Effects of two simulated oxytetracycline dosing regimens on horizontal transfer of antimicrobial resistance plasmids in an in vitro pharmacodynamic model

2011 ◽  
Vol 72 (7) ◽  
pp. 877-883 ◽  
Author(s):  
Brian V. Lubbers ◽  
Greg J. Peterson ◽  
Sanjeev K. Narayanan ◽  
James A. Havel ◽  
Johann F. Coetzee ◽  
...  
2005 ◽  
Vol 49 (7) ◽  
pp. 2735-2745 ◽  
Author(s):  
Brian T. Tsuji ◽  
Michael J. Rybak

ABSTRACT The ability to maximize bactericidal activity while minimizing toxicity is a therapeutic goal in the treatment of infective endocarditis. We evaluated the impact of administering short-course regimens of gentamicin in combination with daptomycin or vancomycin against one methicillin-susceptible (MSSA 1199) and one methicillin-resistant (MRSA 494) Staphylococcus aureus isolate using an in vitro pharmacodynamic model with simulated endocardial vegetations over 96 h. Human therapeutic dosing regimens for daptomycin (6 and 8 mg/kg of body weight), vancomycin, and gentamicin were simulated. Short-course combination regimens involving gentamicin were administered either as a single 5-mg/kg dose or three 1-mg/kg doses for only the first 24 h and compared to the regimens administered for the full 96-h duration. For all experiments, physiologic conditions of albumin, calcium, and pH were simulated. Both regimens of daptomycin achieved 99.9% kill by 32 h and maintained bactericidal activity against both isolates, which was significantly different from vancomycin, which displayed bacteriostatic activity (P < 0.05). The effects of all short-course regimens of gentamicin were equal to those of the full-duration regimens in combination with daptomycin. Adding three doses of gentamicin (1 mg/kg) to daptomycin resulted in enhancement and bactericidal activity at 24 h against both MRSA and MSSA. The addition of a single dose of gentamicin (5 mg/kg) enhanced or improved the activity of daptomycin and resulted in early bactericidal activity at 4 h against both isolates. The addition of three doses of gentamicin (1 mg/kg) did not improve the activity of vancomycin. However, the addition of a single 5-mg/kg dose of gentamicin to vancomycin resulted in early enhancement at 4 h and 99.9% kill at 32 h for MRSA. These results suggest that a single high dose of gentamicin in combination with daptomycin or vancomycin may be of utility to maximize synergistic and bactericidal activity and minimize toxicity. Further investigation is warranted.


2004 ◽  
Vol 48 (12) ◽  
pp. 4665-4672 ◽  
Author(s):  
Kerry L. LaPlante ◽  
Michael J. Rybak

ABSTRACT We evaluated the impact of high (9.5 log10 CFU/g) and moderate (5.5 log10 CFU/g) inocula of methicillin-susceptible and -resistant Staphylococcus aureus (MSSA and MRSA, respectively) on the activities of nafcillin, linezolid, vancomycin, and daptomycin, alone and in combination with gentamicin in an in vitro pharmacodynamic model with simulated endocardial vegetations over 72 h. Human therapeutic dosing regimens for nafcillin, daptomycin, vancomycin, linezolid, and gentamicin were simulated. At a moderate inoculum, nafcillin (MSSA only), vancomycin, and daptomycin demonstrated equivalent and significant (P < 0.01) bactericidal (99.9% kill) activities (decreases of 3.34 ± 1.1, 3.28 ± 0.4, and 3.34 ± 0.8 log10 CFU/g, respectively). Bactericidal activity was demonstrated at 4 h for nafcillin and daptomycin and at 32 h for vancomycin. Linezolid demonstrated bacteriostatic activity over the course of the study period. At a high inoculum, daptomycin exhibited bactericidal activity against both MSSA and MRSA by 24 h (decrease of 5.51 to 6.31 ± 0.10 log10 CFU/g). Nafcillin (versus MSSA), vancomycin, and linezolid (MSSA and MRSA) did not achieve bactericidal activity throughout the 72-h experiment. The addition of gentamicin increased the rate of 99.9% kill to 8 h for daptomycin (P < 0.01) and 48 h for nafcillin (MSSA only) (P = 0.01). The addition of gentamicin did not improve the activity of vancomycin or linezolid for either isolate for the 72-h period. Overall, high-inoculum Staphylococcus aureus had a significant impact on the activities of nafcillin and vancomycin. In contrast, daptomycin was affected minimally and linezolid was not affected by inoculum.


2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Adam Belley ◽  
Francis F. Arhin ◽  
Greg Moeck

ABSTRACT The clinical development of nonsusceptibility to the lipopeptide antibiotic daptomycin remains a serious concern during therapy for infections caused by vancomycin-resistant Enterococcus faecium (VREfm). The long-acting lipoglycopeptide oritavancin exhibits potent in vitro activity against VREfm, although its safety and efficacy for treating clinical VREfm infections have not been established. In this study, novel dosing regimens of daptomycin and oritavancin were assessed against both VREfm and daptomycin-nonsusceptible VREfm isolates in an in vitro pharmacokinetic/pharmacodynamic model.


1997 ◽  
Vol 41 (4) ◽  
pp. 721-727 ◽  
Author(s):  
P D Lister ◽  
A M Prevan ◽  
C C Sanders

An in vitro pharmacokinetic model was used to study the pharmacodynamics of piperacillin-tazobactam and piperacillin-sulbactam against gram-negative bacilli producing plasmid-encoded beta-lactamases. Logarithmic-phase cultures were exposed to peak antibiotic concentrations observed in human serum after the administration of intravenous doses of 3 g of piperacillin and 0.375 g of tazobactam or 0.5 g of sulbactam. Piperacillin and inhibitor were either dosed simultaneously or piperacillin was dosed sequentially 0.5 h after dosing with the inhibitor. In studies with all four test strains, the pharmacodynamics observed after simultaneous dosing were similar to those observed with the sequential regimen. Since the ratio between piperacillin and tazobactam was in constant fluctuation after sequential dosing, these data suggest that the pharmacodynamics of the piperacillin-inhibitor combinations were not dependent upon maintenance of a critical ratio between the components. Furthermore, when regrowth was observed, the time at which bacterial counts began to increase was similar between the simultaneous and sequential dosing regimens. Since the pharmacokinetics of the inhibitors were the same for all regimens, these data suggest that the length of time that the antibacterial activity was maintained over the dosing interval with these combinations was dictated by the pharmacokinetics of the beta-lactamase inhibitor in the combination. The antibacterial activity of the combination appeared to be lost when the amount of inhibitor available fell below some critical concentration. This critical concentration varied depending upon the type and amount of enzyme produced, as well as the specific inhibitor used. These results indicate that the antibacterial activity of drug-inhibitor combinations, when dosed at their currently recommended ratios, is more dependent on the pharmacokinetics of the inhibitor than on those of the beta-lactam drug.


2011 ◽  
Vol 55 (4) ◽  
pp. 1420-1427 ◽  
Author(s):  
Dora E. Wiskirchen ◽  
Pornpan Koomanachai ◽  
Anthony M. Nicasio ◽  
David P. Nicolau ◽  
Joseph L. Kuti

ABSTRACTMultidrug-resistantKlebsiella pneumoniaestrains that produce a serine carbapenemase (KPC) are emerging worldwide, with few therapeutic options that retain consistent susceptibility. The objective of this study was to determine the effect of combination therapy with tigecycline versus tigecycline alone against KPC-producing isolates (KPC isolates). Anin vitropharmacodynamic model was used to simulate adult steady-state epithelial lining fluid concentrations of tigecycline (50 mg every 12 h) given alone and in combination with either meropenem (2 g by 3-hour infusion every 8 h) or rifampin (600 mg every 12 h). Five KPC isolates with various phenotypic profiles were exposed over 48 h. Time-kill curves were constructed, and the areas under the bacterial killing and regrowth curves (AUBCs) were calculated. No regimens tested were able to maintain bactericidal reductions in CFU over 48 h. The AUBCs for tigecycline and meropenem monotherapies at 48 h ranged from 375.37 to 388.11 and from 348.62 to 383.83 (CFU-h/ml), respectively. The combination of tigecycline plus meropenem significantly reduced the AUBCs at 24 and 48 h for isolates with tigecycline MICs of ≤2 μg/ml and meropenem MICs of ≤16 μg/ml (P< 0.001) but added no additional activity when the meropenem MIC was 64 μg/ml (P= 0.5). Rifampin provided no additional reduction in CFU or AUBC over tigecycline alone (P= 0.837). The combination of tigecycline with high-dose, prolonged-infusion meropenem warrants further study as a potential treatment option for these multidrug-resistant organisms.


2006 ◽  
Vol 50 (6) ◽  
pp. 1931-1936 ◽  
Author(s):  
Boubakar B. Ba ◽  
Corinne Arpin ◽  
Céline Vidaillac ◽  
Arnaud Chausse ◽  
Marie-Claude Saux ◽  
...  

ABSTRACT Gatifloxacin (GAT) is a new 8-methoxy fluoroquinolone with enhanced activity against gram-positive cocci. Its activity was studied in an in vitro pharmacokinetic-pharmacodynamic model against five Staphylococcus aureus strains, either susceptible to ciprofloxacin or exhibiting various levels and mechanisms of ciprofloxacin (CIP) resistance: the ATCC 25923 reference strain (MICs of CIP and GAT: 0.5 and 0.1 μg/ml, respectively), its efflux mutant SA-1 (16 and 0.5 μg/ml; mutation in the norA promoter region), and three clinical strains, Sa2102 (2 and 0.2 μg/ml), Sa2667 (4 and 0.5 μg/ml), and Sa2669 (16 and 1 μg/ml), carrying mutations in the grlA (Ser80Tyr or Phe) and gyrA (Ser84Ala) quinolone resistance-determining regions (QRDRs) for Sa2669. Plasmatic pharmacokinetic profiles after daily 1-h perfusion of 400 mg for 48 h were accurately simulated. Thus, mean maximum concentration of drug in serum values for the two administration intervals were 5.36 and 5.80 μg/ml, respectively, and the corresponding half-life at β-phase values were 8.68 and 7.80 h (goodness of fit coefficient, >0.98). Therapeutic concentrations of GAT allowed the complete eradication of the susceptible strain within 12 h (difference between the bacterial counts at the beginning of the treatment and at a defined time: −2.18 at the 1-h time point [t 1] and −6.80 at t 24 and t 48; the bacterial killing and regrowth curve from 0 to 48 h was 30.2 h × log CFU/milliliter). However, mutants (M) with GAT MICs increased by 4- to 40-fold were selected from the other strains. They acquired mutations either supplementary (MSa2102 and MSa2667) or different (Ala84Val for MSa2669) in gyrA or in both gyrA and grlA QRDRs (MSA-1). MSa2667 additionally overproduced efflux system(s) without norA promoter modification. Thus, GAT properties should allow the total elimination of ciprofloxacin-susceptible S. aureus, but resistant mutants might emerge from strains showing reduced susceptibility to older fluoroquinolones independently of the first-step mutation(s).


Microbiology ◽  
2021 ◽  
Vol 167 (11) ◽  
Author(s):  
Alberto Gonçalves Evangelista ◽  
Jessica Audrey Feijó Corrêa ◽  
João Vitor Garcia dos Santos ◽  
Eduardo Henrique Custódio Matté ◽  
Mônica Moura Milek ◽  
...  

The genus Salmonella is closely associated with foodborne outbreaks and animal diseases, and reports of antimicrobial resistance in Salmonella species are frequent. Several alternatives have been developed to control this pathogen, such as cell-free supernatants (CFS). Our objective here was to evaluate the use of lactic acid bacteria (LAB) CFS against Salmonella in vitro. Seventeen strains of LAB were used to produce CFS, and their antimicrobial activity was screened towards six strains of Salmonella . In addition, CFS were also pH-neutralized and/or boiled. Those with the best results were lyophilized. MICs of lyophilized CFS were 11.25–22.5 g l–1. Freeze-dried CFS were also used to supplement swine and poultry feed (11.25 g kg–1) and in vitro simulated digestion of both species was performed, with Salmonella contamination of 5×106 and 2×105 c.f.u. g−1 of swine and poultry feed, respectively. In the antimicrobial screening, all acidic CFS were able to inhibit the growth of Salmonella . After pH neutralization, Lactobacillus acidophilus Llorente, Limosilactobacillus fermentum CCT 1629, Lactiplantibacillus plantarum PUCPR44, Limosilactobacillus reuteri BioGaia, Lacticaseibacillus rhamnosus ATCC 7469 and Pediococcus pentosaceus UM116 CFS were the only strains that partially maintained their antimicrobial activity and, therefore, were chosen for lyophilization. In the simulated swine digestion, Salmonella counts were reduced ≥1.78 log c.f.u. g–1 in the digesta containing either of the CFS. In the chicken simulation, a significant reduction was obtained with all CFS used (average reduction of 0.59±0.01 log c.f.u. ml–1). In general, the lyophilized CFS of L. fermentum CCT 1629, L. rhamnosus ATCC 7469 and L. acidophilus Llorente presented better antimicrobial activity. In conclusion, CFS show potential as feed additives to control Salmonella in animal production and may be an alternative to the use of antibiotics, minimizing problems related to antimicrobial resistance.


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