scholarly journals Adjunctive transferrin to reduce the emergence of antibiotic resistance in Gram-negative bacteria

2019 ◽  
Vol 74 (9) ◽  
pp. 2631-2639 ◽  
Author(s):  
Brian M Luna ◽  
Ksenia Ershova ◽  
Jun Yan ◽  
Amber Ulhaq ◽  
Travis B Nielsen ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Bacterial Pathogens ◽  
Microbial Pathogens ◽  
Gram Negative Bacteria ◽  
Antibiotic Resistant ◽  
Gram Negative ◽  
Resistant Mutants ◽  
Time Kill ◽  
Emergence Of Resistance

AbstractBackgroundNew strategies are needed to slow the emergence of antibiotic resistance among bacterial pathogens. In particular, society is experiencing a crisis of antibiotic-resistant infections caused by Gram-negative bacterial pathogens and novel therapeutics are desperately needed to combat such diseases. Acquisition of iron from the host is a nearly universal requirement for microbial pathogens—including Gram-negative bacteria—to cause infection. We have previously reported that apo-transferrin (lacking iron) can inhibit the growth of Staphylococcus aureus in culture and diminish emergence of resistance to rifampicin.ObjectivesTo define the potential of apo-transferrin to inhibit in vitro growth of Klebsiella pneumoniae and Acinetobacter baumannii, key Gram-negative pathogens, and to reduce emergence of resistance to antibiotics.MethodsThe efficacy of apo-transferrin alone or in combination with meropenem or ciprofloxacin against K. pneumoniae and A. baumannii clinical isolates was tested by MIC assay, time–kill assay and assays for the selection of resistant mutants.ResultsWe confirmed that apo-transferrin had detectable MICs for all strains tested of both pathogens. Apo-transferrin mediated an additive antimicrobial effect for both antibiotics against multiple strains in time–kill assays. Finally, adding apo-transferrin to ciprofloxacin or meropenem reduced the emergence of resistant mutants during 20 day serial passaging of both species.ConclusionsThese results suggest that apo-transferrin may have promise to suppress the emergence of antibiotic-resistant mutants when treating infections caused by Gram-negative bacteria.

scholarly journals Formation in vitro of colistin resistance in carbapenem-resistant Gram-negative bacteria and its biological cost

2021 ◽  
Author(s):  
D. V. Tapalski ◽  
T. A. Petrovskaya ◽  
A. E. Kozlov
Keyword(s):  
Broth Culture ◽  
Exponential Growth Phase ◽  
Lag Phase ◽  
Gram Negative Bacteria ◽  
Colistin Resistance ◽  
Gram Negative ◽  
Broth Microdilution Method ◽  
Resistant Mutants ◽  
Biological Cost

Introduction. The spread of resistance to carbapenems among gram-negative bacteria have led to an increase in the consumption of polymyxins and the emergence of certain strains resistant to them. Polymyxin resistance is mainly associated with mutations in chromosomal genes. The development of mutational resistance to antibiotics can lead to a decrease in the viability of bacteria, which is manifested by an increase in the duration of the cell cycle, a decrease in virulence and competitive fitness. The purpose of the study was to assess in vitro the intensity of the formation of colistin resistance in carbapenemresistant clinical isolates of gram-negative bacteria, the stability of the formed emerged resistance and its biological cost.Materials and methods. For 46 strains of Klebsiella pneumoniae, 77 strains of Pseudomonas aeruginosa and 42 strains of Acinetobacter baumannii, real time polymerase chain reaction (PCR) was used to detect the genes of carbapenemases, the minimum inhibitory concentrations (MIC) of meropenem and colistin were determined by broth microdilution method. The selection of resistant subpopulations on Muller–Hinton agar with the addition of 16 mg/l colistin was carried out. For colistin-resistant mutants and their isogenic sensitive strains, the kinetic parameters of growth in broth culture were determined. Incubation and result recording were performed on an Infinite M200 microplate reader for 18.5 hours at 35°C with measurement of light scatter in the wells every 15 minutes.Results. The production of carbapenemases MBL VIM in P. aeruginosa, MBL NDM, KPC and OXA-48 in K. pneumoniae, OXA-23 and OXA-40 in A. baumannii was observed. All strains were sensitive to colistin (MIC varied from 0.062 to 2 mg/l). The colony growth on a selective medium with16 mg/l colistin was observed for 97.8% of K. pneumoniae strains, 16.9% of P. aeruginosa strains, and 61.9% of A. baumannii strains. The mutational nature of colistin resistance was confirmed for 21.7% of K. pneumoniae strains. For colistin-resistant mutants of K. pneumoniae, a significant increase in the duration of the lag phase (Tlag) was observed: 225.6 ± 7.037 min in the wild-type susceptible strains and 245.5 ± 8.726 in resistant mutants, p = 0.037. The indicators of the doubling time of the number of microbial cells in the exponential growth phase (Tdoubling) and the area under the bacterial growth curve did not differ significantly.Conclusion. A high frequency of formation of colistin resistance in vitro in carbapenemase-producing strains of K. pneumoniae was observed. The absence of significant changes in the kinetics of microbial growth in resistant strains makes it possible to predict the further spread of mutational resistance to colistin, as well as its preservation in microbial populations of K. pneumoniae even in the case of limiting the use of this antibiotic. 

scholarly journals In Vitro Anti-Helicobacter pyloriActivities of New Rifamycin Derivatives, KRM-1648 and KRM-1657

1999 ◽  
Vol 43 (5) ◽  
pp. 1072-1076 ◽  
Author(s):  
Junko K. Akada ◽  
Mutsunori Shirai ◽  
Kenji Fujii ◽  
Kiwamu Okita ◽  
Teruko Nakazawa
Keyword(s):  
Helicobacter Pylori ◽  
Cell Lysis ◽  
Antimicrobial Activities ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Bactericidal Activities ◽  
H Pylori ◽  
Time Kill

ABSTRACT The new rifamycin derivatives KRM-1657 and KRM-1648 were evaluated for their in vitro antimicrobial activities against 44 strains ofHelicobacter pylori. Although the drugs were not very active against other gram-negative bacteria, the MICs at which 90% of isolates are inhibited for these drugs were lower (0.002 and 0.008 μg/ml, respectively) than those of amoxicillin and rifampin forH. pylori. Time-kill studies revealed that the bactericidal activities of these agents were due to cell lysis. The results presented here indicate that these new rifamycin derivatives may be useful for the eradication of H. pylori infections.

scholarly journals Elimination of Extracellular Adenosine Triphosphate for the Rapid Prediction of Quantitative Plate Counts in 24 h Time-Kill Studies against Carbapenem-Resistant Gram-Negative Bacteria

2020 ◽  
Vol 8 (10) ◽  
pp. 1489
Author(s):  
Yiying Cai ◽  
Jonathan J. Ng ◽  
Hui Leck ◽  
Jocelyn Q. Teo ◽  
Jia-Xuan Goh ◽  
...  
Keyword(s):  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Infection Models ◽  
Rapid Prediction ◽  
Atp Bioluminescence ◽  
Plate Counts ◽  
Time Kill

Traditional in vitro time-kill studies (TKSs) require viable plating, which is tedious and time-consuming. We used ATP bioluminescence, with the removal of extracellular ATP (EC-ATP), as a surrogate for viable plating in TKSs against carbapenem-resistant Gram-negative bacteria (CR-GNB). Twenty-four-hour TKSs were conducted using eight clinical CR-GNB (two Escherichia coli, two Klebsiella spp., two Acinetobacter baumannii, two Pseudomonas aeruginosa) with multiple single and two-antibiotic combinations. ATP bioluminescence and viable counts were determined at each timepoint (0, 2, 4, 8, 24 h), with and without apyrase treatment. Correlation between ATP bioluminescence and viable counts was determined for apyrase-treated and non-apyrase-treated samples. Receiver operator characteristic curves were plotted to determine the optimal luminescence threshold to discriminate between inhibitory/non-inhibitory and bactericidal/non-bactericidal combinations, compared to viable counts. After treatment of bacteria with 2 U/mL apyrase for 15 min at 37 °C, correlation to viable counts was significantly higher compared to untreated samples (p < 0.01). Predictive accuracies of ATP bioluminescence were also significantly higher for apyrase-treated samples in distinguishing inhibitory (p < 0.01) and bactericidal (p = 0.03) combinations against CR-GNB compared to untreated samples, when all species were collectively analyzed. We found that ATP bioluminescence can potentially replace viable plating in TKS. Our assay also has applications in in vitro and in vivo infection models.

scholarly journals Antibiotic Resistance of Gram-Negative Bacteria from Wild Captured Loggerhead Sea Turtles

Antibiotics ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 162 ◽  
Author(s):  
Monica Francesca Blasi ◽  
Luciana Migliore ◽  
Daniela Mattei ◽  
Alice Rotini ◽  
Maria Cristina Thaller ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Sea Turtles ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Marine Animals ◽  
Loggerhead Sea Turtles ◽  
Antibiotic Resistant ◽  
Gram Negative ◽  
Marine Habitats ◽  
Resistant Strains

Sea turtles have been proposed as health indicators of marine habitats and carriers of antibiotic-resistant bacterial strains, for their longevity and migratory lifestyle. Up to now, a few studies evaluated the antibacterial resistant flora of Mediterranean loggerhead sea turtles (Caretta caretta) and most of them were carried out on stranded or recovered animals. In this study, the isolation and the antibiotic resistance profile of 90 Gram negative bacteria from cloacal swabs of 33 Mediterranean wild captured loggerhead sea turtles are described. Among sea turtles found in their foraging sites, 23 were in good health and 10 needed recovery for different health problems (hereafter named weak). Isolated cloacal bacteria belonged mainly to Enterobacteriaceae (59%), Shewanellaceae (31%) and Vibrionaceae families (5%). Although slight differences in the bacterial composition, healthy and weak sea turtles shared antibiotic-resistant strains. In total, 74 strains were endowed with one or multi resistance (up to five different drugs) phenotypes, mainly towards ampicillin (~70%) or sulfamethoxazole/trimethoprim (more than 30%). Hence, our results confirmed the presence of antibiotic-resistant strains also in healthy marine animals and the role of the loggerhead sea turtles in spreading antibiotic-resistant bacteria.

scholarly journals Antibiotic-Resistant Gram-Negative Bacteria in Birds From the Brazilian Atlantic Forest

The Condor ◽  
2003 ◽  
Vol 105 (2) ◽  
pp. 358-361 ◽  
Author(s):  
Andréa M. A. Nascimento ◽  
Luciana Cursino ◽  
Higgor Gonçalves-Dornelas ◽  
Andrea Reis ◽  
Edmar Chartone-Souza ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Kanamycin Resistance ◽  
Minas Gerais ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Brazilian Atlantic Forest ◽  
Antibiotic Resistant ◽  
Gram Negative ◽  
Resistant Phenotype ◽  
Animal Farms

Abstract We evaluated the antibiotic resistance of bacteria isolated from cloacal swabs of wild birds collected with mist nets in the Jequitinhonha river valley, in the state of Minas Gerais, Brazil. A total of 191 isolates from 19 individuals of 16 species was obtained and tested for resistance to five antibiotics. At Salto da Divisa 97% of the isolates exhibited a resistant phenotype, and resistance to more than one antibiotic was frequent (71%). At Jequitinhonha 36% of isolates were resistant, but 94% showed resistance to only one antibiotic. Of the five antibiotics tested, resistance to ampicillin was most frequent (in both areas), whereas kanamycin resistance was found in only one isolate. The data here obtained and other data reported in the literature show that the general premise that antibiotic-resistant bacteria arise primarily in hospitals or animal farms should be reconsidered. Bactérias Gram-Negativas Resistentes a Antibióticos em Aves da Mata Atlântica Brasileira Resumo. Avaliamos a resistência a antibióticos de bactérias isoladas por swab cloacal em aves selvagens capturadas com redes de neblina em duas regiões do Vale do Rio Jequitinhonha, Minas Gerais, Brasil. Foram obtidos 191 isolados de 19 indivíduos de 16 espécies e foi testada a resistência desses isolados a cinco antibióticos. Em Salto da Divisa, 97% dos isolados exibiram fenótipo resistente e foi freqüente (71%) a resistência a mais de um antibiótico. Em Jequitinhonha, 36% dos isolados exibiram fenótipo resistente, dos quais 94% apresentaram resistência a apenas um antibiótico. Em ambas as áreas, a maioria dos isolados apresentou resistência à ampicilina, enquanto somente um único isolado foi resistente à canamicina. Os dados aqui obtidos e outros relatados na literatura mostram que a premissa geral de que bactérias resistentes a antibióticos surgem principalmente em hospitais ou fazendas de animais deve ser reconsiderada.

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

2004 ◽  
Vol 48 (8) ◽  
pp. 2831-2837 ◽  
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 ◽  
Time Kill

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.

scholarly journals Repurposing of the Fasciolicide Triclabendazole to Treat Infections Caused by Staphylococcus spp. and Vancomycin-Resistant Enterococci

2021 ◽  
Vol 9 (8) ◽  
pp. 1697
Author(s):  
Hongfei Pi ◽  
Abiodun D. Ogunniyi ◽  
Bhumi Savaliya ◽  
Hang Thi Nguyen ◽  
Stephen W. Page ◽  
...  
Keyword(s):  
Fasciola Hepatica ◽  
Bacterial Pathogens ◽  
Oral Treatment ◽  
Polymyxin B ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant

One approach to combat the increasing incidence of multidrug-resistant (MDR) bacterial pathogens involves repurposing existing compounds with known safety and development pathways as new antibacterial classes with potentially novel mechanisms of action. Here, triclabendazole (TCBZ), a drug originally developed to treat Fasciola hepatica (liver fluke) in sheep and cattle, and later in humans, was evaluated as an antibacterial alone or in combination with sub-inhibitory concentrations of polymyxin B (PMB) against clinical isolates and reference strains of key Gram-positive and Gram-negative bacteria. We show for the first time that in vitro, TCBZ selectively kills methicillin-sensitive and methicillin-resistant Staphylococcus aureus and Staphylococcus pseudintermedius at a minimum inhibitory concentration (MIC) range of 2–4 µg/mL, and vancomycin-resistant enterococci at a MIC range of 4–8 µg/mL. TCBZ also inhibited key Gram-negative bacteria in the presence of sub-inhibitory concentrations of PMB, returning MIC90 values of 1 µg/mL for Escherichia coli, 8 µg/mL for Klebsiella pneumoniae, 2 µg/mL for Acinetobacter baumannii and 4 µg/mL for Pseudomonasaeruginosa. Interestingly, TCBZ was found to be bacteriostatic against intracellular S. aureus but bactericidal against intracellular S. pseudintermedius. Additionally, TCBZ’s favourable pharmacokinetic (PK) and pharmacodynamic (PD) profile was further explored by in vivo safety and efficacy studies using a bioluminescent mouse model of S. aureus sepsis. We show that repeated four-hourly oral treatment of mice with 50 mg/kg TCBZ after systemic S. aureus challenge resulted in a significant reduction in S. aureus populations in the blood to 18 h post-infection (compared to untreated mice) but did not clear the bacterial infection from the bloodstream, consistent with in vivo bacteriostatic activity. These results indicate that additional pharmaceutical development of TCBZ may enhance its PK/PD, allowing it to be an appropriate candidate for the treatment of serious MDR bacterial pathogens.

A novel mechanism-based pharmacokinetic–pharmacodynamic (PKPD) model describing ceftazidime/avibactam efficacy against β-lactamase-producing Gram-negative bacteria

2019 ◽  
Author(s):  
Anders N Kristoffersson ◽  
Caterina Bissantz ◽  
Rusudan Okujava ◽  
Andreas Haldimann ◽  
Isabelle Walter ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Dose Finding ◽  
Gram Negative Bacteria ◽  
Data Set ◽  
Gram Negative ◽  
Pkpd Model ◽  
Index Approach ◽  
Antibiotic Effect ◽  
Time Kill

Abstract Background Diazabicyclooctanes (DBOs) are an increasingly important group of non β-lactam β-lactamase inhibitors, employed clinically in combinations such as ceftazidime/avibactam. The dose finding of such combinations is complicated using the traditional pharmacokinetic/pharmacodynamic (PK/PD) index approach, especially if the β-lactamase inhibitor has an antibiotic effect of its own. Objectives To develop a novel mechanism-based pharmacokinetic–pharmacodynamic (PKPD) model for ceftazidime/avibactam against Gram-negative pathogens, with the potential for combination dosage simulation. Methods Four β-lactamase-producing Enterobacteriaceae, covering Ambler classes A, B and D, were exposed to ceftazidime and avibactam, alone and in combination, in static time–kill experiments. A PKPD model was developed and evaluated using internal and external evaluation, and combined with a population PK model and applied in dosage simulations. Results The developed PKPD model included the effects of ceftazidime alone, avibactam alone and an ‘enhancer’ effect of avibactam on ceftazidime in addition to the β-lactamase inhibitory effect of avibactam. The model could describe an extensive external Pseudomonas aeruginosa data set with minor modifications to the enhancer effect, and the utility of the model for clinical dosage simulation was demonstrated by investigating the influence of the addition of avibactam. Conclusions A novel mechanism-based PKPD model for the DBO/β-lactam combination ceftazidime/avibactam was developed that enables future comparison of the effect of avibactam with other DBO/β-lactam inhibitors in simulations, and may be an aid in translating PKPD results from in vitro to animals and humans.

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

2007 ◽  
Vol 51 (4) ◽  
pp. 1259-1267 ◽  
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 ◽  
Time Kill

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.

Sign in / Sign up

Export Citation Format

Share Document