1 The JONES Group/JMI Laboratories, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317; 2 Tufts University School of Medicine, Boston, MA, USA
Received 10 May 2002; returned 29 July 2002; revised 28 August 2002; accepted 15 September 2002
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Abstract |
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Keywords: BAL9141, parenteral cephalosporin, MRSA, antimicrobial activity, resistance
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Introduction |
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Recently marketed fluoroquinolones (gatifloxacin, moxifloxacin, trovafloxacin) have possessed enhanced activity and spectra against MR staphylococci, although the proportion of these isolates inhibited still falls below 90%.13 In contrast, novel parenteral cephalosporins have not been widely studied or developed in recent years.14,15 Among the recently described cephalosporins, the most studied has been RWJ-54428 (formerly MC-02,479).16,17 This parenteral agent reportedly has MIC50 and MIC90 values for MRSA of 1 and 2 mg/L, respectively, with the highest observed MIC being only 4 mg/L.10 Similar MIC results for MRSA have been reported for BMS-247243 (MIC90 4 mg/L), S-3578 (MIC90 4 mg/L) and SM-197436 (MIC90 2 mg/L), all parenteral cephalosporin derivatives.1820 BAL9141 (formerly Ro63-9141) is a new member of the pyrrolidinone-3-ylidenemethyl cephems that has documented activity against MR staphylococci (MIC90 24 mg/L), Enterococcus faecalis (MIC90 4 mg/L) and penicillin-resistant pneumococci (MIC90 2 mg/L), while preserving the anti-Gram-negative activity of third- or fourth-generation cephalosporins.21,22 The mode of action of BAL9141 against staphylococci with altered PBP2a is a very high PBP enzyme affinity coupled with resistance to ß-lactamases and a more stable acylenzyme complex.21 Reports by the manufacturer of animal models of septicaemia, subcutaneous abscess and endocarditis showed that modest doses (10 mg/kg intraperitoneally) of BAL9141 effectively treated MR and vancomycin-intermediate S. aureus (VISA).23 Andes & Craig24 reported that BAL9141 exhibited in vivo cidal activity, with a moderate post-antibiotic effect (PAE; 3.84.8 h) against MRSA, and that T > MIC was the pharmacokinetic/pharmacodynamic (PK/PD) parameter best predicting in vitro efficacy.
This investigation was designed to confirm and extend the earlier presentations by the manufacturer about the potency and spectrum of BAL9141. A worldwide sample of organisms was selected from recent resistance surveillance trials, and tests were of reference quality2527 against over 2200 isolates. Organism subsets were chosen to include major Gram-positive and -negative species, community-acquired respiratory pathogens, problematic endemic species causing meningitis or sexually transmitted disease, and difficult-to-treat anaerobic pathogens. Each category included isolates with resistance to different classes of drugs to challenge the spectrum of BAL9141 compared with numerous other antimicrobials.28
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Materials and methods |
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The BAL9141 reagent grade compound was provided by Hoffmann-LaRoche AG and Basilea Pharmaceutica AG (Basle, Switzerland). Comparator agents were purchased from Sigma Chemical Co. (St Louis, MO, USA) or obtained from their respective manufacturers in the USA. A total of up to 13 comparators were evaluated depending upon the species tested. These compounds included ß-lactams [penicillins, cephalosporins, penicillin/ß-lactamase inhibitor combinations, a monobactam (aztreonam) and carbapenems], fluoroquinolones, aminoglycosides, trimethoprim/sulfamethoxazole and Gram-positive focused agents (macrolide-lincosamide-streptogramins, glycopeptides, oxazolidinones).
Organisms tested
The test strains (more than 2200) used in this study were derived from worldwide surveillance trials between 1997 and 2000. Larger numbers of resistant phenotypes were selected among the Gram-positive cocci to challenge the BAL9141 spectrum. The following organisms comprised the Gram-positive organism collection: 146 S. aureus (96 MRSA), 116 CoNS (90 MR-CoNS), 132 Enterococcus spp. (50 vancomycin resistant; vanA, vanB, vanC phenotypes), 520 S. pneumoniae (259 penicillin non-susceptible), 85 viridans group streptococci (31 penicillin non-susceptible) and 103 ß-haemolytic streptococci (12 macrolide resistant). A subset of common Gram-negative respiratory tract pathogens included 415 strains of Haemophilus influenzae (155 ampicillin resistant, including 10 that were ß-lactamase negative) and 188 isolates of Moraxella catarrhalis (167 penicillin resistant). Members of the Enterobacteriaceae included Escherichia coli [43 wild-type, 23 having an extended-spectrum ß-lactamase (ESBL) phenotype], Klebsiella pneumoniae (30 wild-type, 25 ESBL phenotypes), Klebsiella oxytoca (12), Enterobacter spp. (95), Citrobacter spp. (52), Salmonella spp. (12), Shigella spp. (12), Serratia spp. (25), indole-positive Proteae (34) and Proteus mirabilis (nine). Non-fermentative species tested include Pseudomonas aeruginosa (23), Acinetobacter spp. (22), Stenotrophomonas maltophilia (17) and Burkholderia cepacia (eight). Neisseria meningitidis (24), Neisseria gonorrhoeae (32), Bacteroides fragilis group (44) and Clostridium spp. (10) were also sampled. All strains were identified by at least two laboratories to species level. Strains were stored at 70°C or below until processed.
Susceptibility testing methods
All tests were carried out using the reference broth microdilution or agar dilution (Neisseria spp. and anaerobes) methods described by the NCCLS.25,26 Cation-adjusted MuellerHinton broth was modified for streptococci by supplementation with 5% lysed horse blood, whereas for H. influenzae the Haemophilus Test Medium (HTM) formulation was used. Brucella blood agar and supplemented GC agar (IsoVitaleX) were used for anaerobes and pathogenic Neisseria spp., respectively. Isolates with ESBL phenotypes for E. coli and K. pneumoniae were selected using the NCCLS criteria26 and all enzymes were shown to be inhibited by clavulanic acid (8-fold reduction in the MIC). All tests followed NCCLS technical details25,27 for incubation temperature and environment, and incubation times before determining MIC endpoints. The quality control organisms used were: E. coli American Type Culture Collection (ATCC) 25922 and 35218, S. aureus ATCC 29213, E. faecalis ATCC 29212, H. influenzae ATCC 49247, S. pneumoniae ATCC 49619, N. gonorrhoeae ATCC 49226, B. fragilis ATCC 25285 and Bacteroides thetaiotaomicron ATCC 29741.
Interpretative criteria were those published in NCCLS M100-S1227 and a conservative 4 mg/L was used for BAL9141 (comparisons only) when testing enterococci, Enterobacteriaceae, non-enteric Gram-negative bacilli and staphylococci, whereas BAL9141 breakpoints for Haemophilus spp. and streptococci were set at
2 and
1 mg/L, respectively (those levels currently utilized for cefepime, cefotaxime and ceftriaxone).27 Particular attention was made to accurately characterize staphylococci for oxacillin (methicillin) resistance29,30 and to detect strains having reduced susceptibilities to glycopeptides.3,4
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Results |
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Table 1 presents the results of testing BAL9141 and 13 other agents against S. aureus and CoNS isolates (262 strains). All BAL9141 MIC values were 2 mg/L for S. aureus, with MIC50 and MIC90 values of 0.5 and 0.5 mg/L and 1 and 2 mg/L for oxacillin-susceptible (OS) and MR (also oxacillin-resistant) strains, respectively. All antimicrobials except penicillin were effective in vitro against OS S. aureus, with susceptibility ranging from 78.0% (erythromycin) to 100.0% (eight agents). However, for the 96 strains of MRSA, only BAL9141, vancomycin (MIC90 2 mg/L; 100.0% susceptible) and linezolid (MIC90 2 mg/L; 100.0% susceptible) remained highly effective. Methicillin-sensitive strains were slightly more susceptible (two- to four-fold) to BAL9141 than MRSA strains.
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BAL9141 activity against enterococci
Table 1 also lists BAL9141 activity tested against 132 strains of enterococci. The BAL9141 activity versus E. faecalis paralleled that of ampicillin (93.5% susceptible), penicillin (90.3%) and co-amoxiclav (93.5%). The BAL9141 MIC90 (4 mg/L) was identical to that of ampicillin and co-amoxiclav. Ciprofloxacin and levofloxacin were active against 40.352.8% of strains at MICs at or below their NCCLS breakpoints.
E. faecium (n = 51) strains, nearly one-half with the vanA resistance pattern, ranged from 19.6% to 25.5% susceptible to tested penicillin derivatives. BAL9141 inhibited 21.6% of E. faecium strains at 4 mg/L. All strains were linezolid susceptible. Quinupristin/dalfopristin inhibited 66.7% of E. faecium at
1 mg/L, with many isolates possessing an MIC of 2 mg/L (intermediate). The remaining Enterococcus spp. tested from five species (six vanC) demonstrated that BAL9141 activity was most like that of the tested penicillins (MIC50 range 0.52 mg/L). Overall, linezolid had the greatest potency against all enterococci tested, a collection enhanced by large numbers of strains with defined resistance mechanisms.
BAL9141 activity against streptococci
Table 2 shows the potency of BAL9141 and 12 comparison agents tested against various streptococcal species groups listed according to their susceptibilities to penicillin. BAL9141 activity was at least four-fold greater than that of ceftriaxone towards strains with reduced susceptibilities to penicillin (MIC 0.12 mg/L). Among the four clinically available ß-lactams tested, ceftriaxone and amoxicillin ± clavulanate demonstrated nearly complete coverage of pneumococci with penicillin MICs of
1 mg/L. However, only 52.658.8% of penicillin-resistant strains were inhibited by these agents. Generally, the fluoroquinolones tended to be more active than the ß-lactams.
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Viridans group streptococci were generally more resistant to the ß-lactams, macrolides, clindamycin, fluoroquinolones and trimethoprim/sulfamethoxazole than the S. pneumoniae isolates. BAL9141 MIC90 results varied from 0.06 mg/L for penicillin-susceptible strains to 0.25 and 1 mg/L for penicillin-intermediate and -resistant strains, respectively. At current NCCLS breakpoints for susceptibility, ceftriaxone and co-amoxiclav were most potent among the ß-lactams, but the glycopeptides (vancomycin, teicoplanin) and quinupristin/dalfopristin had the highest level of susceptibility (90.0%). If the current breakpoint for ceftriaxone (susceptible at
1 mg/L) was applied to BAL9141, only one viridans group streptococcus strain would not have been judged BAL9141 susceptible (1.2%). ß-Haemolytic streptococci were very susceptible to BAL9141 (MIC90
0.015 mg/L) and most other drugs tested. Only erythromycin had a susceptibility rate <98.0% (88.3%).
BAL9141 activity against H. influenzae and M. catarrhalis
H. influenzae strains were uniformly susceptible to BAL9141 (MIC90 0.06 mg/L), as well as to ceftriaxone and cefepime (Table 3). No changes in the MIC50 and MIC90 (0.06 mg/L) values of BAL9141 were observed for strains with a ß-lactamase-positive phenotype (data not shown). ß-Lactamase-negative ampicillin-resistant (BLNAR) H. influenzae isolates (n = 10) showed four- to eight-fold elevated BAL9141 MIC values (MIC50 0.25 mg/L, MIC90 0.5 mg/L) compared with the remaining 405 strains tested. All fluoroquinolone non-susceptible strains tested were inhibited by 0.06 mg/L BAL9141. The least active antimicrobials tested were ampicillin (145 ß-lactamase-positive strains; 64.2% susceptible), clarithromycin (82.8% susceptible) and trimethoprim/sulfamethoxazole (77.8% susceptible).
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BAL9141 activity against Enterobacteriaceae
BAL9141 exhibited good activity against Gram-negative enteric bacilli with susceptibility rates that ranged between 79.4% and 100% using a proposed breakpoint of 4 mg/L (Table 4). Significant BAL9141 potency was most notable for Citrobacter spp., E. coli, Enterobacter cloacae, Klebsiella spp., P. mirabilis, Salmonella spp. and Shigella spp., which collectively had MIC90 values ranging from 0.03 to 0.5 mg/L. Against Citrobacter freundii the MIC90 of BAL9141 (0.5 mg/L) was the same as noted for cefepime and imipenem, with susceptibility rates also similar for these compounds and the two fluoroquinolones tested (>94%). The remaining effective compounds in vitro showed a rank order of: gentamicin (94.1%) > piperacillin/tazobactam, aztreonam (85.3%) > ceftazidime, ceftriaxone (82.4%). The E. coli isolates were all susceptible to BAL9141, cefepime, and the carbapenems with very similar potencies (MIC90
0.120.25 mg/L). The extended- and broad-spectrum cephalosporins piperacillin/tazobactam, gentamicin and aztreonam were slightly less active (95.397.7% susceptible). The two fluoroquinolones showed equivalent activities (86% susceptible), but a rate similar only to that of cefazolin. E. cloacae isolates were most susceptible to cefepime and the carbapenems (100%); however, the potency of BAL9141 (MIC90 0.12 mg/L) was equal to or greater than these compounds, and shared an activity most similar to gentamicin and the fluoroquinolones (98.3% susceptible). Against K. pneumoniae, all test agents showed excellent activity, with BAL9141 activity most similar to that of cefoxitin and ciprofloxacin (96% susceptible). All compounds were active against K. oxytoca (except cefazolin; only 75% susceptible), P. mirabilis, Salmonella spp. (except quinolones; only 90.9% susceptible) and Shigella spp. (except penicillin/ß-lactam inhibitor combinations; only 83.391.7% susceptible).
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Table 5 provides in vitro susceptibility data on E. coli and K. pneumoniae exhibiting confirmed ESBL phenotypes. With the exception of the carbapenems, the potency of all agents tested was diminished compared with wild-type ESBL-negative strains (Table 4). Indeed nearly all MIC90s exceeded the maximum test concentrations, except for the carbapenems, which retained complete activity against the ESBL-positive strains. Among the E. coli isolates, BAL9141 activity was most similar to that of ceftriaxone and aztreonam, which in turn were more active than tetracycline and trimethoprim/sulfamethoxazole.
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BAL9141 demonstrated widely variable activity against the tested non-fermentative Gram-negative bacilli, as shown by 45.5% susceptibility at 4 mg/L and MIC50 values of 32 mg/L for Acinetobacter and nil susceptibility for Burkholderia cepacia (MIC50 32 mg/L) and Stenotrophomonas maltophilia (MIC50 > 32 mg/L). In contrast, BAL9141 potency versus P. aeruginosa was equal (MIC90 8 mg/L) to that of cefepime and ceftazidime (Table 6). The lower utilized breakpoint MIC for BAL9141 (
4 mg/L) in these comparisons reduced its perceived anti-Pseudomonas spectrum. In contrast, the carbapenems demonstrated good activity against P. aeruginosa (90.5%), as did piperacillin/tazobactam (87%), amikacin, gentamicin and tobramycin (95.2100.0%).
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Activity of BAL9141 against Neisseria and anaerobes
Table 7 summarizes the BAL9141 activity compared with a limited number of antimicrobials tested by agar dilution methods against N. meningitidis, N. gonorrhoeae and 54 strains of anaerobic bacteria. BAL9141 proved to be two- to four-fold more active than cefotaxime against the pathogenic Neisseria. The highest MIC of BAL9141 was for the gonococcal strains at 0.06 mg/L (susceptible by criteria applied to either cefotaxime or ceftriaxone).
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Discussion |
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Although highly promising against MR staphylococci, the BAL9141 activity versus penicillin-resistant S. pneumoniae (MIC90 0.25 mg/L), vancomycin-susceptible and -resistant E. faecalis (MIC90 4 mg/L), penicillin-resistant viridans group streptococci (MIC90 1 mg/L), H. influenzae (MIC90 0.060.5 mg/L) and M. catarrhalis (MIC90 0.5 mg/L) was considered excellent. Against the Enterobacteriaceae, the anti-bacterial spectrum of BAL9141 most closely resembled that of cefepime, although some strains of Enterobacter spp., indole-positive Proteae (P. vulgaris) and Serratia appear to be more resistant towards BAL9141. ESBL-producing isolates of E. coli and K. pneumoniae were not inhibited by BAL9141 (MIC50 32 mg/L), suggesting rapid hydrolysis by these enzymes (Table 5). All tested non-fermentative Gram-negative bacilli (except P. aeruginosa) were highly resistant to BAL9141. Cefepime, ceftazidime and BAL9141 had essentially identical activities against P. aeruginosa isolates, and the breakpoint selected by pharmacokinetic/pharmacodyamic analyses (
4 or
8 mg/L) will have a great influence on the role of BAL9141 for therapy of infections caused by this species. At a susceptible breakpoint equal to that of other parenteral cephalosporins, >90% of P. aeruginosa would be judged as BAL9141 treatable, but only 69.6% of strains at
4 mg/L. Like many third- and fourth-generation cephalosporins, BAL9141 was very active against pathogenic Neisseria (MIC90 0.0040.06 mg/L) and Gram-positive anaerobic bacteria (MIC90
0.25 mg/L).
Since all currently marketed ß-lactams are considered clinically inactive against MR staphylococci,25,27 the probability of adverse selection of resistant strains in the hospital environment using cephalosporins remains high. The concurrent co-resistance of these MR staphylococci to the most popularly used parenteral fluoroquinolones (ciprofloxacin, levofloxacin) contributes to an even greater risk of escalating rates of MRSA isolation. The clinical availability of a cephalosporin candidate (BAL9141) with MRSA activity presents the option of a therapeutic broad-spectrum cephalosporin coupled with environmental (patient or hospital) suppression of MR staphylococci. Indeed, in vivo animal model results21 suggest that BAL9141 could be utilized as directed therapy of MRSA infections, including those possessing reduced susceptibility to vancomycin.
Results of initial clinical trials as well as human pharmacokinetic results leading to the establishment of a reliable breakpoint for BAL9141 susceptibility are eagerly awaited. Early trials appear warranted to follow the effects of therapy on patient colonization by resistant Gram-positive pathogens and changes in normal flora.
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Acknowledgements |
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Footnotes |
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References |
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