scholarly journals Comparative in vitro and in vivo activities of piperacillin combined with the beta-lactamase inhibitors tazobactam, clavulanic acid, and sulbactam.

1989 ◽  
Vol 33 (11) ◽  
pp. 1964-1969 ◽  
Author(s):  
N A Kuck ◽  
N V Jacobus ◽  
P J Petersen ◽  
W J Weiss ◽  
R T Testa
Keyword(s):  
Clavulanic Acid ◽  
Beta Lactamase

scholarly journals Clinical extended-spectrum beta-lactamase antibiotic resistance plasmids have diverse transfer rates and can spread in the absence of antibiotic selection

2019 ◽  
Author(s):  
Fabienne Benz ◽  
Jana S. Huisman ◽  
Erik Bakkeren ◽  
Joana A. Herter ◽  
Tanja Stadler ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Conjugative Transfer ◽  
Beta Lactamase ◽  
Extended Spectrum Beta Lactamase ◽  
Extended Spectrum ◽  
Resistance Plasmids ◽  
Serovar Typhimurium ◽  
Spreading Potential

AbstractHorizontal gene transfer, mediated by conjugative plasmids, is a major driver of the global spread of antibiotic resistance. However, the relative contributions of factors that underlie the spread of clinically relevant plasmids are unclear. Here, we quantified conjugative transfer dynamics of Extended Spectrum Beta-Lactamase (ESBL) producing plasmids in the absence of antibiotics. We showed that clinical Escherichia coli strains natively associated with ESBL-plasmids conjugate efficiently with three distinct E. coli strains and one Salmonella enterica serovar Typhimurium strain, reaching final transconjugant frequencies of up to 1% within 24 hours in vitro. The variation of final transconjugant frequencies varied among plasmids, donors and recipients and was better explained by variation in conjugative transfer efficiency than by variable clonal expansion. We identified plasmid-specific genetic factors, specifically the presence/absence of transfer genes, that influenced final transconjugant frequencies. Finally, we investigated plasmid spread within the mouse intestine, demonstrating qualitative agreement between plasmid spread in vitro and in vivo. This suggests a potential for the prediction of plasmid spread in the gut of animals and humans, based on in vitro testing. Altogether, this may allow the identification of resistance plasmids with high spreading potential and help to devise appropriate measures to restrict their spread.

scholarly journals Cefazolin plus Clavulanic Acid Overcomes the Inoculum Effect in a Methicillin-Susceptible Staphylococcus aureus (MSSA) Rat Endocarditis Model

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S12-S13
Author(s):  
William Miller ◽  
Kavindra Singh ◽  
Cesar Arias ◽  
Barbara Murray
Keyword(s):  
Clavulanic Acid ◽  
Brain Heart Infusion ◽  
Type A ◽  
Entire Volume ◽  
Colony Forming Units ◽  
Significant Difference ◽  
Inoculum Effect ◽  
Antibiotic Dose

Abstract Background The inoculum effect (InE) refers to an increase in the MIC of an antibiotic when a large burden of bacteria is present. MSSA producing type A or C β-lactamase (β-lac) that display this effect may be at risk of clinical failure when treated with cefazolin (CFZ) for a deep-seated infection. We have previously shown that CFZ plus clavulanic acid (CL) abolished the InE in vitro. The aim of this study was to evaluate the effectiveness of the combination in vivo at clinically achievable concentrations of both CFZ and CL. Methods S. aureus TX0117, a type A Bla+ clinical isolate from a patient who failed CFZ therapy and TX0117-cured (TX0117c), a derivative of TX0117 which lacks β-lac activity, were used in a rat model of endocarditis. One animal per strain, in addition to historical controls (n = 22), was sacrificed at the start of therapy to assess colony forming units (CFU) per gram of vegetation at T = 0. CFZ 50mg/kg alone (n = 11) or CFZ 50mg/kg plus CL 4mg/kg (n = 7) was given IM every 8 hours for 72 hours. Doses were selected to mimic mean serum concentration of standard doses (given IM (CFZ) or PO (CL)) in humans. Rats were sacrificed 16 hours after the last antibiotic dose, aortic valves were aseptically excised, weighed, homogenized in 1ml of saline and the entire volume was plated in serial 10-fold dilutions on mannitol salt and/or brain-heart infusion agar. Representative recovered colonies were tested for β-lac activity using nitrocefin. Comparisons of CFU between groups were done by the Mann–Whitney, Wilcoxon unpaired test with significance at p < 0.05. Results At baseline, there was no significant difference between the CFU/g of control animals infected with the two strains (TX0117 7.3±1.3 and TX0117c 7.89±0.83, mean log10 ± SD). Compared with untreated controls, the TX0117 group treated with CFZ alone had a reduction of 2±0.6 CFU/g, while the CFZ plus CL arm had a 7.1±0.5 CFU/g reduction, a statistically significant difference between the two arms (P = 0.0002). CFZ treatment of the TX0117c strain lacking blaZ activity was similar to CFZ+CL (6.5±0.6 log10 CFU/g reduction, P < 0.0001). Conclusion Against Bla+ TX0117, the addition of CL, at a dose mimicking human PO kinetics, restored the efficacy of CFZ and overcame the InE. This provides a proof-of-concept for the use of oral CL with CFZ when there is a concern for the InE. Disclosures All authors: No reported disclosures.

Extended-spectrum resistance to β-lactams/β-lactamase inhibitors (ESRI) evolved from low-level resistant Escherichia coli

2019 ◽  
Author(s):  
Ángel Rodríguez-Villodres ◽  
María Luisa Gil-Marqués ◽  
Rocío Álvarez-Marín ◽  
Rémy A Bonnin ◽  
María Eugenia Pachón-Ibáñez ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Clavulanic Acid ◽  
Genomic Analysis ◽  
E Coli ◽  
Extended Spectrum ◽  
Copy Numbers ◽  
Resistance Patterns ◽  
Amoxicillin Clavulanic Acid

Abstract Objectives Escherichia coli is characterized by three resistance patterns to β-lactams/β-lactamase inhibitors (BLs/BLIs): (i) resistance to ampicillin/sulbactam and susceptibility to amoxicillin/clavulanic acid and piperacillin/tazobactam (RSS); (ii) resistance to ampicillin/sulbactam and amoxicillin/clavulanic acid, and susceptibility to piperacillin/tazobactam (RRS); and (iii) resistance to ampicillin/sulbactam, amoxicillin/clavulanic acid and piperacillin/tazobactam (RRR). These resistance patterns are acquired consecutively, indicating a potential risk of developing resistance to piperacillin/tazobactam, but the precise mechanism of this process is not completely understood. Methods Clinical isolates incrementally pressured by piperacillin/tazobactam selection in vitro and in vivo were used. We determined the MIC of piperacillin/tazobactam in the presence and absence of piperacillin/tazobactam pressure. We deciphered the role of the blaTEM genes in the new concept of extended-spectrum resistance to BLs/BLIs (ESRI) using genomic analysis. The activity of β-lactamase was quantified in these isolates. Results We show that piperacillin/tazobactam resistance is induced in E. coli carrying blaTEM genes. This resistance is due to the increase in copy numbers and transcription levels of the blaTEM gene, thus increasing β-lactamase activity and consequently increasing piperacillin/tazobactam MICs. Genome sequencing of two blaTEM-carrying representative isolates showed that piperacillin/tazobactam treatment produced two types of duplications of blaTEM (8 and 60 copies, respectively). In the clinical setting, piperacillin/tazobactam treatment of patients infected by E. coli carrying blaTEM is associated with a risk of therapeutic failure. Conclusions This study describes for the first time the ESRI in E. coli. This new concept is very important in the understanding of the mechanism involved in the acquisition of resistance to BLs/BLIs.

A Practical Look at the Clinical Usefulness of the Beta-Lactam/Beta-Lactamase Inhibitor Combinations

1996 ◽  
Vol 30 (10) ◽  
pp. 1130-1140 ◽  
Author(s):  
Susan M. Hart ◽  
Elaine M. Bailey
Keyword(s):  
English Language ◽  
Antimicrobial Agents ◽  
In Vivo Studies ◽  
Patient Specific ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Intraabdominal Infections ◽  
Lactamase Inhibitor

OBJECTIVE: To aid clinicians in developing an approach to the use of intravenous beta-lactam/beta-lactamase inhibitors on a patient-specific basis. To achieve this, the pharmacology, in vitro activity, and clinical use of the intravenous beta-lactam/beta-lactamase inhibitor combinations in the treatment of selected infections seen in hospitalized patients are discussed. DATA IDENTIFICATION: An English-language literature search using MEDLINE (1987–1995); Index Medicus (1987–1995); program and abstracts of the 32nd (1992), 33rd (1993), 34th (1994), and 35th (1995) Interscience Conference on Antimicrobial Agents and Chemotherapy; bibliographic reviews of review articles; and package inserts. STUDY SELECTION: In vitro and in vivo studies on the pharmacokinetics, microbiology, pharmacology, and clinical effectiveness of ampicillin/sulbactam, ticarcillin/clavulanate, and piperacillin/tazobactam were evaluated. DATA SYNTHESIS: Many properties of the beta-lactam/beta-lactamase inhibitor combinations are similar. Differences in dosing, susceptibilities, and clinical applications are important considerations for clinicians. Potential roles for these agents in the clinical setting include pneumonia, intraabdominal infections, and soft tissue infections. A short discussion on susceptibility data interpretation is also presented. CONCLUSIONS: There are important differences among the available beta-lactam/beta-lactamase inhibitor combinations, such as spectra of activity, which need to be considered in choosing an agent for a patient-specific case. These products can be useful alternatives to conventional two- to three-drug regimens in mixed infections such as foot infections in patients with diabetes and hospital-acquired intraabdominal infections.

Acute Generalized Exanthematous Pustulosis Induced by Amoxicillin/Clavulanic Acid

2015 ◽  
Vol 19 (6) ◽  
pp. 592-594 ◽  
Author(s):  
Ekaterini Syrigou ◽  
Dimitra Grapsa ◽  
Andriani Charpidou ◽  
Konstantinos Syrigos
Keyword(s):  
Clavulanic Acid ◽  
Patch Testing ◽  
Clinical Presentation ◽  
Drug Induced ◽  
Acute Generalized Exanthematous Pustulosis ◽  
Amoxicillin Clavulanic Acid ◽  
Exanthematous Pustulosis ◽  
Histopathologic Features

Drug-induced acute generalized exanthematous pustulosis is a rare pustular skin reaction, most commonly triggered by antibiotics. Although its diagnosis is based primarily on the presence of specific clinical and histopathologic features, additional in vivo (patch testing) or in vitro testing may be required, especially in atypical cases, to more accurately determine the causative agent. The authors report a histologically confirmed case of acute generalized exanthematous pustulosis that was induced by amoxicillin/clavulanic acid, as documented by subsequent patch testing, and presented with generalized painful lymphadenopathy, mimicking an acute infectious process. This is a very rare and diagnostically challenging clinical presentation of acute generalized exanthematous pustulosis, which has been reported, to the best of our knowledge, only once previously.

scholarly journals Assessment of two penicillins plus beta-lactamase inhibitors versus cefotaxime in treatment of murine Klebsiella pneumoniae infections.

1996 ◽  
Vol 40 (2) ◽  
pp. 325-330 ◽  
Author(s):  
J L Fournier ◽  
F Ramisse ◽  
A C Jacolot ◽  
M Szatanik ◽  
O J Petitjean ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Clavulanic Acid ◽  
Survival Rates ◽  
Dose Effect ◽  
Pharmacokinetic Analysis ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Bacterial Killing ◽  
Bacterial Counts

The in vivo efficacies of piperacillin, piperacillin plus tazobactam, ticarcillin, ticarcillin plus clavulanic acid, piperacillin plus clavulanic acid, and cefotaxime were compared in a mouse model of pneumonia induced by the SHV-1 beta-lactamase-producer Klebsiella pneumoniae. Each antibiotic was injected either once intraperitoneally at 24 h postinfection or at repeated times during 24 h. The efficacies of the drugs and therapeutic protocols were assessed by counting viable bacteria recovered from the lungs of mice sacrificed at selected times. No emergence of beta-lactam-resistant organisms was detected. Ticarcillin at 300 mg/kg was ineffective. Repeated injections of piperacillin at 300 mg/kg, either alone or in combination with tazobactam (8:1), led to a significant decrease in bacterial counts, but this was followed by bacterial regrowth. The pharmacokinetic analysis demonstrated that this short-lasting antibacterial effect was not due to a failure of piperacillin and/or tazobactam to penetrate the lungs. The combinations of ticarcillin at 300 mg/kg plus clavulanic acid (15:1) and piperacillin at 300 mg/kg plus tazobactam (4:1) were proven to be effective in that they decreased the bacterial burden in the lungs from 10(5) to < 10(3) CFU. This dose effect of tazobactam can be explained by its dose-dependent penetration in the lungs. Cefotaxime at 100 mg/kg and the combination of piperacillin (slightly hydrolyzed by SHV-1) at 300 mg/kg plus clavulanic acid (15:1) led to the best efficacy. Both of these treatments induced a decrease in bacterial counts of nearly 4 log10 units. The survival rates correlated with the quantitative measurements of in vivo bacterial killing. These experimental results obtained from the restricted animal model used here may help in the design of further protocols for clinical trials.

scholarly journals Predictors of effect of ampicillin-sulbactam against TEM-1 beta-lactamase-producing Escherichia coli in an in vitro dynamic model: enzyme activity versus MIC.

1996 ◽  
Vol 40 (3) ◽  
pp. 734-738 ◽  
Author(s):  
A A Firsov ◽  
D Saverino ◽  
D Savarino ◽  
M Ruble ◽  
D Gilbert ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
In Vitro Model ◽  
Dynamic Models ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Time Curve ◽  
Peripheral Tissues ◽  
Vitro Model

The clinical outcome in patients treated with ampicillin-sulbactam may not always be predictable by disc susceptibility testing or with the MIC as determined with a constant level (4 micrograms/ml) of the beta-lactamase inhibitor (MIC1). The enzyme activities (EA) and the MICs estimated at a constant ratio of ampicillin to sulbactam of 2:1 (MIC2) for 15 TEM-1 beta-lactamase-producing strains of Escherichia coli were examined as alternatives to MIC1 as predictors of the antibacterial effects of this combined drug as studied in an in vitro model which simulates ampicillin-sulbactam pharmacokinetic profiles observed in human peripheral tissues. Integral parameters describing the area under the bacterial count-time curve (AUBC), the area between the normal growth curve, and the killing curve of bacteria exposed to antibiotic (ABBC), and the second parameter expressed as a percentage of its maximal hypothetical value (ABBC/ABBCmax) were calculated. All three parameters correlated well with EA (AUBC, r = 0.93; ABBC, r = -0.88; ABBC/ABBCmax, r = -0.91) and with MIC2 (r = 0.94, -0.94, and -0.95, respectively) but not with MIC1. Both EA and MIC2 can be considered reliable predictors of the antibacterial effect of ampicillin-sulbactam in an in vitro model. These correlations suggest that in vitro kinetic-dynamic models might be useful to reexamine established susceptibility breakpoints obtained with data based on the MIC1 (MICs obtained with constant levels of beta-lactamase inhibitors). These data also suggest that quantitative determinations of bacterial beta-lactamase production and MICs based on the component concentration ratio observed in vivo might be useful predictors of the effect of ampicillin-sulbactam and other beta-lactam-inhibitor combinations.

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