Bactericidal interactions of a beta-lactam and beta-lactamase inhibitors in experimental Pseudomonas aeruginosa endocarditis caused by a constitutive overproducer of type Id beta-lactamase

Bayer, Arnold S.; Selecky, M; Babel, Karen; Hirano, L; Yih, J; Parr, Thomas

doi:10.1128/aac.31.11.1750

Cited by 11 publications

(5 citation statements)

References 30 publications

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“…This occurred more frequently with sulbactam (four of four strains tested) than it did with clavulanate (one of four strains tested). In contrast, Bayer et al (2) found no in vitro synergy between sulbactam or clavulanate plus ceftazidime for a constitutive class I 3-lactamase-overproducing strain of P.…”

Section: Methodsmentioning

confidence: 91%

Influence of beta-lactamase inhibitors on the potency of their companion drug with organisms possessing class I enzymes

Cavalieri

Sanders

New

1991

Antimicrob Agents Chemother

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The ability of ,-lactamase inhibitors to induce class I W-lactamases in certain organisms in vitro suggests a potential for antagonism in vivo. Therefore, a study was designed to assess the ability of sulbactam and clavulanate to induce P-lactamases in two strains each of Enterobacter cloacae, Citrobacterfreundii, Serratia marcescens, and Pseudomonas aeruginosa both in vitro and in vivo. Induction in vitro was observed only with S. marcescens and P. aeruginosa and generally only when inhibitor concentrations greater than 2 ,ug/ml were examined. A mouse model of lethal infection, designed to detect in vivo antagonism arising from P-lactamase induction, was used to determine what effect sulbactam and clavulanate would have on the 50% protective doses (PD50s) of cefoperazone and ticarcillin. Antagonism (a significant increase in the PD50) was observed in only 4 of 32 tests. Three of these involved antagonism of cefoperazone by clavulanate, and one involved antagonism of cefoperazone by sulbactam. In 6 of 32 tests, enhancement of efficacy (a significant decrease in PD50) was observed. In four of these, sulbactam enhanced cefoperazone; in one, sulbactam enhanced ticarcillin; and in one, clavulanate enhanced ticarcillin. Four of the six cases of enhancement occurred when the ,I-lactamase inhibitor was given at the time of challenge. None of these positive or negative in vivo effects were predicted by in vitro tests. These data suggest that P-lactamase inhibitors can influence the in vivo potency of their companion drug in both a beneficial and detrimental fashion against organisms with class I P-lactamases and that these effects cannot be predicted from in vitro assays.Previous studies have shown that B-lactamase inhibitors are in vitro inducers of chromosomal, class I P-lactamases in certain strains of the family Enterobacteriaceae and Pseudomonas aeruginosa (4,11,12,16,(18)(19)(20). Quantitatively, clavulanate induces higher levels of ,-lactamase than does sulbactam, although induction with these compounds is usually manifest only at high, clinically unachievable concentrations (6,12,(18)(19)(20). The in vivo effects of these compounds against organisms possessing class I enzymes are unknown. However, the in vitro data suggest that it is possible for these 3-lactamase inhibitors to antagonize the activity of their companion drug in vivo by inducing class I f-lactamases. Clinically, this could result in treatment failure. Since an animal model of lethal infection which can detect in vivo antagonism via induction of class I ,-lactamases has been developed previously (7), a study was designed to (i) use this model to determine the influence of sulbactam and clavulanate on the efficacies of cefoperazone and ticarcillin and (ii) determine whether in vitro tests for induction predicted the results observed in vivo. MATERIALS AND METHODSBacterial strains. Two strains each of Enterobacter cloacae, Citrobacter freundii, Serratia marcescens, and P. aeruginosa were used in this study. These strains were clinical isolates that ...

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Section: Methodsmentioning

confidence: 91%

Influence of beta-lactamase inhibitors on the potency of their companion drug with organisms possessing class I enzymes

Cavalieri

Sanders

New

1991

Antimicrob Agents Chemother

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“…Interestingly, it was previously reported for a model of rabbit endocarditis caused by a Pseudomonas aeruginosa strain that constitutively overproduced a cephalosporinase that the low efficacy of a combination of ceftazidime and dicloxacillin (used as a reversible inhibitor of the cephalosporinase) was due to the high density of bacteria present in the vegetation (2). A synergy between the ,-lactam (ceftazi-VOL.…”

Section: Methodsmentioning

confidence: 99%

“…A synergy between the ,-lactam (ceftazi-VOL. 34,1990 on May 12, 2018 by guest http://aac.asm.org/ Downloaded from dime) and the reversible ,B-lactamase inhibitor (dicloxacillin) was observed in vitro only at a low inoculum (105 CFU/ml), and it was suggested that at a high inoculum (107 CFU/ml), dicloxacillin was slowly hydrolyzed or rendered incapable of rebinding the enzyme (2).…”

Section: Methodsmentioning

confidence: 99%

Ceftriaxone-sulbactam combination in rabbit endocarditis caused by a strain of Klebsiella pneumoniae producing extended-broad-spectrum TEM-3 beta-lactamase

Caron

Gutmann

Bure

et al. 1990

Antimicrob Agents Chemother

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We studied the activity of the combination of sulbactam and ceftriaxone against a Klebsiella pneumoniae strain producing TEM-3, a new extended-broad-spectrum P-lactamase, in an endocarditis model. In vitro, ceftriaxone was strongly inactivated in the presence of TEM-3 (MBC, 128 ,ug/ml with an inoculum of 5 x 105 CFU/ml). A marked inoculum effect was demonstrated with sulbactam: effective concentrations of inhibitor needed to reduce the MIC and MBC of ceftriaxone to similar levels increased from 1 ,ug/ml in the presence of an inoculum of 5 x 105 CFU/ml to 20 ,ig/ml in the presence of an inoculum of 1 x 107 CFU/ml. In vivo, sulbactam given at 200 mg/kg of body weight every 12 h, a dosage higher than that previously reported to be effective against rabbit endocarditis caused by other microorganisms, was not sufficient to restore the complete activity of ceftriaxone given at 30 mg/kg once daily for 4 days. This insufficient activity may be correlated with the presence of a high level of P-lactamase inside the vegetations, as indicated by a quantitative in vitro assay of P-lactamase activity in the cardiac vegetation, suggesting an insufficient inactivation of the extended-broadspectrum ,I-lactamase in vivo.Infections caused by multiresistant pathogens are frequently epidemic and represent a major therapeutic challenge. Drug combinations that include an irreversible P-lactamase inhibitor may be a novel approach to the treatment of those infections caused by P-lactamase-producing strains (4).TEM-3, previously designated CTX-1, is a new constitutively plasmid-mediated extended-broad-spectrum P-lactamase that has recently been described among members of the family Enterobacteriaceae and that was found to be responsible for nosocomial outbreaks in several hospitals in France (3,13,23). In vitro, TEM-3-producing Klebsiella pneumoniae is resistant to all P-lactams except cephamycins and imipenem (3, 23). Irreversible P-lactamase inhibitors such as clavulanic acid and sulbactam reduce the MICs of hydrolyzed f-lactams to normal and seem to be interesting alternatives for the therapy of infections caused by extended-broad-spectrum 3-lactamase-producing strains (13,15).

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“…Selected vegetations were processed for transmission electron microscopy (see below). All other vegetations from individual animals were pooled, weighed, homogenized in 0.5 ml of sterile saline, and then quantitatively cultured(5).Intravegetation bacterial densities were expressed as log1o CFU per gram of vegetations (+SD). Vegetations were considered culture negative if no growth occurred in subcultures of undiluted vegetation homogenates; however, for purposes of statistical comparisons, such culture-negative vegetations were considered to contain c2 log1o CFU/g because of the average size of vegetation undergoing homogenization (s0.01 g)(5).…”

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confidence: 99%

Effects of alginase on the natural history and antibiotic therapy of experimental endocarditis caused by mucoid Pseudomonas aeruginosa

et al. 1992

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The exopolysaccharide (alginate) of mucoid strains ofPseudomonas aeruginosa is believed to be an important virulence factor. The ability of an alginate-depolymerizing enzyme (alginase) to modify the polymorphonuclear leukocyte (PMN)-directed and antibiotic-mediated phagocytosis and killing of mucoid P. aeruginosa was studied both in vitro and in vivo. In vitro, pretreatment of a mucoid P. aeruginosa strain (144MR) resulted in a significant enhancement of PMN phagocytosis and killing of the organism (P < 0.05), to levels similar to that observed with its nonmucoid mate, strain 144NM. Moreover, alginase treatment of the mucoid strain 144MR caused a substantial removal of bacterial cell surface alginate as assessed by immunofluorescence staining with a murine monoclonal antialginate antibody. The experimental endocarditis model was used to evaluate the in vivo effect of alginase in modifying the course of a deep-seated pseudomonal infection caused by mucoid strain 144MR. In right-sided endocarditis, in which PMNs normally mediate spontaneous clearance of the organism from cardiac vegetations (Chemotherapy 35:278-288, 1989), the presence of the alginate exopolysaccharide on strain 144MR was associated with an inability to reduce intravegetation pseudomonal counts over a 13-day postinfection period; in contrast, right-sided vegetations infected with the nonmucoid strain 144NM underwent significant reductions in bacterial densities over this same time (P < 0.05). Administration of alginase intravenously (i.v.) (750 enzyme units per day for 7 days) to animals with right-sided endocarditis caused by the mucoid strain 144MR was associated with a significant reduction in intravegetation pseudomonal counts (P < 0.05), to levels similar to that seen with endocarditis caused by the nonmucoid strain. In left-sided endocarditis caused by mucoid strain 144MR, animals received either no therapy, amikacin (20 or 40 mg/kg twice a day for 7 or 14 days), or amikacin plus alginase (750 U/day [i.v.]). The coadministration of alginase for 14 days with the higher-dose amikacin regimen rendered more left-sided vegetations culture negative than those in animals receiving the antibiotic alone for 7 or 14 days (P = 0.001 and 0.056, respectively). These salutary effects of alginase in vivo were paralleled by the ability of the enzyme to remove the exopolysaccharide from the surface of mucoid pseudomonal cells within cardiac vegetations, as assessed by transmission electron microscopy. Collectively these data indicate that the alginate exopolysaccharide was an important factor in inhibiting clearance of mucoid pseudomonal organisms from vegetations by both PMN-directed and antibiotic-mediated processes; the coadministration of alginase in vivo enhanced the clearances of mucoid pseudomonal strains from such infection foci.

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Bactericidal interactions of a beta-lactam and beta-lactamase inhibitors in experimental Pseudomonas aeruginosa endocarditis caused by a constitutive overproducer of type Id beta-lactamase

Cited by 11 publications

References 30 publications

Influence of beta-lactamase inhibitors on the potency of their companion drug with organisms possessing class I enzymes

Influence of beta-lactamase inhibitors on the potency of their companion drug with organisms possessing class I enzymes

Ceftriaxone-sulbactam combination in rabbit endocarditis caused by a strain of Klebsiella pneumoniae producing extended-broad-spectrum TEM-3 beta-lactamase

Effects of alginase on the natural history and antibiotic therapy of experimental endocarditis caused by mucoid Pseudomonas aeruginosa

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