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Arnold S Bayer - One of the best experts on this subject based on the ideXlab platform.

  • Ampicillin enhances daptomycin and cationic host defense peptide mediated killing of Ampicillin and vancomycin resistant enterococcus faecium
    Antimicrobial Agents and Chemotherapy, 2012
    Co-Authors: George Sakoulas, Joe Pogliano, Arnold S Bayer, Brian T Tsuji, Soojin Yang, Nagendra N Mishra, Victor Nizet, Michael R Yeaman
    Abstract:

    We studied an Ampicillin- and vancomycin-resistant Enterococcus faecium (VRE) isolate from a patient with endocarditis and bacteremia refractory to treatment with daptomycin (6 mg/kg of body weight) plus linezolid. Blood cultures cleared within 24 h of changing therapy to daptomycin (12 mg/kg) plus Ampicillin. We examined the effects of Ampicillin on daptomycin-induced growth inhibition and killing, surface charge, and susceptibility to several prototypical host defense cationic antimicrobial peptides. MICs and time-kill curves with daptomycin were assessed in the presence and absence of Ampicillin. The impact of Ampicillin on surface charge was assessed by flow cytometry and a poly-l-lysine binding assay. The effects of Ampicillin preexposures upon VRE killing by five distinct cationic peptides of different structure, charge, origin, and mechanism of action were analyzed using the epidermal cathelicidin LL-37, thrombin-induced platelet microbicidal proteins (tPMPs), and a synthetic congener modeled after tPMP microbicidal domains (RP-1), human neutrophil peptide-1 (hNP-1), and polymyxin B (bacteria derived). Fluoroscein-Bodipy-labeled daptomycin was used to evaluate daptomycin binding to VRE membranes in the presence or absence of Ampicillin. In media containing Ampicillin (25 to 100 mg/liter), daptomycin MICs decreased from 1.0 to 0.38 mg/liter. Based on time-kill analysis and an in vitro pharmacodynamic model, Ampicillin enhanced daptomycin activity against the study VRE from a bacteriostatic to a bactericidal profile. VRE grown in Ampicillin (25 to 150 mg/liter) demonstrated an incremental reduction in its relative net positive surface charge. When grown in the presence (versus absence) of Ampicillin (25 and 100 mg/liter), the VRE strain (i) was more susceptible to killing by LL-37, tPMPs, hNP-1, and RP-1 but not to polymyxin B and (ii) exhibited greater binding to Bodipy-labeled daptomycin. We conclude that Ampicillin induces reductions in net positive bacterial surface charge of VRE, correlating with enhanced bactericidal effects of cationic calcium-daptomycin and a diverse range of other cationic peptides in vitro. While the mechanism(s) of such β-lactam-mediated shifts in surface charge remains to be defined, these finding suggest a potential for β-lactam-mediated enhancement of activity of both daptomycin and innate host defense peptides against antibiotic-resistant bacteria.

  • beta lactam beta lactamase inhibitor combinations are active in experimental endocarditis caused by beta lactamase producing oxacillin resistant staphylococci
    Antimicrobial Agents and Chemotherapy, 1991
    Co-Authors: L Hirano, Arnold S Bayer
    Abstract:

    Optimal therapeutic strategies for serious infections caused by borderline and heterotypic oxacillin-resistant Staphylococcus aureus (BORSA and ORSA) strains have not been fully characterized. Recent evidence suggests that the dominant penicillin-binding protein of ORSA strains (PBP 2a) shows good affinity for Ampicillin and that these strains commonly produce beta-lactamase. Therefore, we compared the in vivo efficacy of the combination of Ampicillin plus sulbactam with that of vancomycin against ORSA strains. Also, the moderate resistance of BORSA strains appears to be attributable mainly to the hyperproduction of beta-lactamase. Therefore, we also studied the in vivo efficacy of Ampicillin plus sulbactam against such organisms. Experimental aortic endocarditis was induced in rabbits by the following three strains: beta-lactamase-producing BORSA strain VP-986, beta-lactamase-producing ORSA strain 67-0, and its beta-lactamase-negative clone. In animals with BORSA endocarditis, Ampicillin plus sulbactam and oxacillin were highly effective in reducing mean intravegetation bacterial densities, with each being significantly better than either Ampicillin alone or no therapy. In animals with endocarditis caused by the beta-lactamase-producing ORSA strain, Ampicillin plus sulbactam was significantly better at reducing mean vegetation bacterial densities than the other regimens. For endocarditis caused by the beta-lactamase-negative ORSA clone, Ampicillin was better than vancomycin in reducing mean intravegetation bacterial densities. These data show that infections caused by beta-lactamase-producing BORSA strains respond therapeutically in a manner similar to that of infections caused by oxacillin-susceptible strains, with both oxacillin and Ampicillin plus sulbactam being highly efficacious. Moreover, high-dose Ampicillin treatment strategies were effective in the therapy of ORSA endocarditis; this efficacy is presumably related to the relatively high affinity profile of this compound (compare with that of oxacillin) for the functionally dominant ORSA PBP 2a.

Silja Mentula - One of the best experts on this subject based on the ideXlab platform.

  • p1a recombinant β lactamase prevents emergence of antimicrobial resistance in gut microflora of healthy subjects during intravenous administration of Ampicillin
    Antimicrobial Agents and Chemotherapy, 2009
    Co-Authors: Annmari Tarkkanen, Silja Mentula, Michel Van Der Rest, Curtis J Donskey, Tuula Heinonen, Rain Jogi, Tuomas Kemppainen, Konstantin Gurbanov, Carl Erik Nord
    Abstract:

    Ipsat P1A is a recombinant β-lactamase which degrades antibiotic residue in the gastrointestinal tract. In an open-label, single-center controlled trial, 36 healthy subjects were randomized to receive (i) Ampicillin (1 g intravenously [i.v.] every 6 h [q6h]), (ii) oral P1A recombinant β-lactamase (8.2 mg q6h), or (iii) Ampicillin (1 g i.v. q6h) in combination with oral P1A recombinant β-lactamase (8.2 mg q6h) for 5 days. Fecal samples were collected before treatment, during treatment (days 3 to 5), and at follow-up (day 12). The primary end points were (i) changes in gastrointestinal microflora (determined by temperature gradient gel electrophoresis [TGGE]) and (ii) emergence of bacterial resistance (determined by conventional microbiology and PCR of TEM β-lactamase genes). Thirty-five subjects completed the study. The mean similarity percentages of TGGE profiles between baseline and each treatment day sample were significantly lower for the Ampicillin group than for the group receiving Ampicillin plus P1A recombinant β-lactamase on days 3, 4, and 5 (P < 0.001). Compared with the Ampicillin group, subjects receiving Ampicillin plus P1A recombinant β-lactamase had significantly fewer Ampicillin-resistant coliforms on days 3, 4, and 5 and at follow-up (P ≤ 0.001) and fewer TEM β-lactamase genes on days 3, 4, and 5 (P < 0.02). P1A recombinant β-lactamase was safe and well tolerated. In healthy subjects, P1A recombinant β-lactamase prevents Ampicillin-induced alterations in intestinal microflora, emergence of resistance, and the number of TEM genes.

  • inhibition of Ampicillin induced emergence of resistance in intestinal coliforms by targeted recombinant β lactamase
    International Journal of Antimicrobial Agents, 2004
    Co-Authors: Silja Mentula, Jaana Harmoinen, Pertti Koski, Elias Westermarck, Merja Rautio, Pentti Huovinen, Eija Kononen
    Abstract:

    Abstract The aim of the present study was to determine whether oral targeted recombinant β-lactamase (TRBL) administration could overcome the development of Ampicillin-induced resistance in the gut microbiota. Eighteen laboratory beagles with permanent jejunal fistula were randomised to receive Ampicillin + placebo, Ampicillin + TRBL or placebo. A total of 982 coliform isolates, collected from jejunal and faecal samples before, during and after the treatment were tested against nine antimicrobials. The proportion of Ampicillin resistance (multi-resistance) among coliform isolates increased from 20 to 36% in the Ampicillin + placebo group but far less, 20–36%, in the Ampicillin + TRBL group. These results indicate that TRBL may prevent the emergence of β-lactam-associated resistance in coliforms in the gut.

  • orally administered targeted recombinant beta lactamase prevents Ampicillin induced selective pressure on the gut microbiota a novel approach to reducing antimicrobial resistance
    Antimicrobial Agents and Chemotherapy, 2004
    Co-Authors: Jaana Harmoinen, Silja Mentula, Matti Heikkila, Michel Van Der Rest, Paivi J Rajalaschultz, Curtis J Donskey, Rafael Frias, Pertti Koski, Nina Wickstrand, Hannele Jousimiessomer
    Abstract:

    Antibiotics that are excreted into the intestinal tract promote antibiotic resistance by exerting selective pressure on the gut microbiota. Using a beagle dog model, we show that an orally administered targeted recombinant β-lactamase enzyme eliminates the portion of parenteral Ampicillin that is excreted into the small intestine, preventing Ampicillin-induced changes to the fecal microbiota without affecting Ampicillin levels in serum. In dogs receiving Ampicillin, significant disruption of the fecal microbiota and the emergence of Ampicillin-resistant Escherichia coli and TEM genes were observed, whereas in dogs treated with Ampicillin in combination with an oral β-lactamase, these did not occur. These results suggest a new strategy for reducing antimicrobial resistance in humans.

Seth T Housman - One of the best experts on this subject based on the ideXlab platform.

  • in vitro activity of Ampicillin and ceftriaxone against Ampicillin susceptible enterococcus faecium
    Journal of Antimicrobial Chemotherapy, 2019
    Co-Authors: Michael P Lorenzo, Seth T Housman, David P Nicolau, James M Kidd, Stephen G Jenkins
    Abstract:

    Objectives To assess activity of the combination of ceftriaxone and Ampicillin against clinical isolates of Ampicillin-susceptible Enterococcus faecium. Methods Ampicillin-susceptible E. faecium (n = 29) and Enterococcus faecalis (n = 10) collected from locations in the USA and France were used for this analysis. Susceptibility testing was performed by gradient diffusion strip (GDS) and broth microdilution (BMD). Synergy with the combination of ceftriaxone and Ampicillin was assessed in all isolates using GDS crossing and double disc diffusion methods. Selected isolates (nine E. faecium and three E. faecalis) were assessed for synergy in time-kill studies using Ampicillin alone and in combination with ceftriaxone. Results In isolates of E. faecium, the median (range) Ampicillin MIC by BMD was 0.5 (0.25-4) mg/L and by GDS it was 2 (1-8) mg/L. In E. faecalis, the median (range) Ampicillin MIC by BMD was 0.5 (0.5-1) mg/L and by GDS it was 2 (0.75-3) mg/L. A total of 24/29 (82.8%) isolates of E. faecium displayed synergy by GDS and 22/29 (75.9%) by double disc diffusion. Seven of 10 (70%) isolates of E. faecalis displayed synergy by GDS and 4/10 (40%) by double disc diffusion. Time-kill studies found synergy in 3/9 (33.3%) E. faecium and 3/3 (100%) E. faecalis. Conclusions In contrast to the demonstrated synergy in time-kill models of ceftriaxone and Ampicillin for E. faecalis, this combination does not appear to provide uniform synergy in E. faecium. Antagonism was not observed. Clinical correlation is necessary and caution should be used when considering Ampicillin and ceftriaxone for the treatment of infections caused by Ampicillin-susceptible E. faecium.

  • in vitro pharmacodynamics of human simulated exposures of Ampicillin sulbactam doripenem and tigecycline alone and in combination against multidrug resistant acinetobacter baumannii
    Journal of Antimicrobial Chemotherapy, 2013
    Co-Authors: Seth T Housman, Mao Hagihara, David P Nicolau, Joseph Levente Kuti
    Abstract:

    OBJECTIVES: Multidrug resistance is common among Acinetobacter baumannii, limiting the available options used to treat infections caused by this organism. The objective of this study was to compare monotherapy and combination therapy with Ampicillin/sulbactam, doripenem and tigecycline against multidrug-resistant A. baumannii using an in vitro pharmacodynamic model. METHODS: Human free-drug concentration profiles of clinically relevant Ampicillin/sulbactam, doripenem and tigecycline were simulated alone and in two-drug combinations against four clinical A. baumannii isolates (MICs: Ampicillin/sulbactam, 4/2-64/32 mg/L; doripenem, 16 to ≥64 mg/L; and tigecycline, 1-4 mg/L) over 24 h. Microbiological response was measured as log10 cfu/mL and the area under the bactericidal curve (AUBC). RESULTS: Control strains grew to 7.11 ± 0.13 log10 cfu/mL. Except for Ampicillin/sulbactam-containing regimens against the single Ampicillin/sulbactam-susceptible isolate, all A. baumannii demonstrated regrowth to 24 h control levels against all mono and combination regimens. Using AUBC as an endpoint, the most active regimens were 9 g of Ampicillin/sulbactam every 8 h (3 h infusion) + 2 g of doripenem every 8 h (4 h infusion; 87.8 ± 21.0), 9 g of Ampicillin/sulbactam every 8 h (3 h infusion) + 200 mg of tigecycline every 12 h (30 min infusion; 100.6 ± 33.0) and 9 g of Ampicillin/sulbactam every 8 h (3 h infusion) monotherapy (116.7 ± 31.6), followed by 3 g of Ampicillin/sulbactam every 6 h (30 min infusion) + 200 mg of tigecycline every 12 h (30 min infusion; 134.0 ± 31.5) and 2 g of doripenem every 8 h (4 h infusion) + 200 mg of tigecycline every 12 h (30 min infusion; 142.7 ± 16.9). CONCLUSIONS: Although specific combination regimens displayed additive activity at aggressive doses against these multidrug-resistant A. baumannii, none of the regimens could maintain cfu reductions against the more resistant isolates.

Tadakatsu Shimamura - One of the best experts on this subject based on the ideXlab platform.

Xavier Gomis - One of the best experts on this subject based on the ideXlab platform.

  • efficacy of Ampicillin combined with ceftriaxone and gentamicin in the treatment of experimental endocarditis due to enterococcus faecalis with no high level resistance to aminoglycosides
    Journal of Antimicrobial Chemotherapy, 2003
    Co-Authors: Joan Gavaldà, Pedro Lopez Onrubia, Maria Teresa Martin Gomez, Xavier Gomis, Jose Luis Ramirez, Oscar Len, Dolors Rodriguez, Manuel Crespo, Isabel Ruiz, Albert Pahissa
    Abstract:

    Objective: This study tests the usefulness of ceftriaxone combined with Ampicillin as an alternative to ampi- cillin plus gentamicin for the treatment of experimental endocarditis due to Enterococcus faecalis without high-level resistance to aminoglycosides. It also determines whether adding ceftriaxone to Ampicillin and gentamicin increases the effectiveness against experimental enterococcal endocarditis resulting from E. faecalis. Methods: Animals with catheter-induced endocarditis were infected intravenously with 10 8 cfu of the EF91 strain of E. faecalis and were treated for 3 days with Ampicillin 2 g every 4 h administered as 'human-like' (H-L) pharmacokinetics, plus gentamicin 1 mg/kg every 8 h H-L, or ceftriaxone 2 g every 12 h H-L alone or combined with gentamicin 6 mg/kg every 24 h administered subcutaneously. Results: The results of therapy for experimental endocarditis resulting from EF91 showed that the combin- ation of Ampicillin plus ceftriaxone was as effective as Ampicillin plus gentamicin. The triple combination did not improve on the overall efficacies of the two-drug combinations. Conclusions: Because of its lower nephrotoxicity, Ampicillin plus ceftriaxone may be a useful alternative therapy for E. faecalis endocarditis in selected patients.

  • efficacy of Ampicillin plus ceftriaxone in treatment of experimental endocarditis due to enterococcus faecalis strains highly resistant to aminoglycosides
    Antimicrobial Agents and Chemotherapy, 1999
    Co-Authors: Joan Gavaldà, Benito Almirante, Carmen Torres, Carmen Tenorio, Pedro Lopez, Myriam Zaragoza, J A Capdevila, Fernanda Ruiz, Nuria Borrell, Xavier Gomis
    Abstract:

    The purpose of this work was to evaluate the in vitro possibilities of Ampicillin-ceftriaxone combinations for 10 Enterococcus faecalis strains with high-level resistance to aminoglycosides (HLRAg) and to assess the efficacy of Ampicillin plus ceftriaxone, both administered with humanlike pharmacokinetics, for the treatment of experimental endocarditis due to HLRAg E. faecalis. A reduction of 1 to 4 dilutions in MICs of Ampicillin was obtained when Ampicillin was combined with a fixed subinhibitory ceftriaxone concentration of 4 micrograms/ml. This potentiating effect was also observed by the double disk method with all 10 strains. Time-kill studies performed with 1 and 2 micrograms of Ampicillin alone per ml or in combination with 5, 10, 20, 40, and 60 micrograms of ceftriaxone per ml showed a > or = 2 log10 reduction in CFU per milliliter with respect to Ampicillin alone and to the initial inoculum for all 10 E. faecalis strains studied. This effect was obtained for seven strains with the combination of 2 micrograms of Ampicillin per ml plus 10 micrograms of ceftriaxone per ml and for six strains with 5 micrograms of ceftriaxone per ml. Animals with catheter-induced endocarditis were infected intravenously with 10(8) CFU of E. faecalis V48 or 10(5) CFU of E. faecalis V45 and were treated for 3 days with humanlike pharmacokinetics of 2 g of Ampicillin every 4 h, alone or combined with 2 g of ceftriaxone every 12 h. The levels in serum and the pharmacokinetic parameters of the humanlike pharmacokinetics of Ampicillin or ceftriaxone in rabbits were similar to those found in humans treated with 2 g of Ampicillin or ceftriaxone intravenously. Results of the therapy for experimental endocarditis caused by E. faecalis V48 or V45 showed that the residual bacterial titers in aortic valve vegetations were significantly lower in the animals treated with the combinations of Ampicillin plus ceftriaxone than in those treated with Ampicillin alone (P < 0.001). The combination of Ampicillin and ceftriaxone showed in vitro and in vivo synergism against HLRAg E. faecalis.