Anthelmintic closantel enhances bacterial killing of polymyxin B against multidrug-resistant Acinetobacter baumannii (original) (raw)
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Scientific Reports
The emergence of polymyxin resistance in Gram-negative bacteria infections has motivated the use of combination therapy. This study determined the mutant selection window (MSW) of polymyxin B alone and in combination with meropenem and fosfomycin against A. baumannii strains belonging to clonal lineages I and III. To evaluate the inhibition of in vitro drug resistance, we investigate the MSW-derived pharmacodynamic indices associated with resistance to polymyxin B administrated regimens as monotherapy and combination therapy, such as the percentage of each dosage interval that free plasma concentration was within the MSW (%TMSW) and the percentage of each dosage interval that free plasma concentration exceeded the mutant prevention concentration (%T>MPC). The MSW of polymyxin B varied between 1 and 16 µg/mL for polymyxin B-susceptible strains. The triple combination of polymyxin B with meropenem and fosfomycin inhibited the polymyxin B-resistant subpopulation in meropenem-resista...
Strategies for the treatment of polymyxin B-resistant Acinetobacter baumannii infections
International journal of antimicrobial agents, 2016
In this study, the activity of meropenem (MEM), fosfomycin (FOF) and polymyxin B (PMB), alone and in combination, was analysed. In addition, optimisation of the pharmacodynamic index of MEM and FOF against six isolates of OXA-23-producing Acinetobacter baumannii (including three resistant to PMB) that were not clonally related was assessed. Antimicrobial combinations were evaluated by chequerboard analysis and were considered synergistic when the fractional inhibitory concentration index (FICI) was ≤0.5. Pharmacodynamic analyses of the MEM and FOF dosing schemes were performed by Monte Carlo simulation. The target pharmacodynamic index (%ƒT>MIC) for MEM and FOF was ≥40% and ≥70%, respectively, and a probability of target attainment (PTA) ≥0.9 was considered adequate. Among the PMB-resistant isolates, combinations of PMB+MEM and PMB+FOF+MEM showed the highest synergistic activity (FICI ≤0.125); isolates that were previously PMB-resistant were included in the susceptible category u...
Antimicrobial Agents and Chemotherapy, 2004
Eight unrelated clinical Acinetobacter baumannii isolates resistant to all commonly used antibiotics were subjected to three-dimensional checkerboard microtiter plate dilution and time-kill studies at one-fourth of their MICs of polymyxin B, imipenem, and rifampin. Synergy was demonstrated with combinations of polymyxin B and imipenem, polymyxin B and rifampin, and polymyxin B, imipenem, and rifampin. Double combinations of polymyxin B and imipenem and of polymyxin B and rifampin were bactericidal for seven of eight isolates, and triple combinations were bactericidal for all isolates within 24 h. Future clinical studies using double and triple therapy with these antibacterials may provide an effective option against potentially lethal infection due to multiresistant Acinetobacter baumannii.
Scientific reports, 2016
Polymyxins are last-resort antibiotics for treating infections of Gram-negative bacteria. The recent emergence of polymyxin-resistant bacteria, however, urgently demands clinical optimisation of polymyxin use to minimise further evolution of resistance. In this study we developed a novel combination therapy using minimal concentrations of polymyxin B. After large-scale screening of Streptomyces secondary metabolites, we identified a reliable polymixin synergist and confirmed as netropsin using high-pressure liquid chromatography, nuclear magnetic resonance, and mass spectrometry followed by in vitro assays using various Gram-negative pathogenic bacteria. To evaluate the effectiveness of combining polymixin B and netropsin in vivo, we performed survival analysis on greater wax moth Galleria mellonella infected with colistin-resistant clinical Acinetobacter baumannii isolates as well as Escherichia coli, Shigella flexineri, Salmonella typhimuruim, and Pseudomonas aeruginosa. The survi...
An Update on the arsenal for multidrug-resistant Acinetobacter infections: Polymyxin antibiotics
International Journal of Infectious Diseases, 2015
To review recent clinical pharmacokinetic and pharmacodynamic data to optimize dosing regimens for polymyxin B and colistin for treatment of infections due to A. baumannii. Methods: A literature search was performed using the search terms Acinetobacter, polymyxin, colistin, polymyxin B on MEDLINE. Additional references were identified from the resulting citations. Results: Increasing the dose of polymyxin B or colistin and using either in combination with other antibiotic agents demonstrates improved antimicrobial activity against Acinetobacter spp. Polymyxin B, unlike colistin, is available as an active drug and appears to be relatively unaffected by renal function. This is advantageous both for patients with renal impairment and for those with intact renal function. Achieving therapeutic serum concentrations of colistin may be difficult for those with intact renal function due to rapid clearance of the prodrug, colistimethate sodium (CMS). Clinical data are still lacking for polymyxin B, and it remains to be seen whether advantages demonstrated in PK/PD analyses will persist in the larger scale of patient care and safety. Conclusions: The use of higher doses of either colistin or polymyxin B, as well as combination with other antibiotics, may prevent emerging resistance and preserve the activity of polymyxins against A. baumannii.
Antimicrobial agents and chemotherapy, 2016
Infections caused by multidrug-resistantAcinetobacter baumanniiare a major public health problem and polymyxins are often the last line of therapy for recalcitrant infections by such isolates. The pharmacokinetics of the two clinically-used polymyxins, polymyxin B and colistin, differ considerably, since colistin is administered as an inactive prodrug that undergoes slow conversion to colistin. However, the impact of these substantial pharmacokinetic differences on bacterial killing and resistance emergence is poorly understood. We assessed clinically relevant polymyxin B and colistin dosage regimens against one reference and three clinicalA. baumanniistrains in a dynamic one-compartmentin vitromodel. A new mechanism-based pharmacodynamic model was developed to describe and predict the drug concentrations and viable counts of the total and resistant populations. Rapid attainment of target concentrations was shown to be critical for polymyxin-induced bacterial killing. All polymyxin ...
Antimicrobial agents and chemotherapy, 2016
Against Gram-negative ESKAPE pathogens, administering the polymyxin antibiotics in a traditional fashion may be ineffective. Here, we explored increasing the dose intensity of polymyxin B against two strains ofAcinetobacter baumanniiin the Hollow Fiber Infection Model. The following dosage regimens were simulated for polymyxin B (t1/2=8 h): non-loading dose (1.43 mg/kg q12h), loading dose (2.22 mg/kg q12h x 1 dose then 1.43 mg/kg q12h), 'front-loading' (3.33 mg/kg q12h x 1 dose followed by 1.43 mg/kg q12h), 'burst' (5.53 mg/kg x 1 dose), and 'supra-burst' (18.4 mg/kg x 1 dose). Against bothA. baumanniiisolates, a rapid initial decline in the total population was observed within the first 6h of polymyxin exposure, whereby greater polymyxin B exposure resulted in greater maximal killing of -1.25, -1.43, -2.84, -2.84 and -3.40 log10CFU/ml within the first 6h. Unexpectedly, we observed a paradoxical effect whereby higher polymyxin B exposures dramatically increas...
African Journal of Microbiology Research, 2014
Acinetobacter baumannii is an opportunistic Gram negative coccobacillus that can grow easily in moist as well as dry conditions. During the last decade, A. baumannii emerged as one of the most resistant opportunistic pathogens responsible for nosocomial infections including ventilator associated pneumonia. The bug remains an important and difficult to treat pathogen whose pan-drug resistant nature has created a serious challenge. This has restricted the choice of treatment modalities. Currently, it appears as if all the available antibiotics are failing against this pathogen while single antibiotic therapy is certainly not working anymore. Thus, there is a strong need, thus, to explore new regimens to combat this resistant organism. A wide range of various combinations of drugs should therefore be tested for their synergistic activity against this pathogen. This study was aimed to find some effective combinations against extensively drug resistant (XDR) A. baumannii by combining various antibacterials. The microdilution checkerboard titration method was used for this purpose and fractional inhibitory concentrations (FICs) were calculated. In-vitro synergy was found in polymyxin Bcolistin (n = 3; 15%) and polymyxin B-rifampin (n = 3; 15%) combinations. Only additive effect was noted with polymyxin B-doxycycline (n = 12; 60%), polymyxin B-rifampin (n = 11; 55%), and polymyxin Bcolistin (n = 13; 65%). However, antagonism was detected in the polymyxin B-rifampin combination in one of the 20 strains evaluated for the purpose. Polymyxin B in combination with rifampin and colistin may be exploited against XDR A. baumannii. Synergy between polymyxin B and colistin have been demonstrated in only 15% of strains, this fully warrants the testing of more combinations.
The Brazilian Journal of Infectious Diseases, 2013
Acinetobacter baumannii is a major nosocomial pathogen and carbapenems are the mainstream agents against these organisms. 1 However, carbapenem-resistant A. baumannii (CRAB) isolates have become widely disseminated owing to the emergence of Class D carbapenemases, mainly OXA-23, which are highly prevalent in Brazil. Polymyxins B and colistin are often the last therapeutic options against CRAB isolates. 2 The combination of polymyxins with another antimicrobial has been proposed to overcome some shortcomings of polymyxins in monotherapy, including the potential for the emergence of hetero-resistant subpopulations and a possible limited bactericidal activity in vivo, considering recent pharmacokinetics studies. In vitro studies may provide some support defining that candidate antimicrobials would more likely present a beneficial effect when combined with polymyxins. We evaluated the combination of non-bactericidal concentrations of polymyxin B, which are also more likely to be clinically achieved, 2 with other antimicrobials in concentrations usually reached with common dosage regimes against OXA-23-producing A. baumannii isolates.
Journal of Antimicrobial Chemotherapy, 2016
Objectives: Polymyxin B is being increasingly utilized as a last resort against resistant Gram-negative bacteria. We examined the pharmacodynamics of novel dosing strategies for polymyxin B combinations to maximize efficacy and minimize the emergence of resistance and drug exposure against Acinetobacter baumannii. Methods: The pharmacodynamics of polymyxin B together with doripenem were evaluated in time-kill experiments over 48 h against 10 8 cfu/mL of two polymyxin-heteroresistant A. baumannii isolates (ATCC 19606 and N16870). Pharmacokinetic/pharmacodynamic relationships were mathematically modelled using S-ADAPT. A hollow-fibre infection model (HFIM) was also used to simulate clinically relevant polymyxin B dosing strategies (traditional, augmented 'front-loaded' and 'burst' regimens), together with doripenem, against an initial inoculum of 10 9 cfu/mL of ATCC 19606. Results: In static time-kill studies, polymyxin B concentrations .4 mg/L in combination with doripenem 25 mg/L resulted in rapid bactericidal activity against both strains with undetectable bacterial counts by 24 h. The mathematical model described the rapid, concentration-dependent killing as subpopulation and mechanistic synergy. In the HFIM, the traditional polymyxin B combination regimen was synergistic, with a .7.5 log 10 reduction by 48 h. The polymyxin B 'front-loaded' combination resulted in more rapid and extensive initial killing (.8 log 10) within 24 h, which was sustained over 10 days. With only 25% of the cumulative drug exposure, the polymyxin B 'burst' combination demonstrated antibacterial activity similar to traditional and 'front-loaded' combination strategies. The polymyxin B 'front-loaded' and 'burst' combination regimens suppressed the emergence of resistance. Conclusions: Early aggressive dosing regimens for polymyxin combinations demonstrate promise for treatment of heteroresistant A. baumannii infections.