Comparison of the inoculum effect of cefoxitin and other cephalosporins and of beta-lactamase inhibitors and their penicillin-derived components on the Bacteroides fragilis group

Abstract

We compared the inoculum effects for 109 recent clinical isolates of the Bacteroidesfragilis group of cefoxitin, cefotetan, ceftizoxime, ceftriaxone, and three (3-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) and their penicillin-derived components. Bactericidal activity was assayed and morphologic changes were monitored for selected strains exhibiting a large inoculum effect. Ceftizoxime demonstrated the largest inoculum effect, followed by cefotetan and ceftriaxone. The large inoculum effect of ceftizoxime and ceftriaxone was correlated with filamentous transformation at the high inoculum (108 CFU/ml) and lack of bactericidal activity suggesting drug destruction or inactivation. Cefotetan was bactericidal for B. fragilis isolates but not for other members of the B. fragilis group. Cefoxitin showed the least inoculum effect and was consistently bactericidal at high (108 CFU/ml), standard (106 CFU/ml), and low (104 CFU/ml) inocula, followed by ampicillin-sulbactam. Piperacillin-tazobactam and ticarcillin-clavulanic acid showed an intermediate inoculum effect. The degree of inoculum effect observed generally correlated with bactericidal activity at all inocula.The inoculum effect, a large increase in the MIC occurring with an increase in the inoculum size of a microorganism, is one of the variables that influence susceptibility testing and occurs primarily with beta-lactam antibiotics (7,8,11,16). A number of studies have shown that the Bacteroides fragilis group species produce 1-lactamases and may exhibit an inoculum effect (3,5,7,16,23,24). Sutter et al. (21) have suggested that both large and small inocula should be used to detect resistance of anaerobic bacteria to beta-lactam agents. In a recent review on the inoculum effect, Brook (7) summarized the laboratory experience to date with B. fragilis group species and noted that while some of the cephalosporins had been studied, there was scant data on the P-lactamase inhibitor combinations and their penicillin-derived components (1,3,17,18

In vitro activity of FK037, a new parenteral cephalosporin, against anaerobic bacteria

“…Aminothiazolyl-methoxyimino cephalosporins generally show potent activity against many anaerobic bacteria, while the members of the B. fragilis group show low levels of susceptibility to these compounds (5,10,13 Although the activities of some cephalosporins, such as ceftizoxime, varied depending on inoculum size and medium pH (6,24), the activity of FK037 was not influenced by inoculum size or medium pH, except with a few strains.…”

Comparative activity of ertapenem and piperacillin–tazobactam in a murine systemic infection model with Bacteroides fragilis and Escherichia coli

“…ml 21 ) detected just prior to the first dose. The influence of inoculum size of E. coli and B. fragilis on piperacillin-tazobactam activity has been described in other studies (Goldstein et al, 1991;König et al, 1998;Stearne et al, 2004). König et al (1998) demonstrated that piperacillin activity was diminished at least 128-fold when high inocula of E. coli ATCC 25922 were used.…”

Correlation between In Vitro and In Vivo Activities of GM 237354, a New Sordarin Derivative, against Candida albicans in an In Vitro Pharmacokinetic-Pharmacodynamic Model and Influence of Protein Binding

“…Despite the advantages that MICs offer, especially in the clinical setting, one drawback is the lack of information that they provide concerning antimicrobial activity over time. Several methods yield information not only on killing behavior over time (21,43) (such as killing rates) but also on the duration of the inhibitory activity of the compound, such as the postantibiotic effect. These parameters improve knowledge of the PDs of an anti-infective agent for a set of constant concentrations; however, they do not take into account the PK profiles obtained after dosing in either animals or humans.…”