streptococci among the Gram-positive organisms; and extended-spectrum b-lactamases (ESBLs) in Klebsiella pneumoniae or Escherichia coli and stably derepressed Bush-Jacoby-Medeiros group 1 cephalosporinases in some species of Enterobacteriaceae. This review will focus on the evolution of key antimicrobial resistances, some epidemiologic issues, and the possible therapeutic modalities leading to the discussion of the potential utility of the carbapenems (imipenem, meropenem).

0732-8893/98/$19.00 PII S0732-8893(98)00037-6

R.N. Jones and M.A. Pfaller

380 TABLE 1 Major Emerging Threats to the LongTerm Efficacy of Antimicrobial Agents Organisms

Resistances

Gram-positive species Staphylococci Enterococci Streptococci Corynebacterium spp. Bacillus spp. Gram-negative species Haemophilus spp. M. catarrhalis Klebsiella spp.

Enterobacter spp.a

S. maltophilia Neisseria spp. Acinetobacter spp. Pseudomonas spp. Bacteroides fragilis group

Penicillin, oxacillin, macrolides Glycopeptides, penicillins, aminoglycosides Penicillin, macrolides, some cephalosporins Multiple drugs b-Lactams Penicillins (b-lactamases) b-Lactams (b-lactamases) Newer cephalosporins (extended-spectrum blactamases) Newer cephalosporins (inducible/derepressed b-lactamases) Multiple drugs b-Lactams, fluoroquinolones Multiple drugs Multiple drugs Clindamycin, cephamycins

a

Also Bush-Jacoby-Medeiros group 1 enzyme-producing species such as C. freundii, S. marcescens, and indole-positive proteae.

penicillin by virtue of b-lactamases (.90% in S. aureus), to macrolides-lincosamides, to tetracyclines, to trimethoprim/sulfamethoxazole, and to penicillinase-resistant penicillins such as methicillin or oxacillin (Table 1). The latter resistance has progressively increased, encoded genetically by mec A that produces an altered penicillin-binding protein (PBP 2A) target (Cormican and Jones 1996). The rate of oxacillin resistance in S. aureus appears to have doubled to nearly 35% over the last decade (Cormican and Jones 1996; Jones et al. 1989b, 1994; Panlilio et al. 1992; Schaberg et al. 1991). This has led to the expanded use of vancomycin and ultimately the recent emergence of vancomycin-resistant strains of staphylococci (Hiramatsu et al. 1997) and enterococci (see next section). As resistant strains of staphylococci continue to be reported, we urgently need alternative therapeutic modalities. Some promising agents include streptogramin combinations such as quinupristin/dalfopristin (Cormican and Jones 1996), everninomycin derivatives (SCH 27899), glycylcyclines, newer fluoroquinolones (clinafloxacin, DU-6859, sparfloxacin, trovafloxacin), oxazolidinones (linezolid), and modified glycopeptides (LY 333328). The role of these molecular entities awaits greater definition. The use of fluoroquinolones may be seriously limited by the close relationship (38 – 42 kb) of mec A and altered gyr A loci (Fey et al. 1998).

Oxacillin- and Multiresistant Staphylococci

Glycopeptide Resistance in Enterococci

The importance of staphylococci as causes of community-acquired and nosocomial infections remains high (Cormican and Jones 1996; Schaberg et al. 1991). In fact, S. aureus continues to be a leading pathogen in nosocomial pneumonia, wound infections, and bacteremia (Jones et al. 1997b and c; Schaberg et al. 1991) whereas coagulase-negative species have rapidly emerged as possible causes of blood stream infections (BSI) (Jones et al. 1997b). These Gram-positive species may be refractory to

Table 2 lists the progression of vancomycin resistance among enterococci since 1989. The rapid increase (0.3 to 16.5%) is alarming and significantly compromises the therapeutic role of vancomycin (Cormican and Jones 1996; Leclercq 1997; Murray 1998). Vancomycin and other acquired or intrinsic resistances limit treatment choices, and the species most often associated with glycopeptide (vancomycin, teicoplanin) resistance, Enterococcus faecium, usually harbors high resistance rates to penicillins,

TABLE 2 Evolution of Resistance among Enterococcus spp., Pneumococci, and H. influenzae (b-Lactamase Production) in Clinical Isolates in the United States % Resistance by Year (United States) Organism a

Enterococcus S. pneumoniaeb H. influenzaec a

1989 0.3 4.0 16.5

1990

1991

1992

1993

1994

1995

1996

1997

30.0

7.9 17.8 33.5

23.6 36.0

15.0 35.0 33.4

16.5 45.8 33.3

5.6 6.6

Vancomycin resistance rates. Modified from Gordon et al. (1992), Jones et al. (1994), Jones et al. (1995), and Jones et al. (1997a, b). Penicillin MIC results of $0.12 mg/mL. Modified from Jorgensen et al. (1989), Breiman et al. (1994), Jones et al. (1994), Doern et al. (1996), Ballow et al. (1997), and Jones et al. (1997b). c b-Lactamase production as reported by Jorgensen et al. (1990), Barry et al. (1994), Rittenhouse et al. (1995), Jones et al. (1996), Thornsberry et al. (1997), and Jones et al. (1997b). b

Bacterial Resistance: A Worldwide Problem aminoglycosides (high level), macrolides, newer fluoroquinolones, tetracyclines, and carbapenems (Cormican and Jones, 1996). The mechanism of glycopeptide resistance has been identified as a modified d-alanyl-d-alanine terminus of the peptidoglycan cell-wall precursor (Leclercq 1997; Murray 1998). This resistance seems to be disseminated by the transposon Tn 1546 or similar genetic elements via self-transferable plasmids, but the spread of this resistance beyond the enterococci remains very rare (Leclerq 1997). However, the ability to be transmitted to other genera has been demonstrated by Noble et al. (1992). The recently reported “vancomycin-resistant” S. aureus (oxacillin-resistant) strains do not possess the mechanism of glycopeptide resistance that has been defined among the enterococci (Hiramatsu et al. 1997). The spread of vancomycin-resistant enterococci have been traced to patient-to-patient transmission via health care workers (Sader et al. 1994), but most strains resistant to glycopeptides appear to be the result of independent genetic events. Newer therapeutic agents that show greatest promise are quinupristin/dalfopristin (Enterococcus faecium only), SCH 27899, linezolid, and LY 333328 (Cormican and Jones 1996).

Penicillin-Resistant Streptococcus pneumoniae Again Table 2 demonstrates the rapid increase of a resistance, penicillin-resistant (MIC $0.12 mg/mL) pneumococci. Since 1992, the rate of resistance to penicillins caused by altered penicillin-binding proteins (PBPs) has increased threefold every 3 years in the United States (Breiman et al. 1994; Jones et al. 1995 and 1997c). Alterations in the PBP targets of b-lactams in S. pneumoniae usually affect all b-lactam agents, but to varying extents depending on which targets are modified (1a, 2b, 2x) (Klugman et al. 1997). Generally, aminopenicillins (amoxicillin), cefotaxime, ceftriaxone, cefpirome, cefepime, and carbapenems maintain some activity against these penicillin-resistant streptococci, although the proven rates of clinical success are limited. Klugman et al. (1997) reported imipenem MICs between 0.06 and 1 mg/mL for penicillin-resistant S. pneumoniae and between 1 and 4 mg/mL for viridans group streptococci that had markedly elevated penicillin MIC results. These were the lowest MICs for the b-lactams tested. Our review of the meropenem results in Europe and North America confirms these results (MIC50, 0.016 mg/mL, and MIC90, 0.25 mg/ mL) for the more recently studied carbapenem (Pfaller and Jones, 1997). These b-lactam resistances and coresistances with macrolides, tetracyclines, and sulfonamides require a search for alternative regimens. Glycopeptides and

381 “third-generation” cephems are often used for serious invasive streptococcal disease pending laboratory susceptibility testing results. This practice increases glycopeptide use and potential escalation of resistance to that antimicrobial class. Candidate agents based on available in vitro and some in vivo clinical data include “fourth-generation” cephalosporins and carbapenems.

b-Lactamase Production in Haemophilus influenzae The frequency of occurrence of H. influenzae strains producing a TEM-1 b-lactamase has increased steadily since their discovery in the mid-1970s (Table 2). However, recent nationwide surveillance studies (Ballow et al. 1997; Jones et al. 1996 and 1997c) indicate a stable rate since 1994 (Rittenhouse et al. 1995). This resistance enzyme has compromised the economic use of amoxicillin for many communityacquired respiratory tract infections, and some orally administered cephalosporins (cefaclor, cefprozil, loracarbef) can also be hydrolyzed (Jones et al. 1997c). However, other oral and parenteral cephems, monobactams, and carbapenems are stable to this b-lactamase. Another commonly isolated Gram-negative respiratory tract pathogen, Moraxella catarrhalis, routinely (.90%) produces a b-lactamase (BRO-1 or -2) that provides a resistance to penicillins (Ballow et al. 1997).

ESBLs in Enterobacteriaceae b-Lactamases capable of producing resistance to oxyiminocephalosporins (third-generation) were initially reported in Germany in 1983 (Knothe et al. 1983; Medeiros 1997), derived from minor modification of the SHV-1 enzyme. This occurrence of a novel b-lactamase and the many that followed (Bush et al. 1995; Medeiros 1997) resulted from simple single- or double-amino acid (usually a serine or lysine) mutations. ESBLs of the TEM type emerged just 3 years later in France, and recent epidemiologic reports by Chanal et al. (1996) and others indicate changing frequencies of type and an increasing occurrence. In 1995, The Centers for Disease Control and Prevention reported a ceftazidime resistance rate of 3.6% among Klebsiella spp. isolated in Centers for Disease Control and Prevention-National Nosocomial Infection Surveillance hospitals for the year 1991. This represented over a twofold increase in 1 year, and this rate continues to evolve (Jones et al. 1994 and 1997c). Higher endemic rates of ESBL strains have been observed in other nations and individual hospitals (1–58%) in the United States (Jones et al. 1994 and 1997c).

382 These ESBL strains may not be easily recognized, and screening methods such as the double-disk, three-dimensional disk and a commercial Etest (AB Biodisk, Solna, Sweden) have facilitated recognition (Coudron et al. 1997; Vercauteren et al. 1997). In one recent ESBL frequency evaluation, 84 strains among 956 (9.2%) Enterobacteriaceae were detected in one Veterans Administration Medical Center in Virginia (Coudron et al. 1997). Because of diverse enzyme substrate affinity, laboratories should utilize several drugs (aztreonam, cefotaxime and ceftriaxone, ceftazidime) by dilution tests (MICs $2 mg/mL) to guide additional, confirming tests (National Committee for Clinical Laboratory Standards (NCCLS) 1998). Debate continues on the topic of the clinical use of b-lactamase inhibitor combinations or cephamycins or “fourth-generation” cephalosporins for infections caused by ESBL strains. However, carbapenem activity against these Bush-Jacoby-Medeiros [1995] group 2be strains remains near complete, with meropenem enjoying the greatest potency (Bauernfeind et al. 1989; Edwards 1995; Labia et al. 1989; Sanders et al. 1989; Wiedemann and Zuhlsdorf 1989). Alternative drug class could also be used, but cross-resistances have been observed for aminoglycosides, tetracyclines, fluoroquinolones, and trimethoprim/sulfamethoxazole.

Stably Derepressed Bush-Jacoby-Medeiros Group 1 Enzyme-Mediated Resistance Several excellent review articles have summarized the understanding of this resistance mechanism and established the high endemic rate of occurrence, especially among Enterobacter spp. and Citrobacter freundii (Bush et al. 1995; Jones et al. 1997a; Medeiros 1997). High levels of amp C b-lactamase confer resistance by a hydrolysis mechanism to cephamycins, oxyiminocephalosporins, and monobactams, plus the enzyme is not inhibited by available b-lactamase inhibitors (Medeiros 1997). This enzyme appears regulated by amp R in response to recycle cell wall fragments under the control of a membrane permease (amp G). In addition, an amidase, an amp D product, cleaves the cell wall fragment of its stem peptides and allows new formation of murein (complete recycling). Only excess free cell wall fragments “induce” via activation of amp R (Jones et al. 1997a; Medeiros 1997). In stably derepressed strains the amp D product is modified or absent, therefore producing high enzyme levels. This mutational event occurs at a rate of 1024 to 1026 cells. Under the pressure of various extended spectrum cephalosporin use (ceftazidime, ceftriaxone), the overall rate of stably derepressed mutant isolates among Enterobacter cloacae, Enterobacter aerogenes, and C. freundii have markedly increased (Jones 1996a).

R.N. Jones and M.A. Pfaller Therapeutic options for infections caused by stably derepressed amp C enzyme-producing strains include “fourth-generation” cephalosporins and carbapenems among the b-lactams and the use of other potent drug classes (aminoglycosides, fluoroquinolones) (Jones et al. 1997a; Pfaller and Jones 1997).

ROLE OF MEROPENEM AGAINST RESISTANT PATHOGENS The carbapenems, meropenem and imipenem, are well known for their potent activity against virtually all Gram-negative bacilli, with the exception of Stenotrophomonas maltophilia and some strains of Burkholderia spp. (Chanal et al. 1989; Edwards, 1995; Hoban et al. 1993; Kitzis et al. 1989; Labia et al. 1989; Pfaller and Jones 1997; Sanders et al. 1989; Wiseman et al. 1995). In many medical centers, these agents may be reserved for use against only the most resistant bacterial strains; the stably derepressed amp Cand ESBL-producing enterics and multiply resistant strains of Pseudomonas aeruginosa or Acinetobacter spp. Unfortunately, in an increasing number of hospital settings, these resistant microbes predominate (Jones 1996a and b; Swartz 1994) and result in the escalating use of antimicrobial combinations or monotherapies, such as the carbapenems and fluoroquinolones. Because increased utilization of any antimicrobial agent may encourage the development of resistance (Jones 1996a; Swartz 1994) one must remain concerned about this potential abuse. Although resistance was very rarely observed in a survey of over 30,000 clinical isolates tested against meropenem and imipenem (Pfaller and Jones 1997), many of the isolates in that study were obtained in the latter portion of the 1980s and early 1990s and may not accurately represent contemporary clinical isolates. In this review, we further examine the comparative activity of meropenem, imipenem, and selected other antimicrobial agents against clinically significant Gram-negative BSI isolates obtained from North American and South American hospitals during the first 6 months (January to June) of 1997 (SENTRY Antimicrobial Surveillance Program). The comprehensive analysis of many Gram-positive species (Pfaller and Jones 1997) will also be discussed. These results should define the role of carbapenems in the therapy of resistant pathogens that are increasing in the late 1990s.

Carbapenem Activity versus Blood Stream Infections During the 6-month period (January 1997 through June 1997), a total of 2359 BSI isolates of Enterobacteriaceae, Acinetobacter spp., and P. aeruginosa recovered

Bacterial Resistance: A Worldwide Problem

383

TABLE 3 Summary of Susceptibility of 2359 Clinical Isolates of Gram-Negative Bacilli to Meropenem, Imipenem, and Four Comparative Antimicrobial Agents Meropenem

Imipenem

Pip/Tazoa

Species (no. tested)

MIC90

%S

MIC90

%S

MIC90

%S

E. coli (1057) K. pneumoniae (367) Klebsiella oxytoca (61) E. cloacae (165) E. aerogenes (53) C. freundii (31) Citrobacter koseri (11) Morganella morganii (15) P. agglomerans (33) Proteus mirabilis (84) Salmonella spp. (28) S. marcescens (74) Acinetobacter spp. (102) P. aeruginosa (278)

#0.06 #0.06 #0.06 0.25 0.25 #0.06 #0.06 0.5 0.12 0.25 0.12 0.25 2.0 4.0

99.5 99.7 100 100 100 100 100 100 100 100 96.4 100 93.7 93.4

0.5 0.5 0.5 1.0 2.0 2.0 1.0 4.0 1.0 4.0 1.0 2.0 2.0 .8.0

99.3 100 100 100 97.9 96.7 100 100 100 97.5 100 97.2 91.7 84.1

8.0 64 16 .64 .64 64 4.0 2.0 16 2.0 8.0 64 .64 64

94.7 87.6 93.2 74.8 66.7 76.7 100 100 90.6 95.0 92.9 83.1 64.6 91.9

a

Ceftazidime

Ciprofloxacin

Gentamicin

MIC90

%S

MIC90

%S

MIC90

%S

0.5 97.8 4.0 90.8 1.0 91.7 .16 74.1 .16 70.8 .16 70.0 0.25 100 .16 66.7 .16 83.9 2.0 91.1 0.5 96.4 8.0 91.7 .16 61.1 16 84.3

0.06 0.25 0.25 0.5 0.5 0.5 0.12 0.03 0.25 1.0 .2.0 1.0 .2 .2

96.4 94.6 94.9 91.8 97.9 93.3 100 93.3 93.8 93.8 89.3 93.0 66.7 84.1

2.0 16 2.0 2.0 2.0 4.0 0.5 4.0 2.0 4.0 16 8.0 .16 8.0

95.2 88.4 94.9 93.1 93.8 90.0 100 93.3 93.8 90.0 89.3 87.3 69.8 85.6

Pip/Tazo 5 piperacillin/tazobactam using a fixed concentration of 4 mg/mL of tazobactam in MIC tests.

in the microbiology laboratories of 30 medical centers in the United States (1673 isolates), 8 Canadian hospital (355 isolates), and 10 South American hospitals (331 isolates) were sent to the University of Iowa College of Medicine (coordinating center), where the identifications were confirmed and stock cultures were prepared (frozen at 270°C). Antimicrobial susceptibility testing was performed at the coordinating center using reference broth microdilution methods as described by the NCCLS (1998). Antimicrobial agents were obtained from the respective manufacturers and included meropenem, imipenem, ceftazidime, piperacillin/tazobactam, gentamicin, and ciprofloxacin. Quality control was performed by testing E. coli ATCC 25922, S. aureus

ATCC 29213, P. aeruginosa ATCC 27853, and Enterococcus faecalis ATCC 29212. Interpretive criteria for each antimicrobial tested was that published by NCCLS [1998]. Table 3 lists the results for meropenem and 8 comparative antimicrobial agents tested against 2359 Gram-negative bacilli. Meropenem was active against the 1979 isolates of Enterobacteriaceae with MIC90s ranging from #0.06 mg/mL to 0.5 mg/mL; 96.4 to 100% of these isolates were susceptible at the NCCLS [1998] designated breakpoint concentration of #4 mg/mL. Similar results were obtained with imipenem. The rank order of activity based on the percent susceptible at the NCCLS breakpoint MIC values was meropenem (96.4 to 100%) 5 imipenem

TABLE 4 Meropenem, Imipenem, Ciprofloxacin, and Gentamicin Susceptibility of Ceftazidime-Resistant (MIC .16 mg/mL) Gram-Negative Bacilli % Susceptible to Organism

No. Tested

Meropenem (#4 mg/mL)a

Imipenem (#4 mg/mL)

Ciprofloxacin (#1 mg/mL)

Gentamicin (#4 mg/mL)

C. freundii E. aerogenes E. cloacae E. coli K. pneumoniae K. oxytoca P. agglomerans Proteus spp. S. marcescens Acinetobacter spp. P. aeruginosa

9 14 36 15 35 4 5 5 5 18 25

100 100 100 100 100 100 100 100 100 72.2 72.0

100 100 100 100 100 100 100 100 100 66.7 70.8

77.8 100 69.4 58.8 68.6 50.0 80.0 60.0 100 0 40.0

88.9 100 77.8 47.1 14.3 75.0 60.0 80.0 100 0 44.0

171

93.0

91.8

60.8

52.0

Total a

Concentration in parentheses indicates NCCLS (1998) breakpoint for susceptibility.

R.N. Jones and M.A. Pfaller

384 TABLE 5 Activity of Meropenem Tested against 6802 Gram-Positive Pathogens Isolated in Europe and North America (Pfaller and Jones 1997)

Organism E. faecalis E. faecium S. aureusa Staphylococcus epidermidisa Streptococcus pneumoniae

MIC (mg/mL) 50%

90%

% #4 mg/mL (#8 mg/mL)

1424 229 3169

4 16 0.12

8 128 0.25

73.7 (93.0) 25.3 (39.7) 99.0 (99.3)

1009

0.25

4

90.2 (95.6)

971

0.016

0.25

No. Tested

100.0 (100.0)b

a

Only oxacillin-susceptible strains were tabulated; oxacillinresistant strains were also resistant to carbapenems (NCCLS 1998). b The percentages of strains susceptible at #0.12, #0.25, and #0.5 mg/mL were 85.9, 90.4, and 95.8%, respectively. Isolates from Europe were routinely more susceptible to meropenem because of a lower rate of penicillin resistance.

(96.7 to 100%) . ciprofloxacin (89.3 to 100%) . gentamicin (87.3 to 100%) . ceftriaxone (73.0 to 100%; not shown) . ceftazidime (66.7 to 100%) 5 piperacillin/tazobactam 66.7 to 100%) . piperacillin (60.4 to 100%; not shown). Meropenem was also active against 380 nonenteric Gram-negative bacilli (Table 3). Meropenem was slightly more active than imipenem against Acinetobacter spp. (93.7% versus 91.7%, respectively) and was also more potent against P. aeruginosa (93.4% versus 84.1%). Because meropenem and imipenem are often reserved for treatment of infections due to resistant Gram-negative bacilli, a total of 171 ceftazidimeresistant Gram-negative BSI isolates from 43 geographically separate medical centers were further

evaluated. These isolates were also resistant to ceftriaxone, piperacillin, piperacillin/tazobactam, and aztreonam and likely represent stably derepressed amp C-producing strains of Enterobacter spp., C. freundii, Proteus spp., Serratia marcescens, and P. aeruginosa as well as ESBL-producing strains of E. coli and K. pneumoniae. The susceptibility of these isolates to meropenem, imipenem, ciprofloxacin, and gentamicin is listed in Table 4. Meropenem was the most active agent, inhibiting 93.0% of all ceftazidime-resistant isolates, followed by imipenem (91.8%), ciprofloxacin (60.8%), and gentamicin (52.0%). Both meropenem and imipenem inhibited all strains of ceftazidime-resistant Enterobacteriaceae. Meropenem was more active than imipenem against ceftazidime-resistant Acinetobacter spp., and P. aeruginosa. In contrast to our previous observations (Pfaller and Jones 1997), ciprofloxacin and gentamicin were substantially less active than meropenem or imipenem against ceftazidime-resistant Enterobacteriaceae as well as the Acinetobacter spp. and P. aeruginosa. Moreover, in our earlier report of 746 preclinical isolates of ceftazidime-resistant Enterobacteriaceae, meropenem inhibited 99.2% of strains at #4 mg/mL (Pfaller and Jones 1997). Thus meropenem appears highly effective in vitro against those resistances in Gram-negative bacilli that present treatment problems.

Carbapenem Activity against Gram-Positive Clinical Isolates Table 5, modified from Pfaller and Jones [1997], summarizes the meropenem spectrum and activity for 5 Gram-positive species (6802 isolates). Oxacillinsusceptible staphylococci were very susceptible (MIC50s, 0.12 to 0.25 mg/mL) to meropenem, and 90.2 to 99.0% of strains were inhibited by #4 mg/mL

TABLE 6 Molecular and Other Characteristics of Carbapenem-hydrolyzing Enzymes of the Bush-JacobyMedeiros Groups 2f, 3a, and 3b (Rasmussen and Bush 1997) Enzyme Group

Relative Hydrolysis Ratea Enzyme

Host Organism

Imipenem

Meropenem

2f

IMI-1 Sme-1

E. cloacae S. marcescens

100 100

5.9 8.4

3a

IMP-1 L1

S. marcescens S. maltophilia

100 100

14 44–60

3b

CphA AsbM1 ImiS PCM-I

Aeromonas hydrophila A. jandaei A. sobria Burkholderia cepacia

100 100 100 100

38 310 690 18

a b

Based on Vmax. CA 5 clavulanic acid 50% inhibitory dose of #14 mmol/liter; EDTA 5 metal ion chelator.

pI 7.1 9.7 .9.5 5.9, 6.9 8.0 9.1 9.3 8.5

Inhibition byb CA CA EDTA EDTA EDTA EDTA EDTA EDTA

Bacterial Resistance: A Worldwide Problem

385

TABLE 7 Meropenem Activity against Major Groups of Pathogens Categorized by Gram Stain and Growth in Anaerobic Environments (Pfaller and Jones 1997) Organism Group (no. tested) Gram-positive (6,802) Gram-negative (21,195) P. aeruginosa (4,054) H. influenzae (1,252) Anaerobes (2,257) All bacteria (30,254)

Cumulative % Inhibited at MIC (mg/mL)

% Susceptible

#0.06

0.12

0.25

0.5

1

2

4

8

39

59

65

69

73

81

90

96

90.0

66

76

83

89

93

96

98

99

97.8

6

15

35

56

73

83

91

96

91.0

79

94

98

99

.99

.99

.99

100

99.9

37

67

81

91

96

98

99

.99

99.1

58

71

79

84

89

93

96

98

96.2

(NCCLS 1998). In contrast, enterococci were generally less susceptible to meropenem with E. faecium isolates being frankly resistant (MIC90 128 mg/ml). These results indicate a very limited role for the carbapenem agents for oxacillin-resistant staphylococcal or vancomycin-resistant E. faecium infections. The 971 S. pneumoniae strains examined included organisms isolated in Europe and North America. Only 85.9% of these pneumococci were inhibited at #0.12 mg/mL (NCCLS 1998) of meropenem, but examination of the penicillin susceptibility rates revealed only 49.4 and 79.7% for the North American (22.2% high level resistance) and European isolates, respectively (Pfaller and Jones 1997). In fact, the susceptibility percentages for other b-lactams were: cefotaxime 5 91.7%; ceftriaxone 5 89.2%; and ceftazidime 5 64.9% (#0.5 mg/mL). Thus, meropenem could possess a significant therapeutic role in serious invasive S. pneumoniae disease (meningitis) caused by penicillin-resistant strains.

Resistance Mechanisms Compromising Carbapenem Activity The primary mechanism of contemporary resistance to carbapenems has been secondary to membrane permeability mutations such as the modification (decrease or deletion) of porin proteins (Edwards 1995; Kitzis et al. 1989). This mechanism and/or overproduction of b-lactamase can reduce the carbapenem spectrum of activity of P. aeruginosa (Livermore and Yuan 1996; Pfaller and Jones 1997). Some b-lactamases of the Bush-Jacoby-Medeiros groups 2f, 3a, and 3b (Table 6) are capable of producing resistance to carbapenem action. These enzymes can be divided into two major groups, metallo-b-lactamases (group

3a and 3b) and serine active site, clavulanic acidinhibited enzymes (2f). With the exception of 3b enzymes from Aeromonas jandaei and Aeromonas sobria, meropenem was routinely hydrolyzed at a lower rate (5.9 to 60%) than imipenem (Rasmussen and Bush 1997). These enzyme-mediated resistances remain quite rare in the United States and Europe; however, they may be problematic in Japan as reported by Senda et al. [1996] for P. aeruginosa that also exhibit high resistance rates to ceftazidime.

Comprehensive Overview of Meropenem Spectrum Table 7 describes the cumulative activity of meropenem by MIC versus over 30,000 clinical strains (Pfaller and Jones 1997). The anti-anaerobic activity of meropenem confirms the earlier reports by Nord et al. [1989] and others. The cited spectrum for meropenem (91.0%) against P. aeruginosa was ;5% greater than that of imipenem. Against all strains, meropenem was considered a potential treatment agent for 96.2% of isolates based on reference in vitro testing. This rate was most compromised by the vancomycin-resistant E. faecium, penicillin highly resistant pneumococcal strains and P. aeruginosa isolates probably having membrane protein alterations. Additional reviews of meropenem activity have been consistent with these results, as well as multicenter national studies, and those presented here from recent bacteremias from the comprehensive SENTRY Antimicrobial Surveillance Program in 1997 (Bauernfeind et al. 1989; Edwards 1995; Hoban et al. 1993; Jones et al. 1989a; Schito et al. 1989; Pitkin et al. 1997; Wiseman et al., 1995).

386 Meropenem has demonstrated an activity against the vast majority of clinically relevant bacterial species, sustained since the initial reports for this carbapenem nearly 10 years ago. This meropenem activity suggests a role in the therapy of serious nosocomial infections caused by pathogens that have recently become more refractory to contemporary monotherapies or combination regimens. As we utilize the carbapenems to a greater extent, we must closely monitor organisms for emerging resistances

R.N. Jones and M.A. Pfaller (permeability, b-lactamases, or novel types) via surveillance networks (Jones 1996b; Jones et al. 1997c).

The authors thank K. Meyer for assistance in preparing the manuscript and the participating laboratories within the SENTRY Antimicrobial Surveillance Program (research grant from Bristol-Myers Squibb) for providing the cited results from 1997 bacteremia cases.

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