Long-term multiple micronutrient supplementation can improve LV volumes and LVEF and QoL scores in elderly patients with heart failure due to LV systolic dysfunction.

A clinical isolate of Bacteroides vulgatus was resistant to tetracycline, clindamycin, ampicillin, cephaloridine, cefoxitin, and other 13-lactam antibiotics except imipenem. 13-Lactam resistance was mediated by a membraneassociated, clavulanate-sensitive cephalosporinase capable of degrading cephalosporins and penicillins. Cefoxitin also was degraded but at a slow rate. The cefoxitin resistance (Fxr) ,-Lactamase production is the most important mechanism of resistance to P-lactam antibiotics in gram-negative bacteria, and the Bacteroides fragilis group possesses a wide array of these enzymes. In general, the organisms are moderately or highly resistant to many cephalosporins and penicillins, but a-methoxyl cephamycins such as cefoxitin and the carbapenems have been highly active against Bacteroides species. In the United States, for example, imipenem resistance rates are presently low, at about 0.2%, and cefoxitin resistance (Fxr) rates have ranged up to 16% during the past decade (37, 38). High rates of Fxr are cause for concern since Fxr strains usually encountered are crossresistant to most other P-lactams (38). In the case of strains that possess metallo-p-lactamases, the cross-resistance includes the carbapenems (8, 39).Resistance of Bacteroides species to cefoxitin may involve a number of mechanisms including altered drug permeability, alterations of penicillin binding proteins, 1-lactamase production, or a combination of mechanisms (8,10,41). Excluding the relatively rare imipenem-hydrolyzing metalloenzymes, several P-lactamases capable of cefoxitin degradation have been described. These are generally cephalosporinases with a slow rate of cefoxitin hydrolysis, and they are sensitive to inhibition by clavulanate (9, 13). Recently, Aldridge et al. (1) have found that >93% of Fxr strains were still sensitive to 3-lactam-clavulanate combinations. Thus, based on these criteria, it is possible that the slow cefoxitinhydrolyzing cephalosporinases are one of the most widely disseminated mechanisms of Fxr in the Bacteroides species. In this regard, it has been suggested that these P-lactamases are not novel enzymes but rather that the strains are Fxr * Corresponding author.because of the production of much greater than normal levels of the conventional Bacteroides enzyme (36).The occurrence of high regional Fxr rates indicates the potential for clonal dissemination and/or horizontal transfer of the resistance phenotype. The transfer of Fxr by a conjugation-like mechanism has been demonstrated; however, plasmids were not involved in the transfer (10). The Fxr phenotype was mediated by the acquisition of a new P-lactamase. The present study was initiated to define the genetic basis for transmissible Fxr in Bacteroides species.The results revealed a novel genetic locus designated cfx4, which encodes an Ambler molecular class A 13-lactamase that appears to have diverged significantly from all other class A enzymes. MATERIALS AND METHODSBacterial strains and growth. Bacteroides cells were cultured anaerobically in su...

Bacteroides frgigli& CS30 is a clinical isolate resistant to high concentrations of benzylpenicillin and cephaloridine but not to cephamycin or penem antibiotics. fl-Lactam resistance is mediated by a chromosomally encoded cephalosporinase produced at a high level. The gene encoding this 13-lactamase was cloned from genomic libraries constructed in Escherichia coli and then mated with B. fragilis 638 for identification of ampicillin-resistant (Apr) strains. Apr transconjugants contained a nitrocefin-reactive protein with the physical and enzymatic properties of the original CS30 isolate. The (3-lactamase gene (cepA) was localized by deletion analysis and subcloned, and its nucleotide sequence was determined. The 903-bp cepA open reading frame encoded a 300-amino-acid precursor protein (predicted molecular mass, 34,070 Da). A 13-lactamase-deficient mutant strain of B. fiugilis 638 was constructed by insertional inactivation with the cepA gene of CS30, demonstrating strict functional homology between these chromosomal 13-lactamase genes. An extensive comparison of the CepA protein sequence by alignment with other 13-lactamases revealed the strict conservation of at least four elements common to Ambler class A. A further comparison of the CepA protein sequence with protein sequences of (-lactamases from two other Bacteroides species indicated that they constitute their own distinct subgroup of class A 13-lactamases.Bacteroides fragilis is responsible for approximately half of all human anaerobic infections and is the most common anaerobe recovered from clinical specimens (12). Numerous reports of B. fragilis isolates resistant to a variety of P-lactam antibiotics indicate that these organisms are becoming increasingly refractory to treatment with these drugs. The primary mechanism of 1-lactam resistance in Bacteroides species is the production of ,B-lactamase (40). At least four types of P-lactamase have been described for members of the B. fragilis group, but the most common type is a constitutively produced, chromosomally encoded cephalosporinase having no activity against cefoxitin or imipenem.This "endogenous" P-lactamase is present in over 90% of clinical isolates tested (10). Unlike the class C chromosomally encoded P-lactamases of members of the family Enterobacteriaceae, the B. fragilis P-lactamase has an isoelectric point in the acid range and is susceptible to inhibition by clavulanic acid and sulbactam, placing it in group 2e in the Bush classification scheme (8).Regulation of the endogenous B. fragilis j-lactamase has not been extensively studied, but this enzyme may be growth rate regulated, with maximal activity occurring 3 h into the stationary phase (7). With regard to the production of the endogenous cephalosporinase, others have grouped B.fragilis clinical isolates into three expression classes (18). Low-level j-lactamase producers are susceptible to all 3-lactams, the MICs of benzylpenicillin and cephaloridine being <2 and <16 ,ug/ml, respectively. For intermediate-level 3-lactamase producers, th...

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