scholarly journals Bactericidal Effect of Tomatidine-Tobramycin Combination against Methicillin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa Is Enhanced by Interspecific Small-Molecule Interactions

2015 ◽  
Vol 59 (12) ◽  
pp. 7458-7464 ◽  
Author(s):  
Simon Boulanger ◽  
Gabriel Mitchell ◽  
Kamal Bouarab ◽  
Éric Marsault ◽  
André Cantin ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Bactericidal Effect ◽  
Methicillin Resistant ◽  
Content Type ◽  
New Treatment ◽  
Molecule Interactions ◽  
Kinetics Of ◽  
Related Compounds ◽  
Respiratory Deficient

ABSTRACTThis study investigated the antibacterial activity of the plant alkaloid tomatidine (TO) againstStaphylococcus aureusgrown in the presence ofPseudomonas aeruginosa. Since theP. aeruginosaexoproduct 4-hydroxy-2-heptylquinoline-N-oxide (HQNO) is known to cause a respiratory deficiency inS. aureusand respiratory-deficientS. aureusare known to be hypersensitive to TO, we assessed kill kinetics of TO (8 μg/ml) againstS. aureusin coculture withP. aeruginosa. Kill kinetics were also assessed usingP. aeruginosamutants deficient in the production of different exoproducts and quorum sensing-related compounds. After 24 h in coculture, TO increased the killing ofS. aureusby 3.4 log10CFU/ml in comparison to that observed in a coculture without TO. The effect of TO was abolished whenS. aureuswas in coculture with thelasRrhlR,pqsA,pqsL, orlasAmutant ofP. aeruginosa. The bactericidal effect of TO againstS. aureusin coculture with thepqsLmutant was restored by supplemental HQNO. In anS. aureusmonoculture, the combination of HQNO and TO was bacteriostatic, indicating that thepqsLmutant produced an additional factor required for the bactericidal effect. The bactericidal activity of TO was also observed against a tobramycin-resistant methicillin-resistantS. aureus(MRSA) in coculture withP. aeruginosa, and the addition of tobramycin significantly suppressed the growth of both microorganisms. TO shows a strong bactericidal effect againstS. aureuswhen cocultured withP. aeruginosa. The combination of TO and tobramycin may represent a new treatment approach for cystic fibrosis patients frequently cocolonized by MRSA andP. aeruginosa.

scholarly journals Bactericidal Activity, Absence of Serum Effect, and Time-Kill Kinetics of Ceftazidime-Avibactam against β-Lactamase-Producing Enterobacteriaceae and Pseudomonas aeruginosa

2014 ◽  
Vol 58 (9) ◽  
pp. 5297-5305 ◽  
Author(s):  
Tiffany R. Keepers ◽  
Marcela Gomez ◽  
Chris Celeri ◽  
Wright W. Nichols ◽  
Kevin M. Krause
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Human Serum ◽  
Bactericidal Activity ◽  
Minimum Bactericidal Concentration ◽  
Wild Type ◽  
Content Type ◽  
Positive Isolate ◽  
New Treatment ◽  
Time Kill ◽  
Kinetics Of

ABSTRACTAvibactam, a non-β-lactam β-lactamase inhibitor with activity against extended-spectrum β-lactamases (ESBLs), KPC, AmpC, and some OXA enzymes, extends the antibacterial activity of ceftazidime against most ceftazidime-resistant organisms producing these enzymes. In this study, the bactericidal activity of ceftazidime-avibactam against 18Pseudomonas aeruginosaisolates and 15Enterobacteriaceaeisolates, including wild-type isolates and ESBL, KPC, and/or AmpC producers, was evaluated. Ceftazidime-avibactam MICs (0.016 to 32 μg/ml) were lower than those for ceftazidime alone (0.06 to ≥256 μg/ml) against all isolates except for 2P. aeruginosaisolates (1blaVIM-positive isolate and 1blaOXA-23-positive isolate). The minimum bactericidal concentration/MIC ratios of ceftazidime-avibactam were ≤4 for all isolates, indicating bactericidal activity. Human serum and human serum albumin had a minimal effect on ceftazidime-avibactam MICs. Ceftazidime-avibactam time-kill kinetics were evaluated at low MIC multiples and showed time-dependent reductions in the number of CFU/ml from 0 to 6 h for all strains tested. A ≥3-log10decrease in the number of CFU/ml was observed at 6 h for allEnterobacteriaceae, and a 2-log10reduction in the number of CFU/ml was observed at 6 h for 3 of the 6P. aeruginosaisolates. Regrowth was noted at 24 h for some of the isolates tested in time-kill assays. These data demonstrate the potent bactericidal activity of ceftazidime-avibactam and support the continued clinical development of ceftazidime-avibactam as a new treatment option for infections caused byEnterobacteriaceaeandP. aeruginosa, including isolates resistant to ceftazidime by mechanisms dependent on avibactam-sensitive β-lactamases.

scholarly journals Efficacy of Topically Delivered Moxifloxacin against Wound Infection by Pseudomonas aeruginosa and Methicillin-Resistant Staphylococcus aureus

2011 ◽  
Vol 55 (5) ◽  
pp. 2325-2334 ◽  
Author(s):  
F. Jacobsen ◽  
C. Fisahn ◽  
M. Sorkin ◽  
I. Thiele ◽  
T. Hirsch ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Wound Healing ◽  
Wound Infection ◽  
High Efficiency ◽  
High Morbidity ◽  
Methicillin Resistant ◽  
Bacterial Counts ◽  
Content Type ◽  
Promote Wound Healing

ABSTRACTWound infection is a common risk for patients with chronic nonhealing wounds, causing high morbidity and mortality. Currently, systemic antibiotic treatment is the therapy of choice, despite often leading to several side effects and the risk of an insufficient tissue penetration due to impaired blood supply. If systemically delivered, moxifloxacin penetrates well into inflammatory blister fluid, muscle, and subcutaneous adipose tissues and might therefore be a possible option for the topical treatment of skin and infected skin wounds. In this study, topical application of moxifloxacin was investigated in comparison to mupirocin, linezolid, and gentamicin using a porcine wound infection and a rat burn infection model. Both animal models were performed either by an inoculation with methicillin-resistantStaphylococcus aureus(MRSA) orPseudomonas aeruginosa. Wound fluid, tissue, and blood samples were taken, and bacterial counts as well as the moxifloxacin concentration were determined for a 14-day follow-up. A histological comparison of the rat burn wound tissues was performed. Both strains were susceptible to moxifloxacin and gentamicin, whereas mupirocin and linezolid were effective only against MRSA. All antibiotics showed efficient reduction of bacterial counts, and except with MRSA, infected burn wounds reached bacterial counts below 105CFU/g tissue. Additionally, moxifloxacin was observed to promote wound healing as determined by histologic analysis, while no induction of bacterial resistance was observed during the treatment period. The use of topical antibiotics for the treatment of infected wounds confers many benefits. Moxifloxacin is therefore an ideal candidate, due to its broad antibacterial spectrum, its high efficiency, and its potential to promote wound healing.

scholarly journals Targeting Methicillin-Resistant Staphylococcus aureus with Short Salt-Resistant Synthetic Peptides

2014 ◽  
Vol 58 (7) ◽  
pp. 4113-4122 ◽  
Author(s):  
Mohamed F. Mohamed ◽  
Maha I. Hamed ◽  
Alyssa Panitch ◽  
Mohamed N. Seleem
Keyword(s):  
Staphylococcus Aureus ◽  
Synthetic Peptides ◽  
Bactericidal Effect ◽  
Multidrug Resistant ◽  
Antimicrobial Activities ◽  
Net Charge ◽  
Methicillin Resistant ◽  
Content Type ◽  
C Terminus ◽  
Conventional Antibiotics

ABSTRACTThe seriousness of microbial resistance combined with the lack of new antimicrobials has increased interest in the development of antimicrobial peptides (AMPs) as novel therapeutics. In this study, we evaluated the antimicrobial activities of two short synthetic peptides, namely, RRIKA and RR. These peptides exhibited potent antimicrobial activity againstStaphylococcus aureus, and their antimicrobial effects were significantly enhanced by addition of three amino acids in the C terminus, which consequently increased the amphipathicity, hydrophobicity, and net charge. Moreover, RRIKA and RR demonstrated a significant and rapid bactericidal effect against clinical and drug-resistantStaphylococcusisolates, including methicillin-resistantStaphylococcus aureus(MRSA), vancomycin-intermediateS. aureus(VISA), vancomycin-resistantS. aureus(VRSA), linezolid-resistantS. aureus, and methicillin-resistantStaphylococcus epidermidis. In contrast to many natural AMPs, RRIKA and RR retained their activity in the presence of physiological concentrations of NaCl and MgCl2. Both RRIKA and RR enhanced the killing of lysostaphin more than 1,000-fold and eradicated MRSA and VRSA isolates within 20 min. Furthermore, the peptides presented were superior in reducing adherent biofilms ofS. aureusandS. epidermidiscompared to results with conventional antibiotics. Our findings indicate that the staphylocidal effects of our peptides were through permeabilization of the bacterial membrane, leading to leakage of cytoplasmic contents and cell death. Furthermore, peptides were not toxic to HeLa cells at 4- to 8-fold their antimicrobial concentrations. The potent and salt-insensitive antimicrobial activities of these peptides present an attractive therapeutic candidate for treatment of multidrug-resistantS. aureusinfections.

scholarly journals Efficacy of Human-Simulated Exposures of Tomopenem (Formerly CS-023) in a Murine Model of Pseudomonas aeruginosa and Methicillin-Resistant Staphylococcus aureus Infection

2011 ◽  
Vol 55 (11) ◽  
pp. 5004-5009 ◽  
Author(s):  
Kiyoshi Sugihara ◽  
Kazuhiro Tateda ◽  
Naotoshi Yamamura ◽  
Tetsufumi Koga ◽  
Chika Sugihara ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Clinical Isolates ◽  
Infection Model ◽  
Methicillin Resistant ◽  
Content Type ◽  
Target Values ◽  
Bactericidal Effects ◽  
Dosing Regimens ◽  
Mrsa Strains

ABSTRACTTomopenem (formerly CS-023) is a novel carbapenem with improved activity against diverse hospital pathogens, includingPseudomonas aeruginosaand methicillin-resistantStaphylococcus aureus(MRSA), and has a half-life about twice longer than the half-lives of other carbapenems such as imipenem and meropenem. Our objective in this study was to estimate the efficacy of tomopenem in humans by human-simulated exposures in a neutropenic murine thigh infection model against 9 clinical isolates ofP. aeruginosawith MICs of 4 to 32 μg/ml and 9 clinical isolates of MRSA with MICs of 4 to 16 μg/ml. Human-simulated dosing regimens in neutropenic mice were designed to approximate the cumulative percentage of a 24-h period that the free drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (f%TMIC) observed with tomopenem at 750 and 1,500 mg given as a 0.5-h infusion three times a day (TID) in humans. As reported previously, there was no difference between the target values ofP. aeruginosaand MRSA required for efficacy (K. Sugihara et al., Antimicrob. Agents Chemother.54:5298-5302, 2010). Tomopenem at 750 mg showed bactericidal or bacteriostatic effects against 10 of 11 strains ofP. aeruginosaand MRSA with MICs of ≤8 μg/ml (f%TMIC≥ 41), and tomopenem at 1,500 mg showed bactericidal effects against 16 of 17 strains ofP. aeruginosaand MRSA with MICs of ≤16 μg/ml (f%TMIC≥ 43). Meropenem at 1,000 mg TID was tested for comparison purposes and showed bactericidal or bacteriostatic effects against 3 of 4 strains ofP. aeruginosawith MICs of ≤4 μg/ml (f%TMIC≥ 33). From these results, tomopenem is expected to be effective with anf%TMICof over 40 againstP. aeruginosaand MRSA strains with MICs of ≤8 μg/ml at doses of 750 mg TID and strains with MICs of ≤16 μg/ml at doses of 1,500 mg TID.

scholarly journals The Combination of Daptomycin and Fosfomycin Has Synergistic, Potent, and Rapid Bactericidal Activity against Methicillin-ResistantStaphylococcus aureusin a Rabbit Model of Experimental Endocarditis

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Cristina García-de-la-Mària ◽  
Oriol Gasch ◽  
Javier García-Gonzalez ◽  
Dolors Soy ◽  
Evelyn Shaw ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Combined Therapy ◽  
Rabbit Model ◽  
Bactericidal Effect ◽  
Methicillin Resistant ◽  
Content Type ◽  
Mrsa Strains ◽  
Time Kill

ABSTRACTWe investigated whether the addition of fosfomycin or cloxacillin to daptomycin provides better outcomes in the treatment of methicillin-resistantStaphylococcus aureus(MRSA) experimental aortic endocarditis in rabbits. Five MRSA strains were used to performin vitrotime-kill studies using standard (106) and high (108) inocula. Combined therapy was compared to daptomycin monotherapy treatment in the MRSA experimental endocarditis model. A human-like pharmacokinetics model was applied, and the equivalents of cloxacillin at 2 g/4 h, fosfomycin at 2 g/6 h, and daptomycin at 6 to 10 mg/kg/day were administered intravenously. A combination of daptomycin and either fosfomycin or cloxacillin was synergistic in the five strains tested at both inocula. A bactericidal effect was detected in four of five strains tested with both combinations. The MRSA-277 strain (vancomycin MIC, 2 μg/ml) was used for the experimental endocarditis model. Daptomycin plus fosfomycin significantly improved the efficacy of daptomycin monotherapy at 6 mg/kg/day in terms of both the proportion of sterile vegetations (100% versus 72%,P= 0.046) and the decrease in the density of bacteria within the vegetations (P= 0.025). Daptomycin plus fosfomycin was as effective as daptomycin monotherapy at 10 mg/kg/day (100% versus 93%,P= 1.00) and had activity similar to that of daptomycin plus cloxacillin when daptomycin was administered at 6 mg/kg/day (100% versus 88%,P= 0.48). Daptomycin nonsusceptibility was not detected in any of the isolates recovered from vegetations. In conclusion, for the treatment of MRSA experimental endocarditis, the combination of daptomycin plus fosfomycin showed synergistic and bactericidal activity.

scholarly journals No Decrease in Susceptibility to NVC-422 in Multiple-Passage Studies with Methicillin-Resistant Staphylococcus aureus, S. aureus, Pseudomonas aeruginosa, and Escherichia coli

2012 ◽  
Vol 56 (5) ◽  
pp. 2753-2755 ◽  
Author(s):  
Louisa D'Lima ◽  
Lisa Friedman ◽  
Lu Wang ◽  
Ping Xu ◽  
Mark Anderson ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Fusidic Acid ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Cross Resistance ◽  
Methicillin Resistant ◽  
Content Type ◽  
E Coli ◽  
Resistant Strains

ABSTRACTTwenty-five serial passages ofEscherichia coli,Pseudomonas aeruginosa, andStaphylococcus aureusand 50 passages of methicillin-resistantStaphylococcus aureusresulted in no significant increase in NVC-422 MICs, while ciprofloxacin MICs increased 256-fold forE. coliand 32-fold forP. aeruginosaandS. aureus. Mupirocin, fusidic acid, and retapamulin MICs for MRSA increased 64-, 256-, and 16-fold, respectively. No cross-resistance to NVC-422 was observed with mupirocin-, fusidic acid-, and retapamulin-resistant strains.

scholarly journals Rapid Bactericidal Activity of Daptomycin against Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus Peritonitis in Mice as Measured with Bioluminescent Bacteria

2007 ◽  
Vol 51 (5) ◽  
pp. 1787-1794 ◽  
Author(s):  
Lawrence I. Mortin ◽  
Tongchuan Li ◽  
Andrew D. G. Van Praagh ◽  
Shuxin Zhang ◽  
Xi-Xian Zhang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Bactericidal Effect ◽  
Methicillin Resistant ◽  
Bioluminescent Bacteria ◽  
New Antibiotics ◽  
Luminescent Signal ◽  
Mrsa Strains ◽  
Kinetics Of

ABSTRACT The rising rates of antibiotic resistance accentuate the critical need for new antibiotics. Daptomycin is a new antibiotic with a unique mode of action and a rapid in vitro bactericidal effect against gram-positive organisms. This study examined the kinetics of daptomycin's bactericidal action against peritonitis caused by methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) in healthy and neutropenic mice and compared this activity with those of other commonly used antibiotics. CD-1 mice were inoculated intraperitoneally with lethal doses of MSSA (Xen-29) or MRSA (Xen-1), laboratory strains transformed with a plasmid containing the lux operon, which confers bioluminescence. One hour later, the animals were given a single dose of daptomycin at 50 mg/kg of body weight subcutaneously (s.c.), nafcillin at 100 mg/kg s.c., vancomycin at 100 mg/kg s.c., linezolid at 100 mg/kg via gavage (orally), or saline (10 ml/kg s.c.). The mice were anesthetized hourly, and photon emissions from living bioluminescent bacteria were imaged and quantified. The luminescence in saline-treated control mice either increased (neutropenic mice) or remained relatively unchanged (healthy mice). In contrast, by 2 to 3 h postdosing, daptomycin effected a 90% reduction of luminescence of MSSA or MRSA in both healthy and neutropenic mice. The activity of daptomycin against both MSSA and MRSA strains was superior to those of nafcillin, vancomycin, and linezolid. Against MSSA peritonitis, daptomycin showed greater and more rapid bactericidal activity than nafcillin or linezolid. Against MRSA peritonitis, daptomycin showed greater and more rapid bactericidal activity than vancomycin or linezolid. The rapid decrease in the luminescent signal in the daptomycin-treated neutropenic mice underscores the potency of this antibiotic against S. aureus in the immune-suppressed host.

scholarly journals Pharmacological Properties of the Marine Natural Product Marinopyrrole A against Methicillin-Resistant Staphylococcus aureus

2011 ◽  
Vol 55 (7) ◽  
pp. 3305-3312 ◽  
Author(s):  
Nina M. Haste ◽  
Chambers C. Hughes ◽  
Dan N. Tran ◽  
William Fenical ◽  
Paul R. Jensen ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Effect ◽  
Inhibitory Effect ◽  
Marine Natural Product ◽  
Methicillin Resistant ◽  
Content Type ◽  
Mammalian Cell Lines ◽  
Antistaphylococcal Activity ◽  
New Antibiotics ◽  
Mrsa Strains

ABSTRACTThe ongoing spread of methicillin-resistantStaphylococcus aureus(MRSA) strains in hospital and community settings presents a great challenge to public health and illustrates the urgency of discovering new antibiotics. Marinopyrrole A is a member of a structurally novel class of compounds identified from a species of marine-derived streptomycetes with evidence of antistaphylococcal activity. We show that marinopyrrole A has potent concentration-dependent bactericidal activity against clinically relevant hospital- and community-acquired MRSA strains, a prolonged postantibiotic effect superior to that of the current first-line agents vancomycin and linezolid, and a favorable resistance profile. Marinopyrrole A showed limited toxicity to mammalian cell lines (at >20× MIC). However, its antibiotic activity against MRSA was effectively neutralized by 20% human serum. A variety of marinopyrrole analogs were isolated from culture or synthetically produced to try to overcome the inhibitory effect of serum. While many of these compounds retained potent bactericidal effect against MRSA, their activities were also inhibited by serum. Marinopyrrole A has significant affinity for plastic and may therefore have potential as a potent anti-MRSA agent in cutaneous, intracatheter, or antibiotic-lock applications.

scholarly journals In VivoEffect of Flucloxacillin in Experimental Endocarditis Caused bymecC-positive Staphylococcus aureus Showing Temperature-Dependent SusceptibilityIn Vitro

2015 ◽  
Vol 59 (4) ◽  
pp. 2435-2438 ◽  
Author(s):  
Stefano Mancini ◽  
Frédéric Laurent ◽  
Tiago R. Veloso ◽  
Marlyse Giddey ◽  
Jacques Vouillamoz ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Rat Model ◽  
Temperature Dependent ◽  
Methicillin Resistant ◽  
Content Type ◽  
Mrsa Strains ◽  
Kinetics Of

ABSTRACTMethicillin-resistantStaphylococcus aureus(MRSA) carrying themecCgene (mecC-MRSA) exhibited at 37°C MICs of oxacillin close to those of methicillin-susceptibleS. aureus(MSSA). We investigated whether at this temperature,mecC-MRSA strains respond to flucloxacillin treatment like MSSA strains, using a rat model of endocarditis. Flucloxacillin (human-like kinetics of 2 g intravenously every 6 h) cured 80 to 100% of aortic vegetations infected with five differentmecC-MRSA strains. These results suggest thatmecC-MRSA infections may successfully respond to treatment with β-lactams.

scholarly journals In VitroActivity of Fusidic Acid (CEM-102, Sodium Fusidate) against Staphylococcus aureus Isolates from Cystic Fibrosis Patients and Its Effect on the Activities of Tobramycin and Amikacin against Pseudomonas aeruginosa and Burkholderia cepacia

2011 ◽  
Vol 55 (5) ◽  
pp. 2417-2419 ◽  
Author(s):  
Pamela McGhee ◽  
Catherine Clark ◽  
Kim Credito ◽  
Linda Beachel ◽  
Glenn A. Pankuch ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Protein Binding ◽  
Fusidic Acid ◽  
Burkholderia Cepacia ◽  
Methicillin Resistant ◽  
Content Type ◽  
Mrsa Strains ◽  
Time Kill

ABSTRACTWe tested the MICs of fusidic acid (CEM-102) plus other agents against 40 methicillin-resistantStaphylococcus aureus(MRSA) isolates from cystic fibrosis patients and the activities of fusidic acid with or without tobramycin or amikacin againstPseudomonas aeruginosa, MRSA, andBurkholderia cepaciaisolates from cystic fibrosis patients in a 24-h time-kill study. Fusidic acid was potent (MICs, 0.125 to 0.5 μg/ml; a single 500-mg dose of fusidic acid at 8 h averaged 8 to 12. 5 μg/ml with 91 to 97% protein binding) against all MRSA strains. No antagonism was observed; synergy occurred for one MRSA strain treated with fusidic acid plus tobramycin.

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