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JAC Advance Access originally published online on September 4, 2007
Journal of Antimicrobial Chemotherapy 2007 60(5):1045-1050; doi:10.1093/jac/dkm317
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Broad-spectrum ß-lactams for treating experimental peritonitis in mice due to Escherichia coli producing plasmid-encoded cephalosporinases

Sophie Vimont1,{dagger},{ddagger}, Daniel Aubert1,{dagger},§, Jean-Xavier Mazoit2, Laurent Poirel1 and Patrice Nordmann1,*

1 Service de Bactériologie-Virologie, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine de Paris-Sud, 94275 K.-Bicêtre, France 2 Laboratoire d'Anesthésie-Réanimation, Faculté de Médecine de Paris-Sud, 94276 K.-Bicêtre Cedex, France

* Corresponding author. Tel: +33-1-45-21-36-32; Fax: +33-1-45-21-63-40; E-mail: nordmann.patrice{at}bct.aphp.fr

Received 1 February 2007; returned 7 May 2007; revised 19 July 2007; accepted 31 July 2007


   Abstract
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Objectives: To investigate the correlation between in vitro activity and in vivo efficacy of broad-spectrum ß-lactams for treating experimental infections due to Escherichia coli expressing two types of plasmid-mediated AmpC-type ß-lactamases, LAT-1 and FOX-1.

Methods: Susceptibility testing and time–kill curves were determined for piperacillin/tazobactam, ceftazidime, cefepime and imipenem. A mouse model of peritonitis was developed to determine 50% effective doses (ED50s) of ß-lactams against E. coli clinical strains producing recombinant plasmids pLAT-1 and pFOX-1.

Results: MIC and MBC values correlated with the ED50s for ceftazidime, cefepime and imipenem. Among the ß-lactams tested, both cefepime and imipenem were effective for treating peritonitis caused by E. coli strains harbouring pLAT-1 or pFOX-1, whereas ceftazidime was effective only against E. coli (pLAT-1). Piperacillin/tazobactam was not effective for treating infections with either of these two strains.

Conclusions: Piperacillin/tazobactam was not efficacious for treating infections due to E. coli producing plasmid-mediated AmpC-type ß-lactamases, whereas cefepime and imipenem were efficacious.

Keywords: E. coli , ß-lactamases , AmpC


   Introduction
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Along with plasmid-mediated clavulanic-acid-inhibited extended-spectrum ß-lactamases, plasmid-mediated cephalosporinases are emerging worldwide in Enterobacteriaceae in human and animal isolates.1

The plasmid-mediated Ambler class C ß-lactamases are structurally related to chromosome-encoded cephalosporinases of Gram-negatives and may be divided into five clusters: (i) the Citrobacter freundii group with LAT-type (LAT-1)2 and several CMY-type ß-lactamases; (ii) the Enterobacter group with MIR-1 and ACT-1;3–5 (iii) the Morganella morganii group with DHA-1 and DHA-2;6,7 (iv) the Aeromonas group with MOX-, FOX- (FOX-1)8 and other CMY-type enzymes; and (v) the Hafnia alvei group represented by ACC-1.9,10 Plasmid-mediated class C ß-lactamases are usually self-transferable and have been reported mostly in Klebsiella pneumoniae, Escherichia coli, Klebsiella oxytoca, Proteus mirabilis and Salmonella clinical isolates.1,11 Plasmid location of ampC-type genes increases the gene copy number, leading to overexpression of cephalosporinases.

The aim of this study was to evaluate the in vitro and in vivo bactericidal efficacies of several ß-lactams (piperacillin/tazobactam, ceftazidime, cefepime and imipenem), against two main plasmid-mediated AmpC-type ß-lactamases (LAT-1 and FOX-1) expressed in an isogenic E. coli background by using the mouse model of peritonitis. This study was conducted as in vitro susceptibility results may indicate susceptibility to piperacillin/tazobactam in several cases.


   Materials and methods
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Bacterial strains, plasmids and culture conditions

K. pneumoniae P20 clinical isolate harbouring plasmid HPI-5 and E. coli TG1 harbouring plasmid pGL3 were used as sources of blaLAT-1 and blaFOX-1 genes, respectively.2,8 E. coli DH10B (Life Technologies, Eragny, France) and clinical isolate E. coli DS with a wild-type-resistant phenotype were used as recipient strains. E. coli DS was from a pulmonary infection from a patient hospitalized at the Bicêtre hospital (K.-Bicêtre, France). The pPCRscript Cam vector (Stratagene, La Jolla, CA, USA) was used for cloning experiments. Bacterial cells were grown in Trypticase soy (TS) broth and agar plates (bioMérieux, Marcy-l’Étoile, France).

PCR experiments

Standard PCR amplifications12 were performed with external pairs of primers Hind-LAT (5'-GGGAAGCTTATGATGAAAAAATCGTTATGCTCCGC-3') and Eco-LAT (5'-GGGGAATTCTTATTGCAGCTTTTCAAGAATGCGCC-3') for amplification of the blaLAT-1 gene and Hind-FOX (5'-GGGAAGCTTATGCAACAACGACGTGCGTT-3') and Eco-FOX (5'-AGGGAATTCTCACTCGGCCAACTGACTC-3') for amplification of the blaFOX-1 gene. The PCR products were purified using Qiaquick columns (Qiagen, Courtaboeuf, France), prior to cloning experiments.

DNA extraction, enzymes, cloning experiments and DNA sequencing

Whole-cell DNAs were obtained as described previously.13 Cloning of the blaLAT-1 and blaFOX-1 genes was performed as follows. A 1.2 kb fragment flanked by HindIII and EcoRI restriction sites was amplified with Hind-LAT and Eco-LAT primers and whole-cell DNA of K. pneumoniae P20 (HPI-5) as template. Similarly, whole-cell DNA of E. coli TG1 (pGL3) and the pair of primers Hind-FOX and Eco-FOX were used to amplify a 1.2 kb fragment flanked by HindIII and EcoRI restriction sites. PCR products were cloned into the HindIII–EcoRI-restricted pPCRscript Cam vector (Stratagene), resulting in recombinant plasmids pLAT-1 and pFOX-1. Ligation products were electroporated (Gene Pulser II; Bio-Rad, Ivry-sur-Seine, France) into E. coli DH10B electrocompetent cells (Life Technologies).13 Recombinant clones were selected on TS agar plates containing amoxicillin (100 mg/L) and chloramphenicol (30 mg/L). Cloned DNA fragments from recombinant plasmid were sequenced on both strands using an ABI PRISM 3100 automated sequencer (Applied Biosystems, Les Ulis, France). Recombinant plasmids (pLAT-1 and pFOX-1) and the pPCRScript Cam cloning vector were then electroporated into the E. coli DS clinical strain. Virulence of plasmid-containing E. coli DS strains was enhanced by inoculation in mice.

Antimicrobial agents and in vitro susceptibility testing

Antimicrobial agents and their sources have been described previously.13 Antibiotic-containing discs were used for the detection of antibiotic susceptibility with Mueller–Hinton agar plates (Sanofi Diagnostics Pasteur, Marnes-La-Coquette, France) and a disc diffusion assay (www.sfm.asso.fr). MICs were determined by agar dilution method with an inoculum of 4 log10 cfu per spot and by broth dilution method (Mueller–Hinton broth; bioMérieux) with a final inoculum of 6 log10 cfu/mL.13 Results were interpreted according to the CLSI guidelines.14 MBCs were also determined as described.15 The inoculum effect on the MIC values of piperacillin/tazobactam and cefepime for E. coli DS (pPCRScript), E. coli DS (pLAT-1) and E. coli DS (pFOX-1) was tested with an inoculum of 4, 5, 6, 7, 8 or 9 log10 cfu/mL.

Bactericidal activity of ß-lactams was also determined with cultures of E. coli DS (pLAT-1) or E. coli DS (pFOX-1) to a final concentration of 6 log10 cfu/mL16 that corresponds to the inoculum used in the mouse infection model.

Determination of LD100 and LD50

Six-week-old pathogen-free Swiss female mice (Harlan, Gannat, France) were used. The bacterial inoculum was prepared from a culture of E. coli DS (pPCRScript). Groups of 10 mice were injected intraperitoneally with 0.5 mL of sterile talcum-saline solution (125 mg/mL) containing inocula varying from 102 to 1010 cfu via a 26-gauge syringe.17 Talcum was added to the bacterial inoculum to enhance infection. Mouse mortality was recorded every hour. The lack of lethal effect of talcum alone was assessed. The lethal dose 100 (LD100) and the lethal dose 50 (LD50) (inoculum able to kill 100% or 50% of the animals infected over 24 h, respectively) were calculated using the Probit method.18

In vivo growth curves

In vivo growth curves were determined by inoculating groups of 10 mice intraperitoneally with ~6 log10 cfu and sterile talcum (125 mg/mL). After anaesthetizing the mice with volatile halothane (Belamont, Neuilly sur Seine, France), blood samples were obtained by intracardiac puncture and peritoneal washes were performed by injecting 1 mL of sterile saline intraperitoneally. Analysis of bacterial population was performed by plating 0.1 mL of 10-fold serial dilutions of the blood and peritoneal fluid samples onto TS agar plates. Blood and intraperitoneal fluid samples were obtained from three mice after 3, 6, 9 and 12 h of infection.

Mouse peritonitis model

Peritonitis was established by intraperitoneal injection of 0.5 mL of diluted E. coli DS (pPCRScript), E. coli DS (pLAT-1) or E. coli DS (pFOX-1) suspension corresponding to the LD100 (~6 log10 cfu) and sterile talcum (125 mg/mL).17 Treatment of mice was administered as a single dose of 0.2 mL of ß-lactam or saline solution by subcutaneous injection in the neck 2 h after infection.

Determination of the 50% effective dose of ß-lactams

The effect of four ß-lactam molecules (piperacillin/tazobactam, ceftazidime, cefepime and imipenem) was studied in the mouse model of peritonitis with E. coli DS harbouring plasmids pPCRScript, pLAT-1 or pFOX-1. For each combination of drug and strain, the 50% effective dose (ED50 the single dose giving protection to 50% of the mice), was determined from two trials and calculated using two models including the Hill equation.19 In the first trial, six mice in each of four groups were given the drug in 10-fold dilutions from 0.1 to 100 mg/kg. The observation period was 5 days, a time at which no further death occurred. Cumulative survival rates were recorded 12 h after infection every hour for the day following infection and twice daily for subsequent days of observation.

Statistical analysis

Each strain (consisting of a control group and of each group of six animals receiving the various doses of antibiotics) was fitted simultaneously. The survival versus time data were fitted using mixed effect modelling with the software NONMEM (Version V, level 1).20 First, we compared two structural models, a logistic growth model and a linear first-order absorption model, in order to describe the bacterial growth in the animals. The two models used the bacterial count measured at the time of injection as input dose (CB0) and a lag time (Tlag). The two models were compared using the Akaike information criterion.21

An inter-individual variability parameter was considered for Tlag, CB0 and k or ka and modelled as {theta} exp({eta}), where {theta} is the fixed effect parameter and {eta} is the inter-individual variability parameter with mean zero and variance {omega}2. Each batch of six animals was considered as an individual with an additive error (this homoscedastic model always performed better than the heteroscedastic model). The 95% confidence interval (95% CI) of the estimates was calculated by profiling the log likelihood. Spearman's rank-correlation test was used to test the correlation between MIC values (plate dilution method) and ED50 MIC values (broth dilution method) and ED50 and MBC values and ED50. P values of less than 0.05 were considered significant.


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Susceptibility testing and killing curves

Using an agar dilution method, E. coli DS (pLAT-1) and E. coli DS (pFOX-1) were susceptible to cefepime and imipenem, whereas they had decreased susceptibility to piperacillin/tazobactam and ceftazidime (Table 1). MICs determined in broth gave slighter higher values (Table 1). MBC values of these ß-lactams were close to the MIC values (Table 1).


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  		Table 1. MICs and MBCs of ß-lactams for E. coli DS clinical strain harbouring plasmids pPCRScript, pLAT-1 or pFOX-1

 
Time–killing curves for cultures of E. coli DS (pFOX-1) shown in Figure 1 were superimposable over those obtained for E. coli DS (pLAT-1) (data not shown). As expected, the initial killing rate increased with antibiotic concentrations and time. However, a 24 h regrowth was observed in all cases, suggesting that MBC values are higher than 2x MIC values for all the ß-lactams tested. Among the four antibiotics tested, cefepime had the highest killing rate and was the most efficient even at concentrations below the MIC value. In contrast, piperacillin/tazobactam was the least efficient ß-lactam. An inoculum effect was more important for piperacillin/tazobactam than cefepime (Table 2). By increasing the inoculum size to 7 log10 cfu/mL, the MIC of cefepime (2–8 mg/L) still remained below the in vivo peak concentration of this antibiotic (112.9±21 mg/L).22


Figure 1
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  		Figure 1. In vitro time–killing curves for E. coli DS (pFOX-1). Piperacillin/tazobactam (a), ceftazidime (b), cefepime (c) and imipenem (d) were studied at various concentrations. Filled diamonds, control (saline solution); open diamonds, 0.5x MIC; filled triangles, 1x MIC; crosses, 2x MIC. Error bars for each data point, representing duplicate experiments, are also shown.

 


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  		Table 2. In vitro susceptibility of E. coli DS clinical strain harbouring plasmids pPCRScript, pLAT-1 or pFOX-1 to piperacillin/tazobactam and cefepime at different inocula

 
Experimental model of peritonitis

The calculated LD50 and LD100 for E. coli DS (pPCRScript) were 4.6 log10 and 6 log10 cfu, respectively. No difference was seen for E. coli DS (pLAT-1) or E. coli DS (pFOX-1) (data not shown). Intraperitoneal injection of 6 log10 cfu (LD100) of E. coli DS (pPCRScript) resulted in an exponential growth in vivo in both peritoneal fluid and blood (data not shown). Within 3 h of inoculation, the bacterial concentrations reached 7 log10 cfu per millilitre in peritoneal fluid and 5 log10 cfu per millilitre in blood, indicating that the peritoneal infection was rapidly associated with septicaemia. Morphological analysis of peritonitis fluid identified infection signs [high concentrations of polynuclear leucocytes (data not shown)].

In vivo efficacy of ß-lactams

For each strain tested, animals were inoculated with ~6 log10 cfu (LD100). Mortality in the non-treated group was 100%. Each strain (consisting of a control group and each group of six animals treated with various concentrations of antibiotics) was fitted at a time. First, we compared two structural models, namely, a logistic growth model and a first-order absorption model in order to describe the bacterial growth in the animals. The two models used the bacterial count measured at the time of injection as input dose (CB0) and a lag time (Tlag). The first-order absorption model performed better than the logistic growth model and was used to determine the ED50s (Table 3). MBC and MIC values of ß-lactams determined for E. coli DS strains by the plate and broth dilution had significant correlation with the ED50s (Spearman {rho} = 0.81, P < 0.008; {rho} = 0.84, P < 0.006 and {rho} = 0.84, P < 0.006, respectively). E. coli DS (pLAT-1) and E. coli DS (pFOX-1) strains were susceptible to cefepime and imipenem, which correlated with the efficacy of these molecules in the mouse model of infection (ED50s of 0.12 and 0.56 mg/kg, respectively, Table 3). The ED50 of ceftazidime for E. coli DS (pLAT-1) was relatively low (1.46 mg/kg) when compared with the ED50 for E. coli DS (pFOX-1) (7.45 mg/kg), correlating with the MIC values of ceftazidime for the two strains. This result suggested that ceftazidime may be efficient for treating infections due to E. coli DS (pLAT-1), but not for those due to E. coli DS (pFOX-1). Among the ß-lactams tested, cefepime was the most efficient antibiotic, followed by imipenem.


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  		Table 3. Comparative activities of piperacillin/tazobactam, ceftazidime, cefepime and imipenem against infection caused by E. coli DS strain harbouring plasmids pPCRScript, pLAT-1 or pFOX-1

 
The ED50 of piperacillin/tazobactam ranged from 8.53 mg/kg for E. coli DS (pPCRScript) to 624 mg/kg for E. coli DS (pFOX-1) underlining the lack of efficacy of piperacillin/tazobactam in the mouse model of infection.


   Discussion
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The aim of this work was to study the in vitro and in vivo efficacies of broad-spectrum ß-lactams for treating infections due to E. coli harbouring plasmid-mediated cephalosporinases expressed from the same plasmid backbone in the same E. coli strain. A mouse peritonitis model resulting in a reproducible lethal infection was used to study the correlation between MIC values, bactericidal activity and ED50s of ß-lactams for E. coli strains producing two main types of plasmid-encoded cephalosporinases. Plasmid-mediated cephalosporinases observed in many enterobacterial species usually confer at least resistance to cephalosporins, such as ceftazidime and cefotaxime, that are not antagonized by clavulanic addition. In the absence of additional mechanisms of resistance, these isolates remain susceptible to cefepime, cefpirome and carbapenems.

As reported by previous studies analysing also other types of plasmid-mediated cephalosporinases expressed in E. coli and K. pneumoniae,23,24 cefepime was subjected to an in vitro inoculum effect. Although the rate of hydrolysis of cefepime by plasmid-mediated cephalosporinases is low, the inoculum effect may be due to several factors including amount of enzymes produced in the periplasmic space of bacterial cells and tight binding of ß-lactamases to the ß-lactam molecules. In vivo, our experiments showed that cefepime and imipenem were efficient for treating high inoculum infections with E. coli strains producing plasmid-mediated AmpC-type ß-lactamases. These results correlate with data reporting the in vivo efficacy of these ß-lactams for treating experimental respiratory infections with K. pneumoniae expressing plasmid-mediated cephalosporinases (ACT-1,25 CMY-226 and FOX-527). Despite relatively low MIC values determined by a plate dilution method, piperacillin/tazobactam failed to treat experimental infections, indicating that in vitro susceptibility testing was not a good predictive factor of its in vivo efficacy. The discrepancy between in vitro and in vivo results for piperacillin/tazobactam may be explained in part by an inoculum effect at the site of infection. An inoculum effect was also reported for piperacillin/tazobactam and producers of clavulanic-acid-inhibited extended-spectrum ß-lactamases but it was, in that case, lower than that of cefepime.28

Piperacillin/tazobactam-containing therapy may not be recommended as a first-line therapy for treating life-threatening infections such as peritonitis in geographical regions with high prevalence of plasmid-mediated cephalosporinase producers. This study underlines the need to detect and to survey clinical isolates that produce these plasmid-mediated cephalosporinases for critical interpretation of MIC results. On the basis of the obtained results, we remain quite confident in the good therapeutic value of cefepime for treating infections due to enterobacterial isolates producing plasmid-mediated cephalosporinases.

Imipenem showed high efficacy in this model of infection. Further work will be performed to determine whether similar results can be obtained with meropenem and ertapenem. Several reports have underlined that selection of carbapenem-resistant isolates may occur in enterobacterial isolates expressing plasmid-mediated cephalosporinases.29–32 In those cases, combined mechanisms of resistance result from porin modifications and plasmid-mediated cephalosporinase expression. However, in those cases, carbapenems may still retain the best therapeutic efficacy.27

Finally, a further step may be to study the in vivo activity of cefepime and cefpirome against experimental infections due to those recently reported extended-spectrum plasmid- and chromosome-encoded cephalosporinases mostly from E. coli that significantly hydrolyse cefepime.33,34


   Funding
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This work was funded by a grant from the Ministère de la Recherche (grant UPRES-EA 3539), Université Paris XI, Paris, France and the European Community (6th PCRD, LSHM-CT-2003-503-335).


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None to declare.


   Footnotes
 
{dagger} These authors contributed equally to this work. Back

{ddagger} Present address. Service de Bactériologie-Hygiène, Hôpital Tenon, 4 rue de la Chine, 75970 Paris Cedex 20, France. Back

§ Present address. Department of Microbiology Immunology, University of Western Ontario, London, Canada. Back


   Acknowledgements
 
We thank E. Tzelepi and J. C. Perez-Diaz for providing strains Klebsiella pneumoniae P20 (HPI-5) and Escherichia coli TG1 (pGL3), respectively, and Thierry Naas and Nicolas Fortineau for comments on this work.


   References
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1 Philippon A, Arlet G, Jacoby GA. Plasmid-determined AmpC-type ß-lactamases. Antimicrob Agents Chemother (2002) 46:1–11.[Free Full Text]

2 Tzouvelekis LS, Tzelepi E, Mentis AF, et al. Identification of a novel plasmid-mediated ß-lactamase with chromosomal cephalosporinase characteristics from Klebsiella pneumoniae. J Antimicrob Chemother (1993) 31:645–54.[Abstract/Free Full Text]

3 Jacoby GA, Tran J. Sequence of the MIR-1 ß-lactamase gene. Antimicrob Agents Chemother (1999) 43:1759–60.[Abstract/Free Full Text]

4 Papanicolaou GA, Medeiros AA, Jacoby GA. Novel plasmid-mediated ß-lactamase (MIR-1) conferring resistance to oxyimino- and alpha-methoxy ß-lactams in clinical isolates of Klebsiella pneumoniae. Antimicrob Agents Chemother (1990) 34:2200–9.[Abstract/Free Full Text]

5 Bradford PA, Urban C, Mariano N, et al. Imipenem resistance in Klebsiella pneumoniae is associated with the combination of ACT-1, a plasmid-mediated AmpC ß-lactamase, and the loss of an outer membrane protein. Antimicrob Agents Chemother (1997) 41:563–9.[Abstract/Free Full Text]

6 Gaillot O, Clement C, Simonet M, et al. Novel transferable ß-lactam resistance with cephalosporinase characteristics in Salmonella enteritidis. J Antimicrob Chemother (1997) 39:85–7.[Abstract/Free Full Text]

7 Fortineau N, Poirel L, Nordmann P. Plasmid-mediated and inducible cephalosporinase DHA-2 from Klebsiella pneumoniae. J Antimicrob Chemother (2001) 47:207–10.[Abstract/Free Full Text]

8 Gonzalez Leiza M, Perez-Diaz JC, Ayala J, et al. Gene sequence and biochemical characterization of FOX-1 from Klebsiella pneumoniae, a new AmpC-type plasmid-mediated ß-lactamase with two molecular variants. Antimicrob Agents Chemother (1994) 38:2150–7.[Abstract/Free Full Text]

9 Bauernfeind A, Schneider I, Jungwirth R, et al. A novel type of AmpC ß-lactamase, ACC-1, produced by a Klebsiella pneumoniae strain causing nosocomial pneumonia. Antimicrob Agents Chemother (1999) 43:1924–31.[Abstract/Free Full Text]

10 Nadjar D, Rouveau M, Verdet C, et al. Outbreak of Klebsiella pneumoniae producing transferable AmpC-type ß-lactamase (ACC-1) originating from Hafnia alvei. FEMS Microbiol Lett (2000) 187:35–40.[Web of Science][Medline]

11 Arlet G, Barrett TJ, Butaye P, et al. Salmonella resistant to extended-spectrum cephalosporins: prevalence and epidemiology. Microbes Infect (2006) 8:1945–54.[CrossRef][Web of Science][Medline]

12 Sambrook J, Russell DW. Molecular Cloning: A Laboratory Manual. (2001) Third Edition. New York: Cold Spring Harbor Laboratory Press.

13 Philippon LN, Naas T, Bouthors AT, et al. OXA-18, a class D clavulanic acid-inhibited extended-spectrum ß-lactamase from Pseudomonas aeruginosa. Antimicrob Agents Chemother (1997) 41:2188–95.[Abstract/Free Full Text]

14 Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Fifteenth Informational Supplement M100-S115 (2005) Wayne, PA, USA: CLSI.

15 National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically-Sixth Edition: Approved Standard M7-A6 (2000) Villanova, PA, USA: NCCLS.

16 Pearson RR, Steigbeigel RT, Davis HT, et al. Method for reliable determination of minimal lethal antibiotic concentrations. Antimicrob Agents Chemother (1980) 18:699–708.[Abstract/Free Full Text]

17 Pechere JC, Vladoianu IR. Development of resistance during ceftazidime and cefepime therapy in a murine peritonitis model. J Antimicrob Chemother (1992) 2:563–73.

18 Finney DJ. Probit Analysis (1971) Third Edition. Cambridge, UK: Cambridge University Press.

19 Holford NH, Sheiner LB. Kinetics of pharmacologic response. Pharmacol Ther (1982) 16:143–66.[CrossRef][Web of Science][Medline]

20 Sheiner LB, Beal SL, Boeckmann A, NONMEM. Users guide 1-6. In: Regents of the University of California. California. 1979–99.

21 Yamaoka K, Nakagawa T, Uno T. Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm (1978) 6:165–75.[CrossRef][Web of Science][Medline]

22 Burgess DS, Hastings RW, Hardin TC. Pharmacokinetics of cefepime administred by intermittent and continuous infusion. Clin Ther (2000) 22:66–75.[CrossRef][Web of Science][Medline]

23 Kang CI, Pai H, Kim SH, et al. Cefepime and the inoculum effect in tests with Klebsiella pneumoniae producing plasmid-mediated AmpC-type ß-lactamase. J Antimicrob Chemother (2004) 54:1130–3.[Abstract/Free Full Text]

24 Quennan AM, Foleno B, Gownley C, et al. Effects of inoculum and ß-lactamase activity in AmpC- and extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae clinical isolates tested by using NCCLS ESBL methodology. J Clin Microbiol (2004) 42:269–75.[Abstract/Free Full Text]

25 Padilla E, Alonso D, Domenech-Sanchez A, et al. Effect of porins and plasmid-mediated AmpC ß-lactamases on the efficacy of ß-lactams in rat pneumonia caused by Klebsiella pneumoniae. Antimicrob Agents Chemother (2006) 50:2258–60.[Abstract/Free Full Text]

26 Pichardo C, Rodriguez-Martinez JM, Pachon-Ibanez ME, et al. Efficacy of cefepime and imipenem in experimental murine pneumonia caused by porin-deficient Klebsiella pneumoniae producing CMY-2 ß-lactamase. Antimicrob Agents Chemother (2005) 49:3311–6.[Abstract/Free Full Text]

27 Pichardo C, Del Carmen Conejo M, Bernabeu-Wittel M, et al. Activity of cefepime and carbapenems in experimental pneumonia caused by porin-deficient Klebsiella pneumoniae producing FOX-5 ß-lactamase. Clin Microbiol Infect (2005) 11:31–8.[CrossRef][Web of Science][Medline]

28 Thomson KS, Moland ES. Cefepime, piperacillin–tazobactam, and the inoculum effect in tests with extended-spectrum ß-lactamase-producing Enterobacteriaceae. Antimicrob Agents Chemother (2001) 45:3548–54.[Abstract/Free Full Text]

29 Odeh R, Kelkar S, Hujer AM, et al. Broad resistance due to plasmid-mediated AmpC ß-lactamases in clinical isolates of Escherichia coli. Clin Infect Dis (2002) 35:140–5.[CrossRef][Web of Science][Medline]

30 Poirel L, Héritier C, Spicq C, et al. In vivo acquisition of high-level resistance to imipenem in Escherichia coli. J Clin Microbiol (2004) 42:3831–4.[Abstract/Free Full Text]

31 Stapleton PD, Shannon KP, French GL. Carbapenem resistance in Escherichia coli associated with plasmid-mediated CMY-4 ß-lactamase production and loss of an outer membrane protein. Antimicrob Agents Chemother (1999) 43:1206–10.[Abstract/Free Full Text]

32 Martinez-Martinez L, Pascual A, Hernandez-Alles D, et al. Roles of ß-lactamases and porins in activities of carbapenems and cephalosporins against Klebsiella pneumoniae. Antimicrob Agents Chemother (1999) 43:1669–73.[Abstract/Free Full Text]

33 Mammeri H, Poirel L, Fortineau N, et al. Naturally occurring extended-spectrum cephalosporinases in Escherichia coli. Antimicrob Agents Chemother (2006) 50:2573–6.[Abstract/Free Full Text]

34 Wachino J, Kurokawa H, Suzuki S, et al. Horizontal transfer of blaCMY-bearing plasmids among clinical Escherichia coli and Klebsiella pneumoniae isolates and emergence of cefepime-hydrolyzing CMY-19. Antimicrob Agents Chemother (2006) 50:534–41.[Abstract/Free Full Text]


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AmpC {beta}-Lactamases
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