Bactericidal activity of oxacillin against beta-lactamase-hyperproducing Staphylococcus aureus

Woods, Gail L.; Yam, Paul

doi:10.1128/aac.32.11.1614

Cited by 6 publications

(4 citation statements)

References 20 publications

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“…Bactericidal reductions in viability of 3-log 10 CFU/mL were observed for all strains tested within 2 h following exposure to exebacase. The rapid concentration-dependent bactericidal effect of exebacase was in contrast to the time-dependent cidal activity of vancomycin and oxacillin, two conventional antibiotics that interfere with peptidoglycan biosynthesis, and which showed only about 1-log 10 CFU/mL bactericidal reduction over 3 h, consistent with other reports ( 26 , 27 ). Regrowth at 24 h was observed with exebacase for all isolates in the time-kill assays, a reported phenomenon with lysins ( 21 ).…”

Section: Discussionsupporting

confidence: 91%

Rapid bacteriolysis of Staphylococcus aureus by lysin exebacase

Vila-Farrés

Sauve

et al. 2023

Microbiol Spectr

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Lysins (peptidoglycan hydrolases) are promising new protein-based antimicrobial candidates under development to address rising antibiotic resistance encountered among pathogenic bacteria. Exebacase is an antistaphylococcal lysin and the first member of the lysin class to have entered clinical trials in the United States. In this study, the bacteriolytic activity of exebacase was characterized with time-kill assays, turbidity reduction assays, and microscopy. Three methicillin-susceptible Staphylococcus aureus and three methicillin-resistant S. aureus isolates were tested in time-kill assays over a range of concentrations from 0.25 to 8 × MIC. Exebacase demonstrated a concentration-dependent killing and showed bactericidal activity (≥3 log 10 kill achieved relative to the starting inoculum) within 3 h at 1 × MIC against all strains tested. Dose-dependent lysis by exebacase was, furthermore, observed in the turbidity reduction assay, wherein decreases in initial OD 600 of 50% were observed within ~15 min at concentrations as low as 4 µg/mL. Membrane dissolution, loss of cytoplasmic material, and lysis were confirmed by video and electron microscopy. The demonstrated rapid bacteriolytic effect of exebacase is an important distinguishing feature of this novel modality. IMPORTANCE To guide the development of an investigational new antibacterial entity, microbiological data are required to evaluate the killing kinetics against target organism(s). Exebacase is a lysin (peptidoglycan hydrolase) that represents a novel antimicrobial modality based on degradation of the cell wall of Staphylococcus aureus . Killing by exebacase was determined in multiple assay formats including time-kill assays, wherein reductions of viability of ≥3 log 10 colony-forming units/mL were observed within 3 h for multiple different isolates tested, consistent with very rapid bactericidal activity. Rapid reductions in optical density were likewise observed in exebacase-treated cultures, which were visually consistent with microscopic observations of rapid lysis. Overall, exebacase provides a novel antimicrobial modality against S. aureus , characterized by a rapid cidal and lytic activity.

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Section: Discussionsupporting

confidence: 91%

Rapid bacteriolysis of Staphylococcus aureus by lysin exebacase

Vila-Farrés

Sauve

et al. 2023

Microbiol Spectr

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“…While it is theoretically possible that our results might also be explained by lower virulence of the BOSSA strain, this seems highly unlikely in view of the fact that bacterial titers in vegetations of untreated animals inoculated with either strain were identical both 12 h after infection (8.0 to 8.5 log1o CFU/g) and at sacrifice on day 4 (10.4 to 10.5 log1o CFU/g). Tolerance to the bactericidal effects of oxacillin which we observed with strain 1 (MBC/ MIC ratio, 32) appears to be common among BOSSA isolates (18), but is of uncertain relevance in vivo. Woods and Yam (18) have reported that tolerance to oxacillin among P-lactamase-hyperproducing strains of S. aureus determined by MBC testing did not predict poor bactericidal activity of the drug by time-kill techniques.…”

Section: P-lactamase-hyperproducing S Aureus 731mentioning

confidence: 82%

“…With this regimen, significantly greater reductions in vegetation bacterial titers were observed with the OSSA than with the BOSSA strain (P < 0.05). DISCUSSION Since the recognition that strains for which oxacillin MICs are -1 ,ug/ml constitute a small but significant proportion of recent isolates of S. aureus at some centers (7,18), there has been considerable concern about appropriate therapy of infections due to such strains. Specifically, would a ,-lactam alone prove successful or would such isolates more closely resemble methicillin-resistant S. aureus and fail to respond predictably?…”

Section: Resultsmentioning

confidence: 99%

Efficacy of oxacillin and ampicillin-sulbactam combination in experimental endocarditis caused by beta-lactamase-hyperproducing Staphylococcus aureus

Thauvin-Eliopoulos

Rice

Eliopoulos

et al. 1990

Antimicrob Agents Chemother

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Optimal therapy of infections caused by borderline oxacillin-susceptible, 3-lactamase-hyperproducing Staphylococcus aureus has not been established. We used a rat model of aortic valve endocarditis to examine efficacies of antibiotic regimens against a borderline oxacillin-susceptible strain as compared with a fully susceptible S. aureus strain. Animals were treated with oxacillin alone or in combination with sulbactam or with ampicillin-sulbactam combinations at two dose levels. Infections caused by the borderline susceptible and fully susceptible strains responded equally wel to oxacillin alone, with residual bacterial titers in vegetations falling to 4.8 ± 1.6 and 4.4 ± 1.7 (mean ± standard deviation) log,0 CFU/g, respectively. Addition of sulbactam to oxacillin (1:2) did not enhance the efficacy of oxacillin against either strain in the animal model. A high-dose regimen of ampicillin-sulbactam (2:1) yielding mean (+ standard deviation) levels in serum of 16.8 ± 7.4 and 9.5 ± 1.1 ,ug/ml, respectively, proved equally effective against both strains (bacterial titers, 6.6 log1o CFU/g).However, at lower doses (8.3 + 2.6 and 5.9 ± 2.4 ,ug/ml), the combination showed greater efficacy against the fully susceptible strain, with residual titers of 7.1 + 2.0 versus 9.0 + 1.6 log1o CFU/g (P < 0.05). In vitro studies revealed that the ,B-lactamase inhibitor sulbactam was also a potent inducer of staphylococcal P-lactamase at clinically relevant concentrations. Based on this short-term in vivo therapy study, oxacillin would be predicted to be clinically effective in the therapy of infections caused by borderline oxacillin-susceptible strains of S. aureus, while the combination of ampicillin with sulbactam appears to be inferior to oxacillin alone against such infections.In 1986, McDougal and Thornsberry (8) described isolates of Staphylococcus aureus displaying borderline susceptibility to antistaphylococcal penicillins. These strains were inhibited by methicillin and oxacillin at concentrations of 4 and 2 p,g/ml, respectively, and were characterized by the production of large amounts of P-lactamase. Addition of a f-lactamase inhibitor such as clavulanic acid or sulbactam restored activities of the penicillins to levels which inhibit fully methicillin-susceptible S. aureus strains. Such strains appear to be distinct from those demonstrating chromosomally mediated intrinsic ,-lactamase resistance, which has been associated with the presence of a low-affinity penicillinbinding protein, termed PBP 2a or 2' (5). To differentiate borderline susceptible strains from the latter group of intrinsically resistant organisms further, they have also been called acquired-resistant strains (7,8). Whether infections caused by borderline susceptible staphylococcal isolates would respond to ,B-lactams as well as infections caused by fully susceptible strains, or whether these isolates should be considered the same as intrinsically resistant strains for clinical and therapeutic purposes, is unclear and remains to be determined.In this study...

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“…Such strains have an intermediate methicillin or oxacillin MIC which is lowered by clavulanate (McDougal & Thornsberry 1986). However, there remain problems with the in uitro assessment of these strains (Woods & Yam 1988). Another unknown factor may be in operation in some strains (Sierra-Madero et al 1988), and clavulanate itself has intrinsic inhibitory activity, which further compounds the problem of interpretation of any clavulanate screening test.…”

Section: Hyperproduction Of Andlactamasementioning

confidence: 99%