Comparative in vitro antimicrobial activity of a new carbapenem, doripenem: tentative disc diffusion criteria and quality control

OBJECTIVES: To determine the spectrum of activity of doripenem and to propose tentative MIC and disc diffusion breakpoints. METHODS: The in vitro susceptibilities of 2137 bacterial isolates, representing 28 different species, to doripenem, imipenem and meropenem were determined by the NCCLS broth microdilution and disc diffusion testing methods. RESULTS: The doripenem MIC(50)s/(90)s were (in mg/L) for Enterobacteriaceae, 0.06/0.25; Pseudomonas aeruginosa, 0.25/1; Haemophilus influenzae, 0.12/0.5; streptococci, 0.016/0.5 and for staphylococci, 0.06/4. Like other carbapenems tested, doripenem MIC(50)s/(90)s were >32/>32 and 0.5/32 mg/L for the enterococci and non-fermentative Gram-negative bacilli (excluding P. aeruginosa), respectively. Against members of the Enterobacteriaceae and H. influenzae, doripenem was generally more active than imipenem and the same as or slightly less active than meropenem. Values for the non-fermentative Gram-negative bacilli excluding P. aeruginosa were comparable for all three carbapenems. Doripenem MICs increased with increasing resistance to methicillin (staphylococci), penicillin (streptococci) and strains that were beta-lactamase-negative ampicillin-resistant (Haemophilus). Doripenem exhibits excellent activity against extended-spectrum beta-lactamase-producing strains of Escherichia coli and Klebsiella spp. The NCCLS disc diffusion test was performed simultaneously on all organisms. CONCLUSIONS: Assuming the MIC susceptible breakpoints for doripenem are < or =1 mg/L for the streptococci and < or =2 mg/L for all other genera, then disc diffusion zone diameter breakpoints can be proposed. In addition, MIC and/or disc diffusion quality control ranges of doripenem were determined for 10 ATCC reference strains.     

In vitro activities of aminomethyl-substituted analogs of novel tetrahydrofuranyl carbapenems

CL 188,624, CL 190,294, and CL 191,121 are novel aminomethyl tetrahydrofuranyl (THF)-1 beta-methylcarbapenems. The in vitro antibacterial activities of these THF carbapenems were evaluated and compared with those of biapenem, imipenem, and meropenem against 554 recent clinical isolates obtained from geographically distinct medical centers across North America. The antibacterial activities of the THF carbapenems were equivalent to that of biapenem, and the THF carbapenems were slightly more active than imipenem and less active than meropenem against most of the members of the family Enterobacteriaceae but lacked significant activity against Pseudomonas isolates. In general, CL 191,121 was two- to fourfold more active than CL 188,624 and CL 190,294 against the staphylococcal and enterococcal isolates tested. CL 191,121 was twofold less active than imipenem against methicillin-susceptible staphylococci and was as activity as imipenem against Enterococcus faecalis isolates. Biapenem and meropenem were two- and fourfold less active than CL 191,121, respectively, against the methicillin-susceptible staphylococci and E. faecalis. All the carbapenems displayed equivalent good activities against the streptococci. Biapenem was slightly more active than the other carbapenems against Bacteroides fragilis isolates. Time-kill curve studies demonstrated that the THF carbapenems were bactericidal in 6 h against Escherichia coli and Staphylococcus aureus isolates. The postantibiotic effect exerted by CL 191,121 was comparable to or slightly longer than that of imipenem against isolates of S. aureus, E. coli, and Klebsiella pneumoniae.     

In vitro activity of BMS-181139, a new carbapenem with potent antipseudomonal activity.

The in vitro activities of the carbapenem BMS-181139 were determined in comparison with those of imipenem, meropenem, ciprofloxacin, ceftriaxone, and vancomycin. BMS-181139 was the most active against species of Pseudomonas and related genera Alteromonas and Burkholderia, with MICs for 147 of 149 isolates of < 4 micrograms/ml. Of 22 imipenem-resistant (MIC > 8 micrograms/ml) P. aeruginosa strains, only 1 required an MIC of BMS-181139 of > 4 micrograms/ml, compared with 14 requiring the same meropenem MIC. BMS-181139 was the most active carbapenem against the majority of other gram-negative species except members of the tribe Proteeae, against which meropenem was more active. Although imipenem was more active against gram-positive species, BMS-18139 MICs at which 90% of strain tested were inhibited were < 1 microgram/ml for these species. BMS-181139 was generally active against isolates resistant to ciprofloxacin or broad-spectrum cephalosporins, including those containing plasmid-encoded beta-lactamases or high levels of chromosome-encoded beta-lactamases, as well as anaerobes except Clostridium difficile. Inoculum effects were noted for all three carbapenems against Klebsiella pneumoniae, Enterobacter cloacae, and Serratia marcescens but not Escherichia coli, Pseudomonas aeruginosa, or Staphylococcus aureus. BMS-181139's inoculum effect tended to be more marked. BMS-181139 exhibited bactericidal activity at the MIC for some strains and up to four to eight times the MIC for others. The postantibiotic effect of BMS-181139 was equal to or less than that of imipenem and, like meropenem, exhibited intraspecies variability. BMS-181139 was 30-fold more stable than imipenem and 7-fold more stable than meropenem to hydrolysis by hog kidney dehydropeptidase.     

In-vitro activity of new carbapenem antibiotics: comparative studies with meropenem, L-627 and imipenem against pathogenic Nocardia spp.

MICs of two new carbapenems, meropenem and L-627, and imipenem were determined against 98 strains of the Nocardia asteroides group (i.e. N. asteroides sensu stricto, Nocardia farcinica and Nocardia nova), 46 strains of Nocardia brasiliensis and 17 strains of Nocardia otitidiscaviarum. Meropenem and L-627 were less active against the N. asteroides group than imipenem. Among the three species of the N. asteroides group, N. nova was the most sensitive to all the carbapenems. Meropenem was more active than imipenem against both N. brasiliensis and N. otitidiscaviarum with MIC50 values of 28.3-53.3 mg/L. L-627 was less active than meropenem.     

In-vitro antimicrobial activity of a carbapenem, MK-0826 (L-749,345) and provisional interpretive criteria for disc tests.

The in-vitro activity of MK-0826, a new oral carbapenem, was compared with that of imipenem by broth microdilution susceptibility tests against 545 bacterial isolates. MK-0826 had significantly greater activity against Enterobacteriaceae and poorer activity against Pseudomonas aeruginosa and many gram-positive species. MK-0826 disc diffusion tests were also performed according to the NCCLS procedure and tentative interpretive criteria were determined for possible susceptible MIC breakpoints of < or = 4.0 and < or = 2.0 mg/L.     

Doripenem (S-4661), a novel carbapenem: comparative activity against contemporary pathogens including bactericidal action and preliminary in vitro methods evaluations

OBJECTIVES: To investigate the potency of doripenem, a broad-spectrum carbapenem characterized by a wider spectrum of activity combining antimicrobial and bactericidal features of imipenem and meropenem. METHODS: This parenteral compound was studied against recent clinical isolates (2001-2002) from a worldwide organism collection. A total of 902 strains were susceptibility tested by reference methods against doripenem and six to 28 comparators including ertapenem, imipenem and meropenem. The organisms tested included: Enterobacteriaceae (281 strains), Acinetobacter spp. (33), Pseudomonas aeruginosa (35), Stenotrophomonas maltophilia (36), other non-fermenters (22), Haemophilus influenzae (61), Moraxella catarrhalis (33), oxacillin-susceptible staphylococci (39), enterococci (84), streptococci (163), various anaerobes (98), and other Gram-positive species such as Corynebacterium and Bacillus spp. (17). RESULTS: Against Enterobacteriaceae, the average doripenem MIC90 was 0.03 mg/L (range, < or =0.015-0.25 mg/L). Doripenem was two- to 16-fold more potent than imipenem and comparable to ertapenem and meropenem; all doripenem MIC values with enteric bacilli were < or =4 mg/L. Doripenem was active against Aeromonas (MIC50, 0.03 mg/L), Bacillus spp. (MIC50, 0.03 mg/L) and all tested anaerobic species (MIC range, < or =0.015-4 mg/L), but was less active against S. maltophilia (MIC90, >32 mg/L) and Enterococcus faecium (MIC90, >32 mg/L) among the enterococcal species. Time-dependent bactericidal action was observed for doripenem and broth MIC results were slightly greater when compared to agar MIC results. In pilot testing, the optimal doripenem disc concentration was 10 microg, identical to standardized reagents for other clinically available carbapenems. CONCLUSIONS: Doripenem appears to be a potent carbapenem with a spectrum resembling currently marketed antipseudomonal carbapenems, but with greater activity when tested against some non-fermentative bacillary strains. Continued evaluation of doripenem against isolates resistant to other beta-lactams appears to be warranted.     

Comparative activity of doripenem and three other carbapenems tested against Gram-negative bacilli with various beta-lactamase resistance mechanisms

Doripenem (formerly S-4661), a novel carbapenem antimicrobial, was compared with ertapenem, imipenem, and meropenem using reference broth microdilution test methods against wild-type and various resistant microbial subsets (380 strains). Doripenem and meropenem were consistently more potent than ertapenem or imipenem when tested against Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. Ertapenem exhibited minimum inhibitory concentration (MIC) elevations for some isolates producing AmpC and extended-spectrum beta-lactamases, in contrast to greater enzyme stability for doripenem and other carbapenems tested. Multiple beta-lactamase (TEM, SHV, CTX-M, OXA, CMY types)-producing Escherichia coli had doripenem MIC values at 相似文献   

Comparative in vitro pharmacodynamics of imipenem and meropenem against ATCC strains of Escherichia coli, Staphylococcus aureus and Bacteroides fragilis

We evaluated the pharmacodynamics of imipenem and meropenem, utilizing time-kill studies over a concentration/MIC (C/MIC) range of 0.0625-1024 for E. coli ATCC 35218 (EC) and S. aureus ATCC 29213 (SA) and from 0.125-512 for B. fragilis ATCC 25285 (BF). Area under the time-kill curves were converted to percent response (%R). AUCs were calculated from drug concentrations corrected for degradation and %R vs. C/MIC and AUC/MIC were fit to a sigmoidal Emax model. Emax was similar for both agents for all organisms. Meropenem was 4x more potent than imipenem against EC based on the MIC and required 7 and 13.5-fold lower AUCs to achieve E50 and E90, (50% and 90% of the maximal response, respectively) respectively, whereas imipenem was 8x more potent than meropenem against SA based on the MIC and required 8 and 13-fold lower AUCs to achieve E50 and E90, respectively. The C/MIC and AUC/MIC to achieve E50 and E90 with imipenem were 2- and fourfold higher, respectively than meropenem against EC. There was less than a twofold difference in C/MICs and AUC/MIC between imipenem and meropenem for both E50 and E90 against SA. Against BF, concentrations and AUCs at E50 were similar for both agents; however, imipenem required 4 to 6-fold higher concentrations and AUC to achieve E90. Although there are differences in the potency of these agents as assessed by the MIC or AUC vs. response, when normalized by the MIC and corrected for drug degradation, these agents displayed similar pharmacodynamic parameter-response relationships.     

In vitro antibacterial activity and beta-lactamase stability of a new carbapenem, BO-2727.

The in vitro activity of BO-2727, a new carbapenem, was compared with those of meropenem, biapenem, imipenem, and ceftazidime. BO-2727 was four- or eightfold more active than the other carbapenems against methicillin-resistant staphylococci and Pseudomonas aeruginosa strains, including imipenem- and ceftazidime-resistant bacteria. BO-2727 was quite stable to penicillinases, cephalosporinases, and oxyiminocephalosporinases, but not to metallo-beta-lactamase. Time-kill studies against Staphylococcus aureus Smith, Escherichia coli ML4707, and P. aeruginosa GN11189 showed that BO-2727 has potent bactericidal activity at concentrations greater than the MIC.     

Comparative activity of cefoxitin, ampicillin/sulbactam, and imipenem against clinical isolates of Escherichia coli and Klebsiella pneumoniae

The in vitro activities of cefoxitin, ampicillin/sulbactam, and imipenem were determined by the standard twofold agar dilution method against 62 strains of Escherichia coli and 40 strains of Klebsiella pneumoniae isolated from patients in intensive care units. Judging from the concentrations required to inhibit at least 90% of the test isolates, imipenem (MIC90 less than or equal to 0.125 micrograms/ml) was markedly more active than cefoxitin (MIC90 = 4 micrograms/ml) and ampicillin/sulbactam (MIC90 = 32 micrograms/ml) against both bacterial genera. Cefoxitin, therefore, was more active than ampicillin/sulbactam against these organisms. Breakpoints specified in the prescribing information are less than or equal to 4 micrograms/ml for imipenem, less than or equal to 16 micrograms/ml for cefoxitin, and less than or equal to 8 micrograms/ml for ampicillin/sulbactam. At these breakpoints all organisms were susceptible to imipenem and cefoxitin, while 73% of E coli and 78% of K pneumoniae were susceptible to ampicillin/sulbactam. At recommended susceptible MIC breakpoints of the National Committee for Clinical Laboratory Standards (less than or equal to 4 micrograms/ml for imipenem, less than or equal to 8 micrograms/ml for cefoxitin, and less than or equal to 4 micrograms/ml for ampicillin/sulbactam) all the isolates tested were susceptible to imipenem, while 98% and 73% of the E coli isolates were susceptible to cefoxitin and ampicillin/sulbactam, respectively, and 100% and 78% of the K pneumoniae isolates were susceptible to cefoxitin and ampicillin/sulbactam, respectively. Approximately 14% of E coli and 17% of K pneumoniae isolates were resistant to ampicillin/sulbactam (MIC greater than or equal to 32/16 micrograms/ml).     

In vitro activities of doripenem and comparator agents against 364 anaerobic clinical isolates

The in vitro activities of doripenem against 364 anaerobic isolates were measured and compared to those of ertapenem, imipenem, meropenem, ceftriaxone, and levofloxacin. All of the carbapenems were active against nearly all Bacteroides fragilis group isolates. Doripenem was either comparable to or slightly less active than imipenem and meropenem against most isolates but more active than the other penems against Clostridium difficile. Doripenem appears to have excellent activity against a broad range of anaerobes.     

In vitro and in vivo antibacterial activities of BO-2727, a new carbapenem.

BO-2727, a new injectable carbapenem, was evaluated for its in vitro and in vivo antibacterial activities in comparison with those of biapenem, meropenem, imipenem, cefpirome, and ceftazidime. BO-2727 had activity comparable to that of imipenem against methicillin-susceptible staphylococci and streptococci, with MICs at which 90% of strains tested (MIC90s) are inhibited being equal to 0.5 microgram/ml or less. Against methicillin-resistant staphylococci, BO-2727 was the most active among the antibiotics tested, with MIC90s ranging from 4 to 8 micrograms/ml. BO-2727 was highly active against members of the family Enterobacteriaceae, Haemophilus influenzae, and Moraxella catarrhalis, with MIC90s ranging from 0.006 to 2 micrograms/ml. BO-2727 was also highly active against Pseudomonas aeruginosa (imipenem-susceptible strains), for which the MIC90 was 2 micrograms/ml, which was lower than those of imipenem, cefpirome, and ceftazidime and comparable to those of biapenem and meropenem. Differences in activity between BO-2727 and the other carbapenems against imipenem-resistant P. aeruginosa were particularly striking (MIC90, 8 micrograms/ml). Furthermore, BO-2727 displayed a high degree of activity against many of the ceftazidime-, ciprofloxacin-, and/or gentamicin-resistant isolates of P. aeruginosa. The in vivo efficacy of BO-2727 against experimental septicemia caused by gram-positive and gram-negative bacteria, including methicillin-resistant Staphylococcus aureus and imipenem-resistant P. aeruginosa, reflected its potent in vitro activity and high levels in plasma.     

In vitro activities of ertapenem (MK-0826) against recent clinical bacteria collected in Europe and Australia

Ertapenem (MK-0826, L-749,345) is a 1-beta-methyl carbapenem with a long serum half-life. Its in vitro activity was determined by broth microdilution against 3,478 bacteria from 12 centers in Europe and Australia, with imipenem, cefepime, ceftriaxone, and piperacillin-tazobactam used as comparators. Ertapenem was the most active agent tested against members of the family Enterobacteriaceae, with MICs at which 90% of isolates are inhibited (MIC(90)s) of < or =1 microg/ml for all species. Ertapenem also was more active than imipenem against fastidious gram-negative bacteria and Moraxella spp.; on the other hand, ertapenem was slightly less active than imipenem against streptococci, methicillin-susceptible staphylococci, and anaerobes, but its MIC(90)s for these groups remained < or =0.5 microg/ml. Acinetobacter spp. and Pseudomonas aeruginosa were also much less susceptible to ertapenem than imipenem, and most Enterococcus faecalis strains were resistant. Ertapenem resistance, based on a provisional NCCLS MIC breakpoint of > or =16 microg/ml, was seen in only 3 of 1,611 strains of the family Enterobacteriaceae tested, all of them Enterobacter aerogenes. Resistance was also seen in 2 of 135 anaerobes, comprising 1 Bacteroides fragilis strain and 1 Clostridium difficile strain. Ertapenem breakpoints for streptococci have not been established, but an unofficial susceptibility breakpoint of < or =2 microg/ml was adopted for clinical trials to generate corresponding clinical response data for isolates for which MICs were as high as 2 microg/ml. Of 234 Streptococcus pneumoniae strains tested, 2 required ertapenem MICs of 2 microg/ml and one required an MIC of 4 microg/ml, among 67 non-Streptococcus pyogenes, non-Streptococcus pneumoniae streptococci, single isolates required ertapenem MICs of 2 and 16 microg/ml. These streptococci also had diminished susceptibilities to other beta-lactams, including imipenem as well as ertapenem. The Etest and disk diffusion gave susceptibility test results in good agreement with those of the broth microdilution method for ertapenem.     

MEN 10700, a new penem antibiotic: in vitro antibacterial activity on clinical isolates

MEN 10700 is a new broad-spectrum penem, currently in preclinical development. In the present study, the activity of MEN 10700 was compared to that of imipenem, meropenem, cefotaxime, ampicillin/sulbactam, amikacin and ciprofloxacin against 619 gram-positive and gram-negative bacterial strains, and to that of imipenem, meropenem, cefotaxime, ceftriaxone, ceftazidime, cefepime and ampicillin/sulbactam against 38 strains of ciprofloxacin-resistant Escherichia coli, and against 19 extended-spectrum-beta-lactamase (ESBL)-producing strains of the KES group. MEN 10700 was highly active against most gram-positive and gram-negative strains, and overall demonstrated comparable activity to imipenem and meropenem. Methicillin-susceptible Staphylococcus aureus and methicillin-susceptible Staphylococcus epidermidis were highly susceptible to MEN 10700, which was the most potent among the antibiotics tested. MEN 10700 was less potent than the carbapenem antibiotics on Morganella morganii, Serratia marcescens and Acinetobacter spp. Ciprofloxacin-resistant E. coli were uniformly susceptible to MEN 10700, imipenem and meropenem, with MIC90 values in the range of < or = 0.12-0.25 mg/l, while showing much lower susceptibility to the other antibiotics tested, including the fourth-generation cephalosporin cefepime. This feature was even more evident in ESBL-producing strains of the KES group, with an MIC90 of 1- 2 mg/l for MEN 10700, imipenem and meropenem, and a MIC90 of 16-64 mg/l for the other antibiotics tested, including cefepime.     

Biochemical characterization of novel tetrahydrofuranyl 1beta-methylcarbapenems: stability to hydrolysis by renal dehydropeptidases and bacterial beta-lactamases, binding to penicillin binding proteins, and permeability properties

The biochemical properties of tetrahydrofuranyl (THF) carbapenems, carbapenems with THF substituents, were evaluated with respect to enzyme stability, binding to penicillin-binding proteins (PBPs), and penetration into gram-negative organisms. THF carbapenems showed increased stability to hog renal dehydropeptidases (DHPs) compared to that of imipenem or meropenem and were more stable to human DHP than imipenem (<10% hydrolysis compared to that for imipenem). THF carbapenems were stable to hydrolysis by all serine beta-lactamases tested. CL 191,121, a prototype THF carbapenem, was more stable to hydrolysis by carbapenem-hydrolyzing serine beta-lactamases such as IMI-1 and Sme-1 than imipenem, with a relative k(cat) value of <20% for imipenem. Similar to imipenem and meropenem, THF carbapenems were not stable to the metallo beta-lactamases CcrA and L1. However, CL 191,121 bound to all Staphylococcus aureus PBPs at concentrations that were less than or equal to the MICs. The THF carbapenems bound to PBPs from Escherichia coli and Pseudomonas aeruginosa, with the highest affinities being for PBPs 2 and 4, as noted with imipenem. The affinities for PBPs 1a and 1b in E. coli were reduced for the THF carbapenems compared to that for imipenem, even though the MICs of the THF carbapenems for E. coli strains were lower than those of imipenem. The penetrability of the THF carbapenems into Serratia marcescens S6, which produces the Sme-1 carbapenem-hydrolyzing beta-lactamase, was 2.4 to 7.8 times less than that of imipenem. Compounds CL 190,294 and CL 188,624 showed good penetrability, with permeability coefficient values comparable to those of the rapidly penetrating agents cephaloridine, imipenem, meropenem, and biapenem. Decreased penetration into wild-type P. aeruginosa was suggested by the high MICs of the THF carbapenems (MICs, 16 to 32 microg/ml), despite equivalent or better binding to P. aeruginosa PBPs than that of imipenem. However, the MICs of the THF carbapenems for wild-type P. aeruginosa compared to that for an OprD2 mutant generally varied no more than 2-fold, but those of imipenem and other carbapenems differed 16-fold. These data indicated that THF carbapenems do not appear to enter through protein OprD2. In conclusion, the THF carbapenems exhibited stability to hydrolysis by renal DHPs and serine beta-lactamases, exhibited strong binding to essential PBPs from E. coli and S. aureus, and penetrated gram-negative enteric bacteria at rates comparable to those for meropenem and biapenem.     

Diffusion of meropenem and imipenem through the outer membrane of Escherichia coli K-12 and correlation with their antibacterial activities.

The outer membrane permeability to meropenem and imipenem in Escherichia coli K-12 was investigated, and its porin-deficient mutants were transformed with a constructed vector carrying the carbapenem-hydrolyzing CphA metallo-beta-lactamase gene. By using the method of Zimmermann and Rosselet, meropenem was shown to penetrate through the outer membrane of E. coli K-12 five times faster than cephaloridine but twice as slowly as imipenem. Lack of one or both porins significantly reduced the penetration of both carbapenems. No evidence of specific porin pathways of the type described in Pseudomonas aeruginosa was found. Despite its slower penetration, meropenem was two to eight times more active than imipenem against both parent and porin-defective mutants, whether harbouring CphA beta-lactamase or not. Meropenem was also more active than imipenem against E. coli DC2, a strain with a breakdown in the outer membrane permeability which made periplasmic concentrations of beta-lactams similar to the external concentrations. In this strain, meropenem caused a more than 50% reduction in cell number increase at a concentration very close to the 50% inhibitory concentration for penicillin-binding protein type 2 (PBP 2), whereas imipenem, at the same concentration, did not significantly inhibit cell growth. This result was explained by the higher affinity of meropenem for PBP 3 compared with imipenem and supports the conclusion that synergistic inhibition of both PBPs was the main mechanism in the better antibacterial activity of meropenem.     

替加环素、米诺环素、多黏菌素B对碳青霉烯类敏感性降低和不敏感鲍曼不动杆菌体外抗菌活性

目的调查替加环素、米诺环素、多黏菌素B等对碳青霉烯类抗生素敏感性降低鲍曼不动杆菌（CDSAB）和碳青霉烯不敏感鲍曼不动杆菌（CNSAB）体外抗菌活性,为临床治疗该类菌感染提供依据。方法采用琼脂稀释法检测替加环素、米诺环素、多黏菌素B等15种抗菌药物对2002-2009年深圳市人民医院临床分离56株CDSAB（美罗培南和亚胺培南MIC=1～4mg／L）和178株CNSAB（美罗培南或亚胺培南MIC≥8mg／L）的最低抑菌浓度（MIC）,采用WHONET5．6软件分析处理数据。结果多黏菌素B对CDSAB和CNSAB体外抗菌活性最高,细菌对其均100％敏感,MIC50和MIC90均为1mg／L,其次为替加环素和米诺环素,约80％CDSAB对二者敏感或中介,MIC50／MIC90分别为4／8mg／L和8／16mg／L;约95％CNSAB对替加环素和米诺环素敏感或中介,MIC50／MIC90分别为4／4mg／L和4／8mg／L。结论多黏菌素B、替加环素和米诺环素对碳青霉烯类抗生素敏感性降低和不敏感鲍曼不动杆菌具有较强的体外抗菌活性。     

Pharmacodynamic modeling of carbapenems and fluoroquinolones against bacteria that produce extended-spectrum beta-lactamases

BACKGROUND: Bacteria that produce extended-spectrum beta-lactamases (ESBLs) are resistant to penicillins,cephalosporins, and monobactams. The results of clinical studies suggest that the carbapenems imipenem and meropenem may be effective against bacteria that produce ESBLs, although it is not known whether the new once-daily carbapenem ertapenem or the fluoroquinolones are useful against infections caused by ESBL-producing bacteria. OBJECTIVE: The present study compared the simulated pharmacodynamics of the carbapenems imipenem,meropenem, and ertapenem; the simulated pharmacodynamics of the fluoroquinolones levofloxacin, gatifloxacin, and ciprofloxacin with those of the carbapenems; and the simulated pharmacodynamics of levofloxacin 750 mg with those of levofloxacin 500 mg, all against gram-negative isolates that did and did not produce ESBLs METHODS: Pharmacokinetic data were obtained from studies in healthy humans. Minimum inhibitory concentrationsMICs) for bacteria that did and did not produce ESBLs were determined in triplicate using broth-microdilution techniques as recommended by National Committee for Clinical Laboratory Standards guidelines. Monte Carlo simulation was used to construct pharmacodynamic models for imipenem, meropenem, ertapenem, levofloxacin, gatifloxacin, and ciprofloxacin. Pharmacodynamic measures of interest were the probability of the free concentration remaining above the MIC >-40% of the time (T>MIC > or =40%) for carbapenems and the likelihood of achieving a free AUC:MIC ratio > or =125 for fluoroquinolones. RESULTS: MICs were determined for 39 isolates that produced ESBLs and 45 isolates that did not Bacteria that did not produce ESBLs were > or =93% susceptible to all carbapenems and fluoroquinolones tested. Among bacteria that produced ESBLs, rates of susceptibility to the specific agents were as follows: imipenem, 100%; meropenem, 97%; ertapenem, 87%; levofloxacin, 54%; gatifloxacin, 44%; and ciprofloxacin, 36%. In the pharmacodynamic models, imipenem and meropenem had an equal likelihood of achieving a free T>MIC > or =40% against bacteria that produced ESBLs (> or =97%) and bacteria that did not produce ESBLs (> or =98%). In contrast, the likelihood of ertapenem achieving a free T>MIC > or =40% was lower against bacteria that produced ESBLs (78%) than against bacteria that did not produce ESBLs (94%). Similarly, the fluoroquinolones were less likely to achieve a free AUC:MIC ratio > or =125 against bacteria that produced ESBLs (2%-13%) than against bacteria that did not produce ESBLs (85%-91%). CONCLUSIONS: Carbapenems had superior in vitro activity against bacteria that produced ESBLs compared with fluoroquinolones. Pharmacodynamic modeling based on local ESBL-producing isolates and pharmacokinetic data from healthy humans indicated that imipenem and meropenem may have a greater likelihood of achieving pharmacodynamic targets against bacteria that produce ESBLs than ertapenem or fluoroquinolones.     

Plasmid-encoded metallo-beta-lactamase (IMP-6) conferring resistance to carbapenems, especially meropenem

In 1996, Serratia marcescens KU3838 was isolated from the urine of a patient with a urinary tract infection at a hospital in northern Japan and was found to contain the plasmid pKU501. Previously, we determined that pKU501 carries bla(IMP) and the genes for TEM-1-type beta-lactamases as well as producing both types of beta-lactamases (H. Yano, A. Kuga, K. Irinoda, R. Okamoto, T. Kobayashi, and M. Inoue, J. Antibiot. 52:1135-1139, 1999). pKU502 is a recombinant plasmid that contains a 1.5-kb DNA fragment, including the metallo-beta-lactamase gene, and is obtained by PCR amplification of pKU501. The sequence of the metallo-beta-lactamase gene in pKU502 was determined and revealed that this metallo-beta-lactamase gene differed from the gene encoding IMP-1 by one point mutation, leading to one amino acid substitution: 640-A in the base sequence of the IMP-1 gene was replaced by G, and Ser-196 was replaced by Gly in the mature enzyme. This enzyme was designated IMP-6. The strains that produced IMP-6 were resistant to carbapenems. The MICs of panipenem and especially meropenem were higher than the MIC of imipenem for these strains. The k(cat)/K(m) value of IMP-6 was about sevenfold higher against meropenem than against imipenem, although the MIC of meropenem for KU1917, which produced IMP-1, was lower than that of imipenem, and the MIC of panipenem was equal to that of imipenem. These results support the hypothesis that IMP-6 has extended substrate profiles against carbapenems. However, the activity of IMP-6 was very low against penicillin G and piperacillin. These results suggest that IMP-6 acquired high activity against carbapenems, especially meropenem, via the point mutation but in the process lost activity against penicillins. Although IMP-6 has reduced activity against penicillins due to this point mutation, pKU501 confers resistance to a variety of antimicrobial agents because it also produces TEM-1-type enzyme.     

A review of the in vitro activity of meropenem and comparative antimicrobial agents tested against 30,254 aerobic and anaerobic pathogens isolated world wide

The in vitro activity of meropenem (formerly SM-7738), a new carbapenem, was compared with that of imipenem and five other broad-spectrum antimicrobials (ceftazidime, cefotaxime, piperacillin, piperacillin/tazobactam, and ciprofloxacin) against 30,254 clinically significant pathogens isolated in nine countries worldwide. Overall, the carbapenems, meropenem and imipenem, were the most active drugs. Meropenem was four- to 64-fold more active than imipenem against Gram-negative bacteria, including the Enterobacteriaceae, Pseudomonas aeruginosa, Burkholderia cepacia, Haemophilus influenzae, and Neisseria meningitidis. Meropenem was also quite active against ceftazidime-resistant strains of Enterobacteriaceae, inhibiting 87.5 to 100% at ≤ 4 μg/ml. In contrast, imipenem was four- to eight-fold more active than meropenem against Gram-positive species, including methicillin-susceptible strains of Staphylococcus aureus and Staphylococcus epidermidis, Streptococcus pneumoniae, and Enterococcus faecalis. Among the anaerobes, strains resistant to meropenem or imipenem were encountered very rarely. These extensive data provide additional in vitro support for the clinical use of meropenem as a broad spectrum antimicrobial agent active against key pathogenic species of bacteria.