Synergistic bactericide and antibiotic effects of dimeric, tetrameric, or palindromic peptides containing the RWQWR motif against Gram-positive and Gram-negative strains

Time-kill curve plot. Peptide LfcinB (20–25)4againstS. aureusATCC 25923. The peptide was tested at concentrations corresponding to MIC (blue line), 2 MIC (pink line) and 4 MIC (orange line) values.

In vitro synergy of 5-nitrofurans, vancomycin and sodium deoxycholate against Gram-negative pathogens

Journal of Medical Microbiology ◽

10.1099/jmm.0.001304 ◽

2021 ◽

Author(s):

Catrina Olivera ◽

Vuong Van Hung Le ◽

Catherine Davenport ◽

Jasna Rakonjac

Keyword(s):

Growth Inhibition ◽

Type Species ◽

Sodium Deoxycholate ◽

Gram Positive ◽

Bacterial Killing ◽

Gram Negative ◽

Content Type ◽

Link Type ◽

Introduction. There is an urgent need for effective therapies against bacterial infections, especially those caused by antibiotic-resistant Gram-negative pathogens. Hypothesis. Synergistic combinations of existing antimicrobials show promise due to their enhanced efficacies and reduced dosages which can mitigate adverse effects, and therefore can be used as potential antibacterial therapy. Aim. In this study, we sought to characterize the in vitro interaction of 5-nitrofurans, vancomycin and sodium deoxycholate (NVD) against pathogenic bacteria. Methodology. The synergy of the NVD combination was investigated in terms of growth inhibition and bacterial killing using checkerboard and time-kill assays, respectively. Results. Using a three-dimensional checkerboard assay, we showed that 5-nitrofurans, sodium deoxycholate and vancomycin interact synergistically in the growth inhibition of 15 out of 20 Gram-negative strains tested, including clinically significant pathogens such as carbapenemase-producing Escherichia coli , Klebsiella pneumoniae and Acinetobacter baumannii , and interact indifferently against the Gram-positive strains tested. The time-kill assay further confirmed that the triple combination was bactericidal in a synergistic manner. Conclusion. This study demonstrates the synergistic effect of 5-nitrofurans, sodium deoxycholate and vancomycin against Gram-negative pathogens and highlights the potential of the combination as a treatment for Gram-negative and Gram-positive infections.

In Vitro Activities of ME1036 (CP5609), a Novel Parenteral Carbapenem, against Methicillin-Resistant Staphylococci

10.1128/aac.48.8.2831-2837.2004 ◽

2004 ◽

Vol 48 (8) ◽

pp. 2831-2837 ◽

Cited By ~ 31

Author(s):

Mizuyo Kurazono ◽

Takashi Ida ◽

Keiko Yamada ◽

Yoko Hirai ◽

Takahisa Maruyama ◽

...

Keyword(s):

Multiple Drug ◽

Gram Negative Bacteria ◽

Coagulase Negative Staphylococci ◽

Gram Positive ◽

Gram Negative ◽

Methicillin Resistant ◽

Gram Positive Bacteria ◽

Multiple Drug Resistant ◽

ABSTRACT ME1036, formerly CP5609, is a novel parenteral carbapenem with a 7-acylated imidazo[5,1-b]thiazole-2-yl group directly attached to the carbapenem moiety of the C-2 position. The present study evaluated the in vitro activities of ME1036 against clinical isolates of gram-positive and gram-negative bacteria. ME1036 displayed broad activity against aerobic gram-positive and gram-negative bacteria. Unlike other marketed β-lactam antibiotics, ME1036 maintained excellent activity against multiple-drug-resistant gram-positive bacteria, such as methicillin-resistant staphylococci and penicillin-resistant Streptococcus pneumoniae (PRSP). The MICs of this compound at which 90% of isolates were inhibited were 2 μg/ml for methicillin-resistant Staphylococcus aureus (MRSA), 2 μg/ml for methicillin-resistant coagulase-negative staphylococci, and 0.031 μg/ml for PRSP. In time-kill studies with six strains of MRSA, ME1036 at four times the MIC caused a time-dependent decrease in the numbers of viable MRSA cells. The activity of ME1036 against MRSA is related to its high affinity for penicillin-binding protein 2a, for which the 50% inhibitory concentration of ME1036 was approximately 300-fold lower than that of imipenem. In conclusion, ME1036 demonstrated a broad antibacterial spectrum and high levels of activity in vitro against staphylococci, including β-lactam-resistant strains.

Activity of Telithromycin (HMR 3647) against Anaerobic Bacteria Compared to Those of Eight Other Agents by Time-Kill Methodology

10.1128/aac.43.8.2027 ◽

1999 ◽

Vol 43 (8) ◽

pp. 2027-2031 ◽

Cited By ~ 16

Author(s):

Kim L. Credito ◽

Lois M. Ednie ◽

Michael R. Jacobs ◽

Peter C. Appelbaum

Keyword(s):

Propionibacterium Acnes ◽

Anaerobic Bacteria ◽

Bacteroides Fragilis ◽

Bacteroides Thetaiotaomicron ◽

Gram Positive ◽

Gram Negative ◽

Amoxicillin Clavulanate ◽

Erythromycin A ◽

Time Kill ◽

Kinetics Of

ABSTRACT Time-kill studies examined the activities of telithromycin (HMR 3647), erythromycin A, azithromycin, clarithromycin, roxithromycin, clindamycin, pristinamycin, amoxicillin-clavulanate, and metronidazole against 11 gram-positive and gram-negative anaerobic bacteria. Time-kill studies were carried out with the addition of Oxyrase in order to prevent the introduction of CO2. Macrolide-azalide-ketolide MICs were 0.004 to 32.0 μg/ml. Of the latter group, telithromycin had the lowest MICs, especially against non-Bacteroides fragilis group strains, followed by azithromycin, clarithromycin, erythromycin A, and roxithromycin. Clindamycin was active (MIC ≤ 2.0 μg/ml) against all anaerobes except Peptostreptococcus magnus and Bacteroides thetaiotaomicron, while pristinamycin MICs were 0.06 to 4.0 μg/ml. Amoxicillin-clavulanate had MICs of ≤1.0 μg/ml, while metronidazole was active (MICs, 0.03 to 2.0 μg/ml) against all exceptPropionibacterium acnes. After 48 h at twice the MIC, telithromycin was bactericidal (≥99.9% killing) against 6 strains, with 99% killing of 9 strains and 90% killing of 10 strains. After 24 h at twice the MIC, 90, 99, and 99.9% killing of nine, six, and three strains, respectively, occurred. Lower rates of killing were seen at earlier times. Similar kill kinetics relative to the MIC were seen with other macrolides. After 48 h at the MIC, clindamycin was bactericidal against 8 strains, with 99 and 90% killing of 9 and 10 strains, respectively. After 24 h, 90% killing of 10 strains occurred at the MIC. The kinetics of clindamycin were similar to those of pristinamycin. After 48 h at the MIC, amoxicillin-clavulanate showed 99.9% killing of seven strains, with 99% killing of eight strains and 90% killing of nine strains. At four times the MIC, metronidazole was bactericidal against 8 of 10 strains tested after 48 h and against all 10 strains after 24 h; after 12 h, 99% killing of all 10 strains occurred.

Antimicrobial activity of DU-6681a, a parent compound of novel oral carbapenem DZ-2640.

10.1128/aac.41.6.1260 ◽

1997 ◽

Vol 41 (6) ◽

pp. 1260-1268 ◽

Cited By ~ 15

Author(s):

M Tanaka ◽

M Hohmura ◽

T Nishi ◽

K Sato ◽

I Hayakawa

Keyword(s):

Parent Compound ◽

Inoculum Size ◽

Gram Positive ◽

Gram Positive Bacteria ◽

Alkaline Conditions ◽

In Vitro Antibacterial Activity ◽

Acidic Conditions ◽

Kill Curve ◽

The in vitro antibacterial activity of DU-6681a, a parent compound of DZ-2640, against gram-positive and -negative bacteria was compared with those of penems and cephalosporins currently available. MICs at which 90% of the isolates are inhibited (MIC90s) of the compound for clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus and Staphylococcus epidermidis, including methicillin-susceptible and -resistant strains, were 0.10, 25, and 12.5 microg/ml, respectively. DU-6681a inhibited the growth of all strains of Streptococcus pyogenes and of penicillin-susceptible and -insusceptible Streptococcus pneumoniae at 0.006, 0.025, and 0.20 microg/ml, respectively, and MIC90s of the compound were 6.25 and >100 microg/ml for Enterococcus faecalis and Enterococcus faecium, respectively. MIC90s of DU-6681a were 0.20, 0.10, and 0.025 microg/ml for Haemophilus influenzae, Moraxella catarrhalis, and Neisseria gonorrhoeae, respectively. For Pseudomonas aeruginosa, the MIC50 and MIC90 of DU-6681a were 25 and 50 microg/ml, respectively. DU-6681a activity was not affected by different media, varied inoculum size (10(4) to 10(7) CFU), or the addition of human serum but was decreased under acidic conditions against gram-negative bacteria, under alkaline conditions against gram-positive bacteria, and in human urine, as was the activity of the other antibiotics tested. The frequency of spontaneous resistance to DU-6681a was less than or equal to those of the reference compounds. Time-kill curve studies demonstrated the bactericidal action of DU-6681a against S. aureus, S. pneumoniae, Escherichia coli, and H. influenzae.

In Vitro and In Vivo Antibacterial Activities of Heteroaryl Isothiazolones against Resistant Gram-Positive Pathogens

10.1128/aac.01315-06 ◽

2007 ◽

Vol 51 (4) ◽

pp. 1259-1267 ◽

Cited By ~ 15

Author(s):

Michael J. Pucci ◽

Jijun Cheng ◽

Steven D. Podos ◽

Christy L. Thoma ◽

Jane A. Thanassi ◽

...

Keyword(s):

Legionella Pneumophila ◽

Standard Dose ◽

Antibacterial Activities ◽

Gram Positive ◽

Antibiotic Resistant ◽

Gram Negative ◽

Mrsa Strains ◽

ABSTRACT The activities of several tricyclic heteroaryl isothiazolones (HITZs) against an assortment of gram-positive and gram-negative clinical isolates were assessed. These compounds target bacterial DNA replication and were found to possess broad-spectrum activities especially against gram-positive strains, including antibiotic-resistant staphylococci and streptococci. These included methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-nonsusceptible staphylococci, and quinolone-resistant strains. The HITZs were more active than the comparator antimicrobials in most cases. For gram-negative bacteria, the tested compounds were less active against members of the family Enterobacteriaceae but showed exceptional potencies against Haemophilus influenzae, Moraxella catarrhalis, and Neisseria spp. Good activity against several anaerobes, as well as Legionella pneumophila and Mycoplasma pneumoniae, was also observed. Excellent bactericidal activity against staphylococci was observed in time-kill assays, with an approximately 3-log drop in the numbers of CFU/ml occurring after 4 h of exposure to compound. Postantibiotic effects (PAEs) of 2.0 and 1.7 h for methicillin-susceptible S. aureus and MRSA strains, respectively, were observed, and these were similar to those seen with moxifloxacin at 10× MIC. In vivo efficacy was demonstrated in murine infections by using sepsis and thigh infection models. The 50% protective doses were ≤1 mg/kg of body weight against S. aureus in the sepsis model, while decreases in the numbers of CFU per thigh equal to or greater than those detected in animals treated with a standard dose of vancomycin were seen in the animals with thigh infections. Pharmacokinetic analyses of treated mice indicated exposures similar to those to ciprofloxacin at equivalent dose levels. These promising initial data suggest further study on the use of the HITZs as antibacterial agents.

1077. In Vitro Activity of Delafloxacin Agent Against Bacterial Isolates Recovered from Patients with Cancer

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1271 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S628-S629

Author(s):

Bahgat Gerges ◽

Issam I Raad ◽

Joel Rosenblatt ◽

Samuel Shelbume ◽

Randal Prince ◽

...

Keyword(s):

Bactericidal Activity ◽

Antimicrobial Prophylaxis ◽

Vitro Activity ◽

In Vitro Activity ◽

Bacterial Isolates ◽

Gram Positive ◽

Gram Negative ◽

Patients With Cancer ◽

Abstract Background Fluoroquinolones have been used for infection prevention in patients with cancer (PWC). They are active against many Gram-negative bacilli (GNB) but are less active against Gram-positive organisms (GPO). Quinolone resistance is increasing and many institutions are using combination regimens for antimicrobial prophylaxis. We evaluated the in vitro activity of delafloxacin (DLX), a novel fluoroquinolone, and selected comparators against 560 bacterial isolates from PWC. Methods Isolates were from recent blood cultures. Susceptibility testing and time kill studies (TKS) were performed using CLSI approved methodology. Appropriate ATCC control strains were used. We calculated MIC50, MIC90, MIC ranges and percent susceptibility using FDA breakpoints when available. TKS were performed on 4 streptococcus mitis isolates at concentrations of MIC, 4x MIC, and 8x MIC. Results DLX was more active than ciprofloxacin (CIP) and levofloxacin (LEV) against methicillin-susceptible (MSSA), and resistant (MRSA) S. aureus, coagulase-negative staphylococci (CoNS), and viridans group streptococci (VGS), and had similar activity against beta-hemolytic streptococci. It also had low MICs for Bacillus species (SPP.), Listeria monocytogenes, Micrococcus spp., and Rothia spp. Overall GPO susceptibility was 73% to DLX, 42% to CIP, and 52% to LEV. The activity of DLX against Enterobacterales was similar to CIP and LEV. All 3 agents had moderate activity against Citrobacter spp., and non-MDR P. aeruginosa. Notably, all 3 quinolones had poor activity against E. coli, P. mirabilis, and MDR P. aeruginosa, all common pathogens in PWC. All 3 had low MICs for Acinetobacter spp. DLX and LEV achieved peak bactericidal activity at 6-8 h against all 4 VGS isolates (maximum activity at 8x MIC) but this was not always sustained at 24 h. Table 1. Percent Susceptibility of selected Gram-positive isolates to Delafloxacin, Ciprofloxacin and Levofloxacin Table 2. Percent Susceptibility of selected Gram-negative isolates to Delafloxacin, Ciprofloxacin and Levofloxacin Figure 1. Bactericidal Activity of DLX at 1x , 4x, and 8x MIC against VGS - Time Kill Study Conclusion DLX is more active than CIP and LEV against many GPO from PWC (including S. aureus and VGS), but like these agents there are significant gaps in its coverage against GNB. It is probably not suitable as a single agent for antimicrobial prophylaxis in high-risk PWC. The current practice of combining a quinolone with a beta-lactam probably still represents the best option in PWC who need prophylaxis. Disclosures Kenneth Rolston, MD, Tetraphase Pharmaceuticals (Grant/Research Support)

Repositioning rafoxanide to treat Gram-negative bacilli infections

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa103 ◽

2020 ◽

Vol 75 (7) ◽

pp. 1895-1905 ◽

Cited By ~ 1

Author(s):

Andrea Miró-Canturri ◽

Rafael Ayerbe-Algaba ◽

Ángel Rodríguez Villodres ◽

Jerónimo Pachón ◽

Younes Smani

Keyword(s):

Electron Microscopy ◽

Transmission Electron Microscopy ◽

Morphological Changes ◽

Gram Negative ◽

Sepsis Model ◽

Transmission Electron ◽

Kill Curve ◽

Abstract Objectives Repurposing drugs provides a new approach to the fight against MDR Gram-negative bacilli (MDR-GNB). Rafoxanide, a veterinary antihelminthic drug, has shown antibacterial activity in vitro against Gram-positive bacteria. We aimed to analyse the in vitro and in vivo efficacy of rafoxanide in combination with colistin against colistin-susceptible (Col-S) and colistin-resistant (Col-R) GNB. Methods A collection of Col-S and Col-R Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae were used. Chequerboard and time–kill curve analyses were performed to determine the synergy between rafoxanide and colistin. Changes in membrane structure and permeability were analysed using transmission electron microscopy and fluorescence assays. A murine peritoneal sepsis model using Col-R strains of these pathogens was performed to study the efficacy of rafoxanide (10 mg/kg/24 h, IV), colistimethate sodium (CMS) (20 mg/kg/8 h, intraperitoneally) and rafoxanide (10 mg/kg/24 h, IV) plus CMS (20 mg/kg/8 h, intraperitoneally) for 72 h. Results Rafoxanide showed MICs ≥256 mg/L for all Col-S and Col-R strains. Chequerboard and time–kill curve analyses showed that rafoxanide (1 mg/L) is more synergistic with colistin against Col-R than Col-S strains. Col-R, but not Col-S, strains treated with rafoxanide demonstrated higher membrane permeabilization. Transmission electron microscopy visualization confirmed that Col-R strains suffer morphological changes. In the murine peritoneal sepsis model with Col-R strains, rafoxanide plus CMS, compared with CMS alone, increased mouse survival to 53.8% and 73.3%, and reduced bacterial loads in tissues and blood between 2.34 and 4.99 log10 cfu/g or mL, respectively. Conclusions Rafoxanide repurposing, as monotherapy and in combination with CMS, may address the urgent need for new treatments for infections caused by MDR-GNB.

Pharmacodynamic properties of BAY 12-8039 on gram-positive and gram-negative organisms as demonstrated by studies of time-kill kinetics and postantibiotic effect.

10.1128/aac.41.6.1377 ◽

1997 ◽

Vol 41 (6) ◽

pp. 1377-1379 ◽

Cited By ~ 28

Author(s):

F J Boswell ◽

J M Andrews ◽

R Wise

Keyword(s):

Streptococcus Pyogenes ◽

Coli Strain ◽

Postantibiotic Effect ◽

Gram Positive ◽

Gram Negative ◽

E Coli ◽

Marked Activity ◽

Gram Negative Organisms ◽

Time Kill ◽

Kinetics Of

Time-kill kinetics of BAY 12-8039 were studied at two inocula against three strains each of Bacteroides fragilis, Escherichia coli, Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pyogenes. The postantibiotic effects of BAY 12-8039 were studied on three strains each of E. coli, S. aureus, H. influenzae, Streptococcus pyogenes, and Streptococcus pneumoniae. The pharmacodynamic data demonstrated that BAY 12-8039 has marked activity against gram-positive and gram-negative organisms (under both anaerobic and aerobic conditions) and anaerobes. BAY 12-8039 also exhibited a postantibiotic effect of >1 h for all strains except one E. coli strain.

Activities of Clinafloxacin, Alone and in Combination with Other Compounds, against 45 Gram-Positive and -Negative Organisms for Which Clinafloxacin MICs Are High

10.1128/aac.43.9.2295 ◽

1999 ◽

Vol 43 (9) ◽

pp. 2295-2298 ◽

Cited By ~ 5

Author(s):

Catherine L. Clark ◽

Michael R. Jacobs ◽

Peter C. Appelbaum

Keyword(s):

Gram Positive ◽

Gram Negative ◽

ABSTRACT Time-kill studies indicated that clinafloxacin showed synergy after 24 h with ceftazidime, amikacin, and imipenem against 12, 8, and 10 of 33 gram-negative rods, respectively; with vancomycin, teicoplanin, cefotaxime, and amikacin against 3, 3, 1, and 1 of 9 staphylococci and enterococci, respectively; and with vancomycin, penicillin, and cefotaxime against 0, 2, and 2 of 3 pneumococci, respectively. The MICs of clinafloxacin alone for most strains were ≥1 μg/ml.

Antibacterial Activity of Colloidal Silver against Gram-Negative and Gram-Positive Bacteria

Antibiotics ◽

10.3390/antibiotics9010036 ◽

2020 ◽

Vol 9 (1) ◽

pp. 36 ◽

Cited By ~ 4

Author(s):

Andrea Vila Domínguez ◽

Rafael Ayerbe Algaba ◽

Andrea Miró Canturri ◽

Ángel Rodríguez Villodres ◽

Younes Smani

Keyword(s):

Bacterial Infections ◽

Antimicrobial Properties ◽

Multidrug Resistant ◽

Colloidal Silver ◽

Ros Production ◽

Gram Positive ◽

Gram Negative ◽

Gram Positive Bacteria ◽

Kill Curve

Due to the emergence of antimicrobial resistance, new alternative therapies are needed. Silver was used to treat bacterial infections since antiquity due to its known antimicrobial properties. Here, we aimed to evaluate the in vitro activity of colloidal silver (CS) against multidrug-resistant (MDR) Gram-negative and Gram-positive bacteria. A total of 270 strains (Acinetobacter baumannii (n = 45), Pseudomonas aeruginosa (n = 25), Escherichia coli (n = 79), Klebsiella pneumoniae (n = 58)], Staphylococcus aureus (n = 34), Staphylococcus epidermidis (n = 14), and Enterococcus species (n = 15)) were used. The minimal inhibitory concentration (MIC) of CS was determined for all strains by using microdilution assay, and time–kill curve assays of representative reference and MDR strains of these bacteria were performed. Membrane permeation and bacterial reactive oxygen species (ROS) production were determined in presence of CS. CS MIC90 was 4–8 mg/L for all strains. CS was bactericidal, during 24 h, at 1× and 2× MIC against Gram-negative bacteria, and at 2× MIC against Gram-positive bacteria, and it did not affect their membrane permeabilization. Furthermore, we found that CS significantly increased the ROS production in Gram-negative with respect to Gram-positive bacteria at 24 h of incubation. Altogether, these results suggest that CS could be an effective treatment for infections caused by MDR Gram-negative and Gram-positive bacteria.