Effect of inoculum size on the antibacterial activity of cefpirome and cefepime against Klebsiella pneumoniae strains producing SHV extended-spectrum β-lactamases

Bedenić, Branka; Beader, Nataša; Zagar, Z

doi:10.1046/j.1198-743x.2001.x

Cited by 32 publications

(24 citation statements)

References 17 publications

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“…2. As anticipated from other previous investigations (1,3,6,9,12,20), the killing of piperacillin was considerably reduced as the baseline inoculum increased from 1 ϫ 10 5 to 1 ϫ 10 8 CFU/ml. Significant reduction in bacterial burden (Ͼ2-log drop at 24 h) was observed with 4ϫ MIC when the baseline inoculum was 1 ϫ 10 5 CFU/ml ( Fig.…”

Section: Resultssupporting

confidence: 68%

“…Such a modeling approach could be used as a decision-support tool for dosing regimen design, and it may be used at different stages of drug development. It is often observed that killing could be more pronounced against a lower bacterial burden than with a higher bacterial burden (1,3,18). Capturing this phenomenon in a mathematical model would require a killing function dependent on bacterial burden.…”

mentioning

confidence: 99%

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Mathematical Modeling To Characterize the Inoculum Effect

Bhagunde¹,

Chang

Singh

et al. 2010

Antimicrob Agents Chemother

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Killing by beta-lactams is well known to be reduced against a dense bacterial population, commonly known as the inoculum effect. However, the underlying mechanism of this phenomenon is not well understood. We proposed a semimechanistic mathematical model to account for the reduced in vitro killing observed. Time-kill studies were performed with 4 baseline inocula (ranging from approximately 1 ؋ 10 5 to 1 ؋ 10 8 CFU/ml) of Escherichia coli ATCC 25922 (MIC, 2 mg/liter). Constant but escalating piperacillin concentrations used ranged from 0.25؋ to 256؋ MIC. Serial samples were taken over 24 h to quantify viable bacterial burden, and all the killing profiles were mathematically modeled. The inoculum effect was attributed to a reduction of effective drug concentration available for bacterial killing, which was expressed as a function of the baseline inoculum. Biomasses associated with different inocula were examined using a colorimetric method. Despite identical drug-pathogen combinations, the baseline inoculum had a significant impact on bacterial killing. Our proposed mathematical model was unbiased and reasonable in capturing all 28 killing profiles collectively (r 2 ‫؍‬ 0.88). Biomass was found to be significantly more after 24 h with a baseline inoculum of 1 ؋ 10 8 CFU/ml, compared to one where the initial inoculum was 1 ؋ 10 5 CFU/ml (P ‫؍‬ 0.002). Our results corroborated previous observations that in vitro killing by piperacillin was significantly reduced against a dense bacterial inoculum. This phenomenon can be reasonably captured by our proposed mathematical model, and it may improve prediction of bacterial response to various drug exposures in future investigations.

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Section: Resultssupporting

confidence: 68%

mentioning

confidence: 99%

Mathematical Modeling To Characterize the Inoculum Effect

Bhagunde¹,

Chang

Singh

et al. 2010

Antimicrob Agents Chemother

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“…Factors that could contribute to these effects are the number, type, and amount of ␤-lactamases; outer membrane permeability; efflux; number and susceptibility of penicillin-binding protein targets; and phase of growth. Strain dependence has also been observed (1). In this work, we sought to correlate the NCCLS ESBL testing protocols and inoculum effects with levels and hydrolysis properties of ESBL and AmpC ␤-lactamases.…”

Section: Discussionmentioning

confidence: 99%

Effects of Inoculum and β-Lactamase Activity in AmpC- and Extended-Spectrum β-Lactamase (ESBL)-Producing Escherichia coli and Klebsiella pneumoniae Clinical Isolates Tested by Using NCCLS ESBL Methodology

et al. 2004

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Escherichia coli and Klebsiella pneumoniae isolates with extended-spectrum ␤-lactamases (ESBLs) or AmpC cephalosporinases generally respond as predicted to NCCLS tests for ESBL production. However, inoculum size may affect MICs. The effect of inoculum level in clinical isolates expressing ␤-lactamases were studied at inocula within 0.5 log unit of the standard inoculum, using broth microdilution methodology with ceftazidime, cefotaxime, cefepime, cefpodoxime, and aztreonam. Strains with TEM-1 or no ␤-lactamases gave consistent MIC results with inocula of 10 5 and 10 6 CFU/ml. When the bacteria were screened for ESBL production and the lower inoculum was used, several strains with ESBLs, including CTX-M-10, TEM-3, TEM-10, TEM-12, TEM-6, SHV-18, and K1, gave false-negative results for one or more antimicrobial agents (MICs below the NCCLS screening concentration for detecting suspected ESBLs). When the higher inoculum was used, MICs of at least one antimicrobial agent increased at least fourfold in strains producing TEM-3, TEM-10, TEM-28, TEM-43, SHV-5, SHV-18, and K1. All antimicrobial agents showed an inoculum effect with at least one ESBL producer. Confirmatory clavulanate effects were seen for both inocula for all ESBL-producing strains with all antimicrobial agents tested, except for the CTX-M-10-producing E. coli with ceftazidime and the SHV-18-producing K. pneumoniae with cefotaxime. In kinetic studies, cefpodoxime and cefepime were hydrolyzed by ESBLs in a manner similar to that of cefotaxime. When total ␤-lactamase activity and hydrolysis parameters were evaluated, however, no single factor was predictive of inoculum effects. These results indicate that the NCCLS screening and confirmation tests are generally predictive of ESBL production, but false-negative results can arise when a lower inoculum is used in testing.Extended-spectrum ␤-lactamases (ESBLs) are considered one of the most important resistance mechanisms for penicillins and cephalosporins when these enzymes are produced in Escherichia coli and Klebsiella spp. (7). The genes encoding these enzymes are most often carried by multidrug-resistant plasmids and are capable of being readily transferred among different species of the family Enterobacteriaceae (2). Infections caused by ESBL-producing pathogens may not be responsive to treatment by most penicillins and cephalosporins (32). Hence, their appearance in a hospital setting creates a situation in which ESBL-producing organisms should be identified quickly so that appropriate antibiotic usage and containment measures can be implemented (21).Clinical microbiologists have devised a number of testing strategies based on phenotypic testing to identify putative ESBL-producing organisms. One testing strategy is the recently adopted set of NCCLS guidelines for E. coli, Klebsiella pneumoniae, and Klebsiella oxytoca isolates with elevated cephalosporin MICs (16). In the protocol for MIC testing, strains with cefotaxime, ceftazidime, ceftriaxone, or aztreonam MICs of Ն2 g/ml or cefpodoxime MICs of Ն8 g/m...

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“…This so called "inoculum effect, " in which drug MICs increase dramatically in the presence of an increased bacterial load despite apparent initial susceptibility, has been observed in both in vitro and animal studies [25][26][27][28][29][30][31]. Highlighting one experience, Burgess and colleagues evaluated cefepime and meropenem against standard-and high-inoculum ESBL Klebsiella pneumoniae infections [32].…”

Section: Cefepimementioning

confidence: 99%

The Use of Noncarbapenem β-Lactams for the Treatment of Extended-Spectrum β-Lactamase Infections

Tamma¹,

Rodríguez‐Baño

2017

Clinical Infectious Diseases

152

117

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The continued rise in infections caused by extended-spectrum β-lactamase (ESBL)-producing pathogens is recognized globally as one of the most pressing concerns facing the healthcare community. Carbapenems are widely regarded as the antibiotics of choice for the treatment of ESBL-producing infections, even when in vitro activity to other β-lactams has been demonstrated. However, indiscriminant carbapenem use is not without consequence, and carbapenem overuse has contributed to the emergence of carbapenem-resistant Enterobacteriaceae. The use of non-carbapenem β-lactams for the treatment of ESBL infections has yielded conflicting results. In this review, we discuss the available data for the use of cephamycins, cefepime, piperacillin-tazobactam, ceftolozane-tazobactam, and ceftazidime-avibactam for the treatment of ESBL infections.

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Effect of inoculum size on the antibacterial activity of cefpirome and cefepime against Klebsiella pneumoniae strains producing SHV extended-spectrum β-lactamases

Cited by 32 publications

References 17 publications

Mathematical Modeling To Characterize the Inoculum Effect

Mathematical Modeling To Characterize the Inoculum Effect

Effects of Inoculum and β-Lactamase Activity in AmpC- and Extended-Spectrum β-Lactamase (ESBL)-Producing Escherichia coli and Klebsiella pneumoniae Clinical Isolates Tested by Using NCCLS ESBL Methodology

The Use of Noncarbapenem β-Lactams for the Treatment of Extended-Spectrum β-Lactamase Infections

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