scholarly journals In vitro antimicrobial combination testing of and evolution of resistance to the first-in-class spiropyrimidinetrione zoliflodacin combined with six therapeutically relevant antimicrobials for Neisseria gonorrhoeae

2019 ◽  
Vol 74 (12) ◽  
pp. 3521-3529 ◽  
Author(s):  
Sunniva Foerster ◽  
George Drusano ◽  
Daniel Golparian ◽  
Michael Neely ◽  
Laura J V Piddock ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Single Agent ◽  
Curve Analysis ◽  
Phase Iii ◽  
Transmitted Infection ◽  
Kill Curve ◽  
Time Kill ◽  
Selection Of ◽  
Selection Of Resistance

Abstract Objectives Resistance in Neisseria gonorrhoeae to all gonorrhoea therapeutic antimicrobials has emerged. Novel therapeutic antimicrobials are imperative and the first-in-class spiropyrimidinetrione zoliflodacin appears promising. Zoliflodacin could be introduced in dual antimicrobial therapies to prevent the emergence and/or spread of resistance. We investigated the in vitro activity of and selection of resistance to zoliflodacin alone and in combination with six gonorrhoea therapeutic antimicrobials against N. gonorrhoeae. Methods The international gonococcal reference strains WHO F (WT) and WHO O, WHO V and WHO X (strains with different AMR profiles) were examined. Zoliflodacin was evaluated alone or combined with ceftriaxone, cefixime, spectinomycin, gentamicin, tetracycline, cethromycin or sitafloxacin in chequerboard assays, time–kill curve analysis and selection-of-resistance studies. Results Zoliflodacin alone or in combination with all six antimicrobials showed rapid growth inhibition against all examined strains. The time–kill curve analysis indicated that tetracycline or cethromycin combined with zoliflodacin can significantly decrease the zoliflodacin kill rate in vitro. The frequency of selected zoliflodacin-resistance mutations was low when evaluated as a single agent and further reduced for all antimicrobial combinations. All resistant mutants contained the GyrB mutations D429N, K450T or K450N, resulting in zoliflodacin MICs of 0.5–4 mg/L. Conclusions Zoliflodacin, alone or in combination with sexually transmitted infection therapeutic antimicrobials, rapidly kills gonococci with infrequent resistance emergence. Zoliflodacin remains promising for gonorrhoea oral monotherapy and as part of dual antimicrobial therapy with low resistance emergence potential. A Phase III trial evaluating efficacy and safety of zoliflodacin for uncomplicated gonorrhoea treatment is planned in 2019.

In vitro activity and time-kill curve analysis of sitafloxacin against a global panel of antimicrobial-resistant and multidrug-resistant Neisseria gonorrhoeae isolates

Apmis ◽  
2017 ◽  
Vol 126 (1) ◽  
pp. 29-37 ◽  
Author(s):  
Agnez Jönsson ◽  
Sunniva Foerster ◽  
Daniel Golparian ◽  
Ryoichi Hamasuna ◽  
Susanne Jacobsson ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Multidrug Resistant ◽  
Curve Analysis ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Kill Curve ◽  
Time Kill

scholarly journals Time-kill curve analysis and pharmacodynamic functions for in vitro evaluation of antimicrobials againstNeisseria gonorrhoeae

2015 ◽  
Author(s):  
Sunniva Foerster ◽  
Magnus Unemo ◽  
Lucy J Hathaway ◽  
Nicola Low ◽  
Christian L Althaus
Keyword(s):  
Bactericidal Effect ◽  
World Health ◽  
Transmitted Infection ◽  
In Vitro Evaluation ◽  
Sexually Transmitted ◽  
Dosing Strategies ◽  
Kill Curve ◽  
Health Organization ◽  
Time Kill

Gonorrhea is a sexually transmitted infection caused by the Gram-negative bacteriumNeisseria gonorrhoeae. Resistance to first-line empirical monotherapy has emerged, so robust methods are needed to appropriately evaluate the activity of existing and novel antimicrobials against the bacterium. Pharmacodynamic functions, which describe the relationship between the concentration of antimicrobials and the bacterial net growth rate, provide more detailed information than the MIC only. In this study, a novel standardized in vitro time-kill curve assay was developed. The assay was validated using five World Health OrganizationN. gonorrhoeaereference strains and various concentrations of ciprofloxacin, and then the activity of nine antimicrobials with different target mechanisms were examined against a highly susceptible clinical wild type isolate (cultured in 1964). From the time-kill curves, the bacterial net growth rates at each antimicrobial concentration were estimated. Finally, a pharmacodynamic function was fitted to the data, resulting in four parameters that describe the pharmacodynamic properties of each antimicrobial. Ciprofloxacin resistance determinants shifted the pharmacodynamic MIC (zMIC) and attenuated the bactericidal effect at antimicrobial concentrations above the zMIC. Ciprofloxacin, spectinomycin and gentamicin had the strongest bactericidal effect during the first six hours of the assay. Only tetracycline and chloramphenicol showed a purely bacteriostatic effect. The pharmacodynamic functions differed between antimicrobials, showing that the effect of the drugs at concentrations below and above the MIC vary widely. In conclusion,N. gonorrhoeaetime-kill curve experiments analyzed with pharmacodynamic functions have potential for in vitro evaluation of new and existing antimicrobials and dosing strategies to treat gonorrhea.

scholarly journals In Vitro Selection of Resistance to Clinafloxacin, Ciprofloxacin, and Trovafloxacin in Streptococcus pneumoniae

2000 ◽  
Vol 44 (10) ◽  
pp. 2740-2746 ◽  
Author(s):  
Kensuke Nagai ◽  
Todd A. Davies ◽  
Glenn A. Pankuch ◽  
Bonifacio E. Dewasse ◽  
Michael R. Jacobs ◽  
...  
Keyword(s):  
In Vitro Selection ◽  
Single Step ◽  
Mutation Rates ◽  
Mutant Strains ◽  
Efflux Mechanism ◽  
Resistant Mutants ◽  
Time Kill ◽  
Selection Of ◽  
Selection Of Resistance

ABSTRACT Ability of daily sequential subcultures in subinhibitory concentrations of clinafloxacin, ciprofloxacin, and trovafloxacin to select resistant mutants was studied in 10 pneumococci (ciprofloxacin MICs, 1 to 4 μg/ml, and clinafloxacin and trovafloxacin MICs, 0.06 to 0.125 μg/ml [n = 9]; ciprofloxacin, clinafloxacin, and trovafloxacin MICs, 32, 0.5, and 2 μg/ml, respectively [n = 1]). Subculturing was done 50 times, or until MICs increased fourfold or more. Mutants for which MICs were fourfold (or more) higher than those for parent strains were selected in five strains by clinafloxacin, in six strains by trovafloxacin, and nine strains by ciprofloxacin. Sequence analysis of type II topoisomerase showed that most mutants had mutations in ParC at Ser79 or Asp83 and in GyrA at Ser81, while a few mutants had mutations in ParE or GyrB. In the presence of reserpine, the MICs of ciprofloxacin and clinafloxacin for most mutants were lower (four to eight times lower), but for none of the mutants were trovafloxacin MICs lower, suggesting an efflux mechanism affecting the first two agents but not trovafloxacin. Single-step mutation rates were also determined for eight strains for which the MICs were as follows: 0.06 μg/ml (clinafloxacin), 0.06 to 0.125 μg/ml (trovafloxacin), and 1 μg/ml (ciprofloxacin). Single-step mutation rates with drugs at the MIC were 2.0×10−9 to <1.1×10−11, 5.0×10−4 to 3.6×10−9, and 4.8×10−4 to 6.7×10−9, respectively. For two strains with clinafloxacin MICs of 0.125 to 0.5 μg/ml trovafloxacin MICs of 0.125 to 2 μg/ml, ciprofloxacin MICs of 4 to 32 μg/ml mutation rates with drugs at the MIC were 1.1×10−8−9.6×10−8, 3.3×10−6−6.7×10−8, and 2.3×10−5−2.4×10−7, respectively. Clinafloxacin was bactericidal at four times the MIC after 24 h against three parent and nine mutant strains by time-kill study. This study showed that single and multistep clinafloxacin exposure selected for resistant mutants less frequently than similar exposures to other drugs studied.

The Effects of Shock Vancomycin Concentrations on the Formation of Heteroresistance in Staphylococcus aureus

2020 ◽  
Vol 65 (9-10) ◽  
pp. 3-7
Author(s):  
V. V. Gostev ◽  
Yu. V. Sopova ◽  
O. S. Kalinogorskaya ◽  
M. E. Velizhanina ◽  
I. V. Lazareva ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
In Vitro Selection ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
High Concentration ◽  
Short Term ◽  
High Concentrations ◽  
Selection Of ◽  
Selection Of Resistance ◽  
Test Cultures

Glycopeptides are the basis of the treatment of infections caused by MRSA (Methicillin-Resistant Staphylococcus aureus). Previously, it was demonstrated that antibiotic tolerant phenotypes are formed during selection of resistance under the influence of high concentrations of antibiotics. The present study uses a similar in vitro selection model with vancomycin. Clinical isolates of MRSA belonging to genetic lines ST8 and ST239, as well as the MSSA (ATCC29213) strain, were included in the experiment. Test isolates were incubated for five hours in a medium with a high concentration of vancomycin (50 μg/ml). Test cultures were grown on the medium without antibiotic for 18 hours after each exposure. A total of ten exposure cycles were performed. Vancomycin was characterized by bacteriostatic action; the proportion of surviving cells after exposure was 70–100%. After selection, there was a slight increase in the MIC to vancomycin (MIC 2 μg/ml), teicoplanin (MIC 1.5–3 μg/ml) and daptomycin (MIC 0.25–2 μg/ml). According to the results of PAP analysis, all strains showed an increase in the area under curve depending on the concentration of vancomycin after selection, while a heteroresistant phenotype (with PAP/AUC 0.9) was detected in three isolates. All isolates showed walK mutations (T188S, D235N, E261V, V380I, and G223D). Exposure to short-term shock concentrations of vancomycin promotes the formation of heteroresistance in both MRSA and MSSA. Formation of VISA phenotypes is possible during therapy with vancomycin.

Solithromycin as A Potential Novel Antibiotic Against Neisseria Gonorrhoeae Resistance

2020 ◽  
Author(s):  
Muhammad Habiburrahman ◽  
Vivian  Soetikno ◽  
Wani Riselia Sirait ◽  
Missy Savira
Keyword(s):  
Clinical Trial ◽  
Neisseria Gonorrhoeae ◽  
Wide Distribution ◽  
Phase Iii ◽  
Financial Loss ◽  
Anatomic Site ◽  
Transmitted Infection ◽  
Sexually Transmitted ◽  
Phase Iii Clinical Trials ◽  
New Treatment

Gonorrhea is one of the most often sexually transmitted infection in the world. In 2016, WHO stated the Southeast Asia region as the fourth-highest incidence rate and prevalence of gonorrhea. One of the current problems with gonorrhea is related to its emerging resistance to first-line drugs such as cephalosporins, macrolides, and fluoroquinolones. This resistance has an impact on the difficulty of finding effective antibiotics to eradicate the infection, thus risking financial loss and infertility in sexually active age patients. This literature review will discuss solithromycin, the first fluoroketolide in phase III clinical trial, and show its potential as a new antibiotic against infection with resistant Neisseria gonorrhoeae. Literatures are searched using Pubmed and Google Scholar search engines with keywords: antibiotics, CEM-101, clinical trial, Neisseria gonorrhoeae, new treatment, pharmacology, pharmacokinetics, resistance, safety, and solithromycin. This semisynthetic antibiotic is supported by a different chemical structure from previous macrolides; improving solithromycin becomes more stable and able to bind easier with bacterial ribosomes. Pharmacologically, solithromycin provides an advantage in its high bioavailability, easy oral administration route, wide distribution, metabolism mainly in the liver, but not required dosage adjustments due to hepatic impairment, and a single dosage preparation that can increase patient compliance in healing gonorrhea infections. Also, its lower MIC50 than previous antibiotics makes it well-tolerated, therefore making this antibiotic as a potential recommendation for the management of multi-drug resistant gonorrhea in the future. Solithromycin is not inferior to the standard therapy (ceftriaxone and azithromycin), with 80% vs. 84% gonorrhea eradication rates. Per the anatomic site, the eradication rate is 92% in genital, 94% in the pharynx, and 83% in the rectum. However, special attention needs to be paid to the side effects of the gastrointestinal tract of solithromycin, as observed in phase III clinical trials at a dose of 1000 mg in the form of diarrhea (24%) and nausea (21%).

scholarly journals Pharmacodynamic Analysis of the Activity of Quinupristin-Dalfopristin against Vancomycin-ResistantEnterococcus faecium with Differing MBCs via Time-Kill-Curve and Postantibiotic Effect Methods

1998 ◽  
Vol 42 (9) ◽  
pp. 2188-2192 ◽  
Author(s):  
Jeffrey R. Aeschlimann ◽  
Michael J. Rybak
Keyword(s):  
Antibacterial Activities ◽  
Water Soluble ◽  
Postantibiotic Effect ◽  
Curve Method ◽  
Highly Correlated ◽  
Kill Curve ◽  
The Individual ◽  
Time Kill

ABSTRACT Quinupristin-dalfopristin (Q-D) is a new water-soluble, semisynthetic antibiotic that is derived from natural streptogramins and that is combined in a 30:70 ratio. A number of studies have described the pharmacodynamic properties of this drug, but most have investigated only staphylococci or streptococci. We evaluated the relationship between Q-D, quinupristin (Q), and/or dalfopristin (D) susceptibility parameters and antibacterial activities against 22 clinical isolates of vancomycin-resistant Enterococcus faecium (VREF) by using the concentration-time-kill-curve method and by measuring postantibiotic effects. Q-D, Q, and D MICs and minimum bactericidal concentrations (MBCs) ranged from 0.125 to 1 and 0.25 to 64, 8 to 512 and >512, and 2 to 8 and 8 to 512 μg/ml, respectively. There were no significant relationships between susceptibilities to the individual components and the susceptibilities to the Q-D combination product. In the time-kill-curves studies, Q-D at a concentration of 6 μg/ml was at least bacteriostatic against all VREF tested. There was increased activity against more susceptible isolates when the isolates were grouped either by Q-D MBCs or by Q MICs. By multivariate regression analyses, the percent change in the inoculum from that at the baseline was significantly correlated with the Q MIC (R = 0.74; P = 0.008) and the Q-D concentration-to-MBC ratio (R = 0.58;P = 0.02) and was inversely correlated with the Q-D MBC-to-MIC ratio (R = 0.68; P = 0.003). A strong correlation existed between the killing rate and the Q-D concentration-to-MBC ratio (R = 0.99;P < 0.0001). Time to 99.9% killing was best correlated with the Q-D MBC (R = 0.96;P < 0.0001). The postantibiotic effect ranged from 0.2 to 3.2 h and was highly correlated with the Q-D concentration-to-MBC ratio (R = 0.96;P < 0.0001) and was less highly correlated with the Q MIC (R = 0.42; P = 0.04). Further study of these relationships with in vitro or in vivo infection models that simulate Q-D pharmacokinetics should further define the utility of these pharmacodynamic parameters in the prediction of Q-D activity for the treatment of VREF infections in humans.

In vitro selection of resistance to sofosbuvir in HCV replicons of genotype 1 to 6

2017 ◽  
Vol 22 (7) ◽  
pp. 587-597 ◽  
Author(s):  
Simin Xu ◽  
Brian Doehle ◽  
Sonal Rajyaguru ◽  
Bin Han ◽  
Ona Barauskas ◽  
...  
Keyword(s):  
In Vitro Selection ◽  
Genotype 1 ◽  
Selection Of ◽  
Selection Of Resistance
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