JAC Advance Access originally published online on November 18, 2002
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Journal of Antimicrobial Chemotherapy (2002) 50, 915-932
© 2002 The British Society for Antimicrobial Chemotherapy
In vitro evaluation of BAL9141, a novel parenteral cephalosporin active against oxacillin-resistant staphylococci
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
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Community-acquired and nosocomial infections caused by multidrug-resistant Gram-positive pathogens continue to increase in prevalence and have become a serious problem in many parts of the world. BAL9141 is a member of the class of parenteral pyrrolidinone-3-ylidenemethyl cephalosporins, and has a broad spectrum of activity. In the current study, BAL9141 was tested against a large number (n = 2263) of recent isolates from various international surveillance programmes including 1097 Gram-positive strains. Susceptibility to (S) and activity of (mg/L) to BAL9141, based on proposed breakpoints (MIC50/MIC90/% S) were as follows: methicillin-susceptible Staphylococcus aureus (0.5/0.5/100%), methicillin-resistant S. aureus (MRSA) (1/2/100%), methicillin-susceptible coagulase-negative staphylococci (CoNS) (0.12/0.25/100%), methicillin-resistant CoNS (MR-CoNS) (1/2/100%), Streptococcus pneumoniae (
0.015/0.25/100%), viridans group streptococci (0.03/0.5/99%), ß-haemolytic streptococci (0.015/0.015/100%), Enterococcus faecalis (0.5/16/90%), Enterococcus faecium (>32/>32/22%), Haemophilus influenzae (0.06/0.06/100%), Moraxella catarrhalis (0.06/0.5/100%), Neisseria gonorrhoeae (0.03/0.06/100%) and Neisseria meningitidis (0.002/0.004/100%). BAL9141 susceptibility at 4 mg/L (100% S) surpassed that of ceftriaxone (CRO; 1% S) and quinupristin/dalfopristin (Q-D; 92% S) against MRSA and MR-CoNS (CRO 0.9% S; Q-D 94% S). All S. pneumoniae were inhibited by BAL9141 at 1 mg/L compared with CRO (90% S) and levofloxacin (LVX; 98% S). Susceptibility rates for viridans group streptococci to BAL9141 (>98%) were also higher than to CRO (86%) and LVX (96%). BAL9141 demonstrated excellent activity against most species of wild-type enteric bacilli, with 
95% of isolates being susceptible; however, only modest activity was observed for BAL9141 against non-fermentative Gram-negative species and ESBL-producing Escherichia coli or Klebsiella pneumoniae. BAL9141 demonstrated excellent activity against many tested pathogens displaying various resistance phenotypes, and should be particularly valuable in the treatment of MRSA as well as for drug-resistant streptococci, while maintaining a spectrum resembling a ‘third-generation’ cephalosporin against other clinically important species. Keywords: BAL9141, parenteral cephalosporin, MRSA, antimicrobial activity, resistance
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
The problem of antimicrobial resistance among Gram-positive cocci has become critical to effective therapy of these organisms in many parts of the world.1–11 Various types of resistance continue to increase, whereas others, such as penicillin resistance in Streptococcus pneumoniae7,8 or glycopeptide resistance among enterococci,2,9,12 have stabilized at a worrisome elevated level. A number of factors have contributed to the emerging resistances, principally antimicrobial usage patterns (local, regional, national) and the quality of the infection control or public health infra-structures.6 Even under better controls of formulary practice and hospital hygiene, the incidence of methicillin-resistant (MR) staphylococci in North American and European medical centres appears to be on the rise, as documented by the SENTRY Antimicrobial Surveillance Program. In the SENTRY Program, the MR Staphylococcus aureus (MRSA) rates between 1997 and 2000 increased in Europe (23–34%), North America (26–36%) and in the Asia–Pacific region (49–54%). Methicillin resistance among S. aureus or coagulase-negative staphylococci (CoNS) has been associated with high rates of co-resistance to fluoroquinolones such as ciprofloxacin and levofloxacin.2,12 Therefore, continued use of broad-spectrum ß-lactams (third- or fourth-generation cephalosporins, some penicillin/ß-lactamase inhibitor combinations, carbapenems) and fluoroquinolones is likely to foster an environment conducive to increased occurrence of MR staphylococci as infecting pathogens or colonizing microflora. An attempt to develop drugs in both of these antimicrobial classes with significant activity versus MR staphylococci could facilitate a reduction in this clinical problem.
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.18–20 BAL9141 (formerly Ro63-9141) is a new member of the pyrrolidinone-3-ylidenemethyl cephems that has documented activity against MR staphylococci (MIC90 2–4 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 acyl–enzyme 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; 3.8–4.8 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 quality25–27 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
|
Materials and methods |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Antimicrobials tested
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 Mueller–Hinton 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
|
Results |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
BAL9141 activity against staphylococci
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.
|
CoNS strains were slightly more susceptible to BAL9141 than S. aureus isolates, although the highest BAL9141 MIC was identified for an MR-CoNS isolate. OS-CoNS strains were more susceptible to BAL9141 when compared with MR-CoNS isolates. All antimicrobials tested had a
92.3% susceptibility rate versus OS-CoNS, except penicillin (42.3% susceptible), erythromycin (73.1%) and trimethoprim/sulfamethoxazole (73.1%). Only four tested antimicrobials inhibited MR-CoNS strains at a rate >90%: BAL9141 (100.0% inhibited at 4 mg/L), linezolid (100.0% susceptible), vancomycin (98.9% susceptible) and quinupristin/dalfopristin (94.4% susceptible). All CoNS strains selected to challenge BAL9141 against defined glycopeptide-intermediate (one strain), macrolide and clindamycin-resistant (56 strains), streptogramin-resistant (five strains) and fluoroquinolone-resistant (59 strains) populations were inhibited by 4 mg/L BAL9141. 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 40.3–52.8% 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 0.5–2 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 52.6–58.8% of penicillin-resistant strains were inhibited by these agents. Generally, the fluoroquinolones tended to be more active than the ß-lactams.
|
Activity of the ß-lactams (including BAL9141), macrolides, clindamycin and trimethoprim/sulfamethoxazole decreased as the penicillin MIC increased. The potency of BAL9141 was equal to that of the fluoroquinolones against penicillin-resistant S. pneumoniae on a weight–weight basis (Table 2).
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).
|
M. catarrhalis isolates lacking ß-lactamase production (11.2%) were significantly more susceptible (MIC90 0.015 mg/L) to BAL9141 compared with their ß-lactamase-positive counterparts (MIC90 0.5 mg/L; data not shown). Only three isolates among 188 strains tested (1.6%) had a BAL9141 MIC of 1 mg/L (Table 3). Overall, M. catarrhalis isolates were very susceptible to all ß-lactams tested (
95.2% susceptible) with the exception of penicillin. 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 0.12–0.25 mg/L). The extended- and broad-spectrum cephalosporins piperacillin/tazobactam, gentamicin and aztreonam were slightly less active (95.3–97.7% 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 83.3–91.7% susceptible).
|
Some isolates of Enterobacter aerogenes, Serratia spp. and certain species of indole-positive Proteae showed more limited BAL9141 inhibition. Against E. aerogenes the rank order of activity was: carbapenems (100% susceptible) > cefepime > gentamicin > fluoroquinolones > BAL9141, ceftriaxone (83.8% and 81.1%), with the remaining compounds having marginal or no activity. Among the indole-positive Proteae, P. vulgaris (one-third of the isolates in this group) was refractory to BAL9141 (MIC50/MIC90, % susceptible were 32/>32 mg/L, 36.4%). Regardless, the activity of BAL9141 (79.4%) towards these cited species remained higher than that of the comparator fluoroquinolones (76.9% susceptible), but lower than that of other ‘broad-spectrum’ cephalosporins, piperacillin/tazobactam, gentamicin, aztreonam and the carbapenems (88.5–100% susceptible).
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.
|
BAL9141 activity against non-fermentative Gram-negative bacilli
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 (95.2–100.0%).
|
Most agents tested against Acinetobacter spp. demonstrated low susceptibility rates (Table 6), with the exception of tobramycin (78.9%) and the carbapenems (68.4%). B. cepacia demonstrated high rates of resistance to most agents tested, with the exception of the carbapenems (83.3–100.0%), levofloxacin (83.3%) and trimethoprim/sulfamethoxazole (100%). Of the agents tested against S. maltophilia, only piperacillin/tazobactam (82.4%), levofloxacin (82.4%) and trimethoprim/sulfamethoxazole (88.2%) showed an acceptable level of in vitro efficacy.
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).
|
The Clostridium spp. strains were generally BAL9141-susceptible with an MIC90 of
0.25 mg/L, rates comparable to cefotaxime, but inferior to the comparison carbapenem. In contrast, B. fragilis group anaerobes were less susceptible to inhibition by BAL9141 (MIC90 > 64 mg/L). However, BAL9141 seems to be slightly more active than cefotaxime versus these B. fragilis group isolates (Table 7). |
Discussion |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Since the first reports of methicillin resistance in S. aureus nearly four decades ago,31 pharmaceutical scientists have sought ß-lactam molecules active against these strains. Numerous candidate agents have been studied, many with high affinities for the mecA gene product (PBP2a) responsible for the resistance.32 Structurally diverse ß-lactams have been developed to address this need, including carbapenems14,15,32–34 and numerous cephalosporin derivat- ives,14–17,21,22 including BAL9141. In this report, we confirm the potency of BAL9141 against MR staphylococci, including multidrug-resistant strains and those organisms with elevated glycopeptide MICs.3,4 Specifically, BAL9141 was eight-fold more active than ceftriaxone against OS staphylococci and no MRSA had a BAL9141 MIC of >2 mg/L, validating the report by Hebeisen et al.21 and showing activity similar to that of RWJ-54428.16
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 0.06–0.5 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 0.004–0.06 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.
|
Acknowledgements |
|---|
We would like to express our appreciation to the following people for technical support and in the preparation of the manuscript: K. Meyer, M. Beach, S. Shapiro and P. Hohl. This study was sponsored by an educational/research grant from Basilea Pharmaceutica AG (Basle, Switzerland).
|
Footnotes |
|---|
* Corresponding author. Tel: +1-319-665-3370; Fax: +1-319-665-3371; E-mail: ronald-jones{at}jmilabs.com
|
References |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
1 . Chen, D. K., McGeer, A., de Azavedo, J. C. & Low, D. E. (1999). Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. New England Journal of Medicine 341, 233–9.
2 . Diekema, D. J., Pfaller, M. A., Jones, R. N., Doern, G. V., Kugler, K. C., Beach, M. L. et al. (2000). Trends in antimicrobial susceptibility of bacterial pathogens isolated from patients with blood stream infections in the USA, Canada and Latin America. International Journal of Antimicrobial Agents 13, 257–71.[Web of Science][Medline]
3 . Fridkin, S. K. (2001). Vancomycin-intermediate and -resistant Staphylococcus aureus: What the infectious disease specialist needs to know. Clinical Infectious Diseases 32, 108–15.[Web of Science][Medline]
4
.
Hiramatsu, K., Hanaki, H., Ino, T., Yabuta, K., Oguri, T. & Tenover, F. C. (1997). Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. Journal of Antimicrobial Chemotherapy 40, 135–6.
5 . Hoban, D. J., Doern, G. V., Fluit, A. C., Roussel-Delvallez, M. & Jones, R. N. (2001). World-wide prevalence of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the SENTRY Antimicrobial Surveillance Program, 1997–99. Clinical Infectious Diseases 32, Suppl. 2, S81–93.
6 . Jones, R. N. & Pfaller, M. A. (1998). Bacterial resistance: a worldwide problem. Diagnostic Microbiology and Infectious Disease 31, 379–88.[Web of Science][Medline]
7 . Jones, R. N. & Pfaller, M. A. (2000). In vitro activity of newer fluoroquinolones for respiratory tract infections and emerging patterns of antimicrobial resistance: data from the SENTRY Antimicrobial Surveillance Program. Clinical Infectious Diseases 31, Suppl. 2, S16–23.
8
.
Jones, R. N. & Pfaller, M. A. (2000). Macrolide and fluoroquinolone (levofloxacin) resistances among Streptococcus pneumoniae strains: significant trends from the SENTRY Antimicrobial Surveillance Program (North America, 1997–1999). Journal of Clinical Microbiology 38, 4298–9.
9 . Low, D. E., Keller, N., Barth, A. & Jones, R. N. (2001). Clinical prevalence, antimicrobial susceptibility, and geographic resistance patterns of enterococci: results from the SENTRY Antimicrobial Surveillance Program, 1997–1999. Clinical Infectious Diseases 32, Suppl. 2, S133–45.
10 . Schwalbe, R. S., Stapleton, J. T. & Gilligan, P. H. (1987). Emergence of vancomycin resistance in coagulase-negative staphylococci. New England Journal of Medicine 316, 927–31.[Web of Science][Medline]
11
.
Sieradzki, K., Villari, P. & Tomasz, A. (1998). Decreased susceptibilities to teicoplanin and vancomycin among coagulase-negative methicillin-resistant clinical isolates of staphylococci. Antimicrobial Agents and Chemotherapy 42, 100–7.
12 . Pfaller, M. A., Jones, R. N., Marshall, S. A., Edmond, M. B. & Wenzel, R. P. (1997). Nosocomial streptococcal blood stream infections in the SCOPE program: species occurrence and antimicrobial resistance. The SCOPE Hospital Study Group. Diagnostic Microbiology and Infectious Disease 29, 259–63.[Web of Science][Medline]
13 . Jones, R. N., Beach, M. L., Pfaller, M. A. & Doern G. V. (1998). Antimicrobial activity of gatifloxacin tested against 1676 strains of ciprofloxacin-resistant Gram-positive cocci isolated from patient infections in North and South America. Diagnostic Microbiology and Infectious Disease 32, 247–52.[Web of Science][Medline]
14 . Bryskier, A. (1999). Novelties in the field of anti-infectives in 1998. Clinical Infectious Diseases 29, 632–58.[Web of Science][Medline]
15 . Bryskier, A. (2000). Novelties in the field of anti-infective compounds in 1999. Clinical Infectious Diseases 31, 1423–66.[Web of Science][Medline]
16
.
Chamberland, S., Blais, J., Hoang, M., Dinh, C., Cotter, D., Bond, E. et al. (2001). In vitro activities of RWJ-54428 (MC-02,479) against multiresistant Gram-positive bacteria. Antimicrobial Agents and Chemotherapy 45, 1422–30.
17 . Hecker, S. J., Glinka, T. W., Cho, A., Zhang, Z. J., Price, M. E., Chamberland, S. et al. (2000). Discovery of RWJ-54428 (MC-02,479), a new cephalosporin active against resistant Gram-positive bacteria. Journal of Antibiotics 53, 1272–81.[Medline]
18 . Fung-Tomc, J., Minassian, B., Pucci, M., Cradelski, E., Huczko, E., Washo, T. et al. (2000). Antistaphylococcal activity of a novel MRSA (methicillin-resistant Staphylococcus aureus) cephem BMS-247243. In Program and Abstracts of the Fortieth Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, 2000. Abstract F-1063, p. 193. American Society for Microbiology, Washington, DC, USA.
19 . Yamano, Y., Miwa, H., Motokawa, K., Yoshida, T., Shimada, J. & Kuwahara, S. (2001). S-3578, a new broad-spectrum cephalosporin: II. In vitro activity against Gram-positive and -negative clinical isolates including methicillin-resistant Staphylococcus aureus (MRSA). In Program and Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, USA, 2001. Abstract F-371, p. 210. American Society for Microbiology, Washington, DC, USA.
20 . Ueda, Y. & Sunagawa, M. (2001). New parenteral 2-(thiazol- 2-ylthio)-1ß-methylcarbapenems; antimicrobial spectrum including drug-resistant Gram-positive bacteria. In Program and Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, USA, 2001. Abstract F-364, p. 208. American Society for Microbiology, Washington, DC, USA.
21
.
Hebeisen, P., Heinze-Krauss, I., Angehrn, P., Hohl, P., Page, M. G. P. & Then, R. L. (2001). In vitro and in vivo properties of Ro63-9141, a novel broad-spectrum cephalosporin with activity against methicillin-resistant staphylococci. Antimicrobial Agents and Chemotherapy 45, 825–36.
22 . Heinze-Krauss, L., Angehru, P., Guerry, P., Hebeisen, P., Hubschwerlen, C., Kompis, I. et al. (1996). Synthesis and structure–activity relationship of (lactamylvinyl)cephalosporins exhibiting activity against staphylococci, pneumococci, and enterococci. Journal of Medicinal Chemistry 39, 1864–71.[Web of Science][Medline]
23 . Entenza, J. M., Hohl, P., Heinze-Krauss, I., Vouillamoz, J., Glauser, M. P. & Moreillon, P. (1998). Ro63-9141, a novel broad spectrum cephalosporin active against methicillin resistant S. aureus in the treatment of experimental endocarditis. In Program and Abstracts of the Thirty-eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, USA, 1998. Abstract F-14, p. 236. American Society for Microbiology, Washington, DC, USA.
24 . Andes, D. R. & Craig, W. A. (2000). In-vivo pharmacodynamics of RO 63-9141 against multiple bacterial pathogens. In Program and Abstracts of the Fortieth Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, 2000. Abstract F-1079, p. 198. American Society for Microbiology, Washington, DC, USA.
25 . National Committee for Clinical Laboratory Standards. (2000). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Fourth Edition: Approved Standard M7-A5. NCCLS, Wayne, PA, USA.
26 . National Committee for Clinical Laboratory Standards. (2001). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria—Fourth Edition: Approved Standard M11-A5. NCCLS, Wayne, PA, USA.
27 . National Committee for Clinical Laboratory Standards. (2002). MIC Testing. Supplemental Tables M100-S12 (M7). NCCLS, Wayne, PA, USA.
28 . Deshpande, L. M., Jones, R. N., Biedenbach, D. J. & Beach, M. L. (2001). Antimicrobial potency and spectrum for Ro63-9141 (RO), a novel cephalosporin with activity against methicillin-resistant staphylococci (MRS). In Program and Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, USA, 2001. Abstract F-375, p. 211. American Society for Microbiology, Washington, DC, USA.
29
.
McDougal, L. K. & Thornsberry, C. (1984). New recommendations for disk diffusion antimicrobial susceptibility tests for methicillin-resistant (heteroresistant) staphylococci. Journal of Clinical Microbiology 19, 482–8.
30
.
Tenover, F. C., Jones, R. N., Swenson, J. M., Zimmer, B., McAllister, S. & Jorgensen, J. H. (1999). Methods for improved detection of oxacillin resistance in coagulase-negative staphylococci: results of a multicenter study. Journal of Clinical Microbiology 37, 4051–8.
31 . Colley, E. W., McNicol, M. W. & Bracket, P. M. (1965). Methicillin-resistant staphylococci in a general hospital. Lancet 191, 595–7.[Medline]
32
.
Chambers, H. F. (1995). In vitro and in vivo antistaphylococcal activities of L-695,256, a carbapenem with high affinity for penicillin-binding protein PBP 2a. Antimicrobial Agents and Chemotherapy 39, 462–6.
33
.
Nagano, R., Shibata, K., Adachi, Y., Imamura, H., Hashizume, T. & Morishima, H. (2000). In vitro activities of novel trans-3,5-disubstituted pyrrolidinylthio-1ß-methyl-carbapenems with potent activities against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy 44, 489–95.
34
.
Sumita, Y., Nouda, H., Kanazawa, K. & Fukasawa, M. (1995). Antimicrobial activity of SM-17466, a novel carbapenem antibiotic with potent activity against methicillin-resistant Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 39, 910–6.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  X. Henry, A. Amoroso, J. Coyette, and B. Joris Interaction of Ceftobiprole with the Low-Affinity PBP 5 of Enterococcus faecium Antimicrob. Agents Chemother., February 1, 2010; 54(2): 953 - 955. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Barbour, S. Schmidt, S. N. Sabarinath, M. Grant, C. Seubert, D. Skee, B. Murthy, and H. Derendorf Soft-Tissue Penetration of Ceftobiprole in Healthy Volunteers Determined by In Vivo Microdialysis Antimicrob. Agents Chemother., July 1, 2009; 53(7): 2773 - 2776. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. A. Craig and D. R. Andes In Vivo Pharmacodynamics of Ceftobiprole against Multiple Bacterial Pathogens in Murine Thigh and Lung Infection Models Antimicrob. Agents Chemother., October 1, 2008; 52(10): 3492 - 3496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Amsler, T. A. Davies, W. Shang, M. R. Jacobs, and K. Bush In Vitro Activity of Ceftobiprole against Pathogens from Two Phase 3 Clinical Trials of Complicated Skin and Skin Structure Infections Antimicrob. Agents Chemother., September 1, 2008; 52(9): 3418 - 3423. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. N. Leonard, C. M. Cheung, and M. J. Rybak Activities of Ceftobiprole, Linezolid, Vancomycin, and Daptomycin against Community-Associated and Hospital-Associated Methicillin-Resistant Staphylococcus aureus Antimicrob. Agents Chemother., August 1, 2008; 52(8): 2974 - 2976. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-C. Hsieh, K.-Y. Chang, Y.-C. Huang, H.-C. Lin, Y.-H. Ho, L.-M. Huang, and P.-R. Hsueh Clonal Spread of Highly {beta}-Lactam-Resistant Streptococcus pneumoniae Isolates in Taiwan Antimicrob. Agents Chemother., June 1, 2008; 52(6): 2266 - 2269. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. D Anderson and J. G Gums Ceftobiprole: An Extended-Spectrum Anti-Methicillin-Resistant Staphylococcus aureus Cephalosporin Ann. Pharmacother., June 1, 2008; 42(6): 806 - 816. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Pillar, M. K. Aranza, D. Shah, and D. F. Sahm In vitro activity profile of ceftobiprole, an anti-MRSA cephalosporin, against recent Gram-positive and Gram-negative isolates of European origin J. Antimicrob. Chemother., March 1, 2008; 61(3): 595 - 602. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Thamlikitkul and S. Trakulsomboon In vitro activity of ceftobiprole against Burkholderia pseudomallei J. Antimicrob. Chemother., February 1, 2008; 61(2): 460 - 461. [Full Text] [PDF]
|
|
|
|
|
|
G. J. Noel, R. S. Strauss, K. Amsler, M. Heep, R. Pypstra, and J. S. Solomkin Results of a Double-Blind, Randomized Trial of Ceftobiprole Treatment of Complicated Skin and Skin Structure Infections Caused by Gram-Positive Bacteria Antimicrob. Agents Chemother., January 1, 2008; 52(1): 37 - 44. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Queenan, W. Shang, M. Kania, M. G. P. Page, and K. Bush Interactions of Ceftobiprole with {beta}-Lactamases from Molecular Classes A to D Antimicrob. Agents Chemother., September 1, 2007; 51(9): 3089 - 3095. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mushtaq, M. Warner, Y. Ge, K. Kaniga, and D. M. Livermore In vitro activity of ceftaroline (PPI-0903M, T-91825) against bacteria with defined resistance mechanisms and phenotypes J. Antimicrob. Chemother., August 1, 2007; 60(2): 300 - 311. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. P. Lodise Jr., R. Pypstra, J. B. Kahn, B. P. Murthy, H. C. Kimko, K. Bush, G. J. Noel, and G. L. Drusano Probability of Target Attainment for Ceftobiprole as Derived from a Population Pharmacokinetic Analysis of 150 Subjects Antimicrob. Agents Chemother., July 1, 2007; 51(7): 2378 - 2387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. A. Davies, M. G. P. Page, W. Shang, T. Andrew, M. Kania, and K. Bush Binding of Ceftobiprole and Comparators to the Penicillin-Binding Proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae Antimicrob. Agents Chemother., July 1, 2007; 51(7): 2621 - 2624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. N. Jeffres, W. Isakow, J. A. Doherty, P. S. McKinnon, D. J. Ritchie, S. T. Micek, and M. H. Kollef Predictors of Mortality for Methicillin-Resistant Staphylococcus aureus Health-Care-Associated Pneumonia: Specific Evaluation of Vancomycin Pharmacokinetic Indices. Chest, October 1, 2006; 130(4): 947 - 955. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. A. Davies, W. Shang, and K. Bush Activities of Ceftobiprole and Other {beta}-Lactams against Streptococcus pneumoniae Clinical Isolates from the United States with Defined Substitutions in Penicillin-Binding Proteins PBP 1a, PBP 2b, and PBP 2x Antimicrob. Agents Chemother., July 1, 2006; 50(7): 2530 - 2532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Bogdanovich, C. Clark, L. Ednie, G. Lin, K. Smith, S. Shapiro, and P. C. Appelbaum Activities of Ceftobiprole, a Novel Broad-Spectrum Cephalosporin, against Haemophilus influenzae and Moraxella catarrhalis Antimicrob. Agents Chemother., June 1, 2006; 50(6): 2050 - 2057. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. N. Jones, T. R. Fritsche, Y. Ge, K. Kaniga, and H. S. Sader Evaluation of PPI-0903M (T91825), a novel cephalosporin: bactericidal activity, effects of modifying in vitro testing parameters and optimization of disc diffusion tests J. Antimicrob. Chemother., December 1, 2005; 56(6): 1047 - 1052. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Bogdanovich, L. M. Ednie, S. Shapiro, and P. C. Appelbaum Antistaphylococcal Activity of Ceftobiprole, a New Broad-Spectrum Cephalosporin Antimicrob. Agents Chemother., October 1, 2005; 49(10): 4210 - 4219. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. von Eiff, A. W. Friedrich, K. Becker, and G. Peters Comparative In Vitro Activity of Ceftobiprole against Staphylococci Displaying Normal and Small-Colony Variant Phenotypes Antimicrob. Agents Chemother., October 1, 2005; 49(10): 4372 - 4374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Vaudaux, A. Gjinovci, M. Bento, D. Li, J. Schrenzel, and D. P. Lew Intensive Therapy with Ceftobiprole Medocaril of Experimental Foreign-Body Infection by Methicillin-Resistant Staphylococcus aureus Antimicrob. Agents Chemother., September 1, 2005; 49(9): 3789 - 3793. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. S. Sader, T. R. Fritsche, K. Kaniga, Y. Ge, and R. N. Jones Antimicrobial Activity and Spectrum of PPI-0903M (T-91825), a Novel Cephalosporin, Tested against a Worldwide Collection of Clinical Strains Antimicrob. Agents Chemother., August 1, 2005; 49(8): 3501 - 3512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kosowska, D. B. Hoellman, G. Lin, C. Clark, K. Credito, P. McGhee, B. Dewasse, B. Bozdogan, S. Shapiro, and P. C. Appelbaum Antipneumococcal Activity of Ceftobiprole, a Novel Broad-Spectrum Cephalosporin Antimicrob. Agents Chemother., May 1, 2005; 49(5): 1932 - 1942. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Schmitt-Hoffmann, B. Roos, M. Schleimer, J. Sauer, A. Man, N. Nashed, T. Brown, A. Perez, E. Weidekamm, and P. Kovacs Single-Dose Pharmacokinetics and Safety of a Novel Broad-Spectrum Cephalosporin (BAL5788) in Healthy Volunteers Antimicrob. Agents Chemother., July 1, 2004; 48(7): 2570 - 2575. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Schmitt-Hoffmann, L. Nyman, B. Roos, M. Schleimer, J. Sauer, N. Nashed, T. Brown, A. Man, and E. Weidekamm Multiple-Dose Pharmacokinetics and Safety of a Novel Broad-Spectrum Cephalosporin (BAL5788) in Healthy Volunteers Antimicrob. Agents Chemother., July 1, 2004; 48(7): 2576 - 2580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Huang, W. J. Brown, and M. J. Rybak In Vitro Activities of a Novel Cephalosporin, CB-181963 (CAB-175), against Methicillin-Susceptible or -Resistant Staphylococcus aureus and Glycopeptide-Intermediate Susceptible Staphylococci Antimicrob. Agents Chemother., July 1, 2004; 48(7): 2719 - 2723. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. R. Anderegg, R. N. Jones, and H. S. Sader Quality Control Guidelines for BAL9141 (Ro 63-9141), an Investigational Cephalosporin, When Reference MIC and Standardized Disk Diffusion Susceptibility Test Methods Are Used J. Clin. Microbiol., July 1, 2004; 42(7): 3356 - 3358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Mouton, A. Schmitt-Hoffmann, S. Shapiro, N. Nashed, and N. C. Punt Use of Monte Carlo Simulations To Select Therapeutic Doses and Provisional Breakpoints of BAL9141 Antimicrob. Agents Chemother., May 1, 2004; 48(5): 1713 - 1718. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Bernard, P. Hoffmeyer, M. Assal, P. Vaudaux, J. Schrenzel, and D. Lew Reply J. Antimicrob. Chemother., May 1, 2004; 53(5): 887 - 887. [Full Text] [PDF]
|
|
|
|
|
|
E. Azoulay-Dupuis, J. P. Bedos, J. Mohler, A. Schmitt-Hoffmann, M. Schleimer, and S. Shapiro Efficacy of BAL5788, a Prodrug of Cephalosporin BAL9141, in a Mouse Model of Acute Pneumococcal Pneumonia Antimicrob. Agents Chemother., April 1, 2004; 48(4): 1105 - 1111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. S. Sader, D. M. Johnson, and R. N. Jones In Vitro Activities of the Novel Cephalosporin LB 11058 against Multidrug-Resistant Staphylococci and Streptococci Antimicrob. Agents Chemother., January 1, 2004; 48(1): 53 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Hardy, P. M. Hawkey, F. Gao, and B. A. Oppenheim Methicillin resistant Staphylococcus aureus in the critically ill Br. J. Anaesth., January 1, 2004; 92(1): 121 - 130. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||