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Roger L Nation - One of the best experts on this subject based on the ideXlab platform.
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pharmacodynamics of Colistin and fosfomycin a treasure trove combination combats kpc producing klebsiella pneumoniae
Journal of Antimicrobial Chemotherapy, 2017Co-Authors: Miao Zhao, Amanda Marrocco, Zackery P Bulman, Phillip J. Bergen, Thomas J. Walsh, Jerome R Lenhard, Michael J Satlin, Barry N Kreiswirth, Roger L NationAbstract:Objectives: KPC-producing Klebsiella pneumoniae are an emerging public health problem around the globe. We defined the combinatorial pharmacodynamics and ability to suppress resistance of two 'old' antibiotics, fosfomycin and Colistin, in time-kill experiments and hollow-fibre infection models (HFIM). Methods: Two KPC-2-producing K. pneumoniae isolates were used: one susceptible to both Colistin and fosfomycin (KPC 9A: MIC Colistin 0.25 mg/L and MIC fosfomycin ≤8 mg/L) and the other resistant to Colistin and susceptible to fosfomycin (KPC 5A: MIC Colistin 64 mg/L and MIC fosfomycin 32 mg/L). Time-kill experiments assessed an array of Colistin and fosfomycin concentrations against both isolates. Colistin and fosfomycin pharmacokinetics from critically ill patients were simulated in the HFIM to define the pharmacodynamic activity of humanized regimens over 5 days against KPC 9A. Results: In time-kill experiments, synergy was demonstrated for all Colistin/fosfomycin combinations containing >8 mg/L fosfomycin against the double-susceptible KPC strain, 9A. Synergy versus KPC strain 5A was only achieved at the highest concentrations of Colistin (4 mg/L) and fosfomycin (512 mg/L) at 48 h. In the HFIM, Colistin or fosfomycin monotherapies resulted in rapid proliferation of resistant subpopulations; KPC 9A regrew by 24 h. In contrast to the monotherapies, the Colistin/fosfomycin combination resulted in a rapid 6.15 log 10 cfu/mL reduction of KPC 9A by 6 h and complete suppression of resistant subpopulations until 120 h. Conclusions: Colistin and fosfomycin may represent an important treatment option for KPC-producing K. pneumoniae otherwise resistant to traditional antibiotics.
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antimicrobial activity and toxicity of the major lipopeptide components of polymyxin b and Colistin last line antibiotics against multidrug resistant gram negative bacteria
ACS Infectious Diseases, 2015Co-Authors: Kade D Roberts, Mohammad Abul Kalam Azad, Andrew S Horne, Philip E Thompson, Tony Velkov, Roger L Nation, Jiping Wang, Jian LiAbstract:Polymyxin B and Colistin are currently used as a “last-line” treatment for multidrug-resistant Gram-negative bacteria. However, very little is known about the pharmacological differences between polymyxin B1, polymyxin B2, Colistin A, and Colistin B, the major cyclic lipopeptide components present in polymyxin B and Colistin products. Here, we report on the in vitro and in vivo antimicrobial activity and toxicity of these major lipopeptide components. All four lipopeptides had comparable minimum inhibitory concentrations (MICs) ( −3) and nephrotoxicity (mild to moderate histological damage) in mouse models. However, polymyxin B1 and Colistin A showed significantly higher (>3-fold) in vitro apoptotic effect on human kidney proximal tubular HK-2 cells than polymyxin B2 and Colistin B, respectively. Compared to the commercial polymyxin and Colistin ...
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synergistic activity of Colistin and rifampin combination against multidrug resistant acinetobacter baumannii in an in vitro pharmacokinetic pharmacodynamic model
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Phillip J. Bergen, Roger L Nation, Jurgen B Bulitta, Brian T Tsuji, Alan Forrest, Jian LiAbstract:ABSTRACT Combination therapy may be required for multidrug-resistant (MDR) Acinetobacter baumannii. This study systematically investigated bacterial killing and emergence of Colistin resistance with Colistin and rifampin combinations against MDR A. baumannii. Studies were conducted over 72 h in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model at inocula of ∼10 6 and ∼10 8 CFU/ml using two MDR clinical isolates of A. baumannii, FADDI-AB030 (Colistin susceptible) and FADDI-AB156 (Colistin resistant). Three combination regimens achieving clinically relevant concentrations (constant Colistin concentration of 0.5, 2, or 5 mg/liter and a rifampin maximum concentration [ C max ] of 5 mg/liter every 24 hours; half-life, 3 h) were investigated. Microbiological response was measured by serial bacterial counts. Population analysis profiles assessed emergence of Colistin resistance. Against both isolates, combinations resulted in substantially greater killing at the low inoculum; combinations containing 2 and 5 mg/liter Colistin increased killing at the high inoculum. Combinations were additive or synergistic at 6, 24, 48, and 72 h with all Colistin concentrations against FADDI-AB030 and FADDI-AB156 in, respectively, 8 and 11 of 12 cases (i.e., all 3 combinations) at the 10 6 -CFU/ml inoculum and 8 and 7 of 8 cases with the 2- and 5-mg/liter Colistin regimens at the 10 8 -CFU/ml inoculum. For FADDI-AB156, killing by the combination was ∼2.5 to 7.5 and ∼2.5 to 5 log 10 CFU/ml greater at the low inoculum (all Colistin concentrations) and high inoculum (2 and 5 mg/liter Colistin), respectively. Emergence of Colistin-resistant subpopulations was completely suppressed in the Colistin-susceptible isolate with all combinations at both inocula. Our study provides important information for optimizing Colistin-rifampin combinations against Colistin-susceptible and -resistant MDR A. baumannii.
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Interaction of Colistin and Colistin methanesulfonate with liposomes: Colloidal aspects and implications for formulation
Journal of pharmaceutical sciences, 2012Co-Authors: Stephanie Jean Wallace, Roger L Nation, Richard John Prankerd, Benjamin James BoydAbstract:ABSTRACT: Interaction of Colistin and Colistin methanesulfonate (CMS) with liposomes has been studied with the view to understanding the limitations to the use of liposomes as a more effective delivery system for pulmonary inhalation of this important class of antibiotic. Thus, in this study, liposomes containing Colistin or CMS were prepared and characterized with respect to colloidal behavior and drug encapsulation and release. Association of anionic CMS with liposomes induced negative charge on the particles. However, degradation of the CMS to form cationic Colistin over time was directly correlated with charge reversal and particle aggregation. The rate of degradation of CMS was significantly more rapid when associated with the liposome bilayer than when compared with the same concentration in aqueous solution. Colistin liposomes carried positive charge and were stable. Encapsulation efficiency for Colistin was approximately 50%, decreasing with increasing concentration of Colistin. Colistin was rapidly released from liposomes on dilution. Although the studies indicate limited utility of Colistin or CMS liposomes for long duration controlled-release applications, Colistin liposomes were highly stable and may present a potential opportunity for coformulation of Colistin with a second antibiotic to colocalize the two drugs after pulmonary delivery. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association
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Melatonin attenuates Colistin-induced nephrotoxicity in rats
Antimicrobial agents and chemotherapy, 2011Co-Authors: Jumana Mohammad Yousef, Gong Chen, Prue Hill, Roger L NationAbstract:Colistin-induced nephrotoxicity is a dose-limiting adverse effect when Colistin is used against Gram-negative pathogens. This study examined the nephroprotective effect of melatonin against Colistin in rats. Rats (n = 7 per group) were treated intravenously twice daily with saline, Colistin (at increasing doses from 0.5 to 4.0 mg/kg), melatonin (5 mg/kg), or both melatonin and Colistin for 7 days. The severity of renal alteration was examined both biochemically and histologically. The effect of coadministration of melatonin on Colistin pharmacokinetics was investigated. Significantly lower urinary N-acetyl-β-d-glucosaminidase excretion was observed from day 1 in the Colistin-melatonin group compared to the Colistin group (P < 0.0001). Plasma creatinine increased significantly (P = 0.023) only in the Colistin group on day 6. Significant histological abnormalities (P < 0.0001) were detected only in the kidneys of the Colistin group. Melatonin altered Colistin pharmacokinetics; the total body clearance in the Colistin-melatonin group (1.82 ± 0.26 ml/min/kg) was lower than in the Colistin group (4.28 ± 0.93 ml/min/kg). This is the first study demonstrating the protective effect of melatonin against Colistin-induced nephrotoxicity, which indicates that Colistin-induced nephrotoxicity is mediated through oxidative stress. It also highlights the potential of coadministering an antioxidant to widen the therapeutic window of this very important last-line antibiotic.
Phillip J. Bergen - One of the best experts on this subject based on the ideXlab platform.
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pharmacodynamics of Colistin and fosfomycin a treasure trove combination combats kpc producing klebsiella pneumoniae
Journal of Antimicrobial Chemotherapy, 2017Co-Authors: Miao Zhao, Amanda Marrocco, Zackery P Bulman, Phillip J. Bergen, Thomas J. Walsh, Jerome R Lenhard, Michael J Satlin, Barry N Kreiswirth, Roger L NationAbstract:Objectives: KPC-producing Klebsiella pneumoniae are an emerging public health problem around the globe. We defined the combinatorial pharmacodynamics and ability to suppress resistance of two 'old' antibiotics, fosfomycin and Colistin, in time-kill experiments and hollow-fibre infection models (HFIM). Methods: Two KPC-2-producing K. pneumoniae isolates were used: one susceptible to both Colistin and fosfomycin (KPC 9A: MIC Colistin 0.25 mg/L and MIC fosfomycin ≤8 mg/L) and the other resistant to Colistin and susceptible to fosfomycin (KPC 5A: MIC Colistin 64 mg/L and MIC fosfomycin 32 mg/L). Time-kill experiments assessed an array of Colistin and fosfomycin concentrations against both isolates. Colistin and fosfomycin pharmacokinetics from critically ill patients were simulated in the HFIM to define the pharmacodynamic activity of humanized regimens over 5 days against KPC 9A. Results: In time-kill experiments, synergy was demonstrated for all Colistin/fosfomycin combinations containing >8 mg/L fosfomycin against the double-susceptible KPC strain, 9A. Synergy versus KPC strain 5A was only achieved at the highest concentrations of Colistin (4 mg/L) and fosfomycin (512 mg/L) at 48 h. In the HFIM, Colistin or fosfomycin monotherapies resulted in rapid proliferation of resistant subpopulations; KPC 9A regrew by 24 h. In contrast to the monotherapies, the Colistin/fosfomycin combination resulted in a rapid 6.15 log 10 cfu/mL reduction of KPC 9A by 6 h and complete suppression of resistant subpopulations until 120 h. Conclusions: Colistin and fosfomycin may represent an important treatment option for KPC-producing K. pneumoniae otherwise resistant to traditional antibiotics.
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synergistic activity of Colistin and rifampin combination against multidrug resistant acinetobacter baumannii in an in vitro pharmacokinetic pharmacodynamic model
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Phillip J. Bergen, Roger L Nation, Jurgen B Bulitta, Brian T Tsuji, Alan Forrest, Jian LiAbstract:ABSTRACT Combination therapy may be required for multidrug-resistant (MDR) Acinetobacter baumannii. This study systematically investigated bacterial killing and emergence of Colistin resistance with Colistin and rifampin combinations against MDR A. baumannii. Studies were conducted over 72 h in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model at inocula of ∼10 6 and ∼10 8 CFU/ml using two MDR clinical isolates of A. baumannii, FADDI-AB030 (Colistin susceptible) and FADDI-AB156 (Colistin resistant). Three combination regimens achieving clinically relevant concentrations (constant Colistin concentration of 0.5, 2, or 5 mg/liter and a rifampin maximum concentration [ C max ] of 5 mg/liter every 24 hours; half-life, 3 h) were investigated. Microbiological response was measured by serial bacterial counts. Population analysis profiles assessed emergence of Colistin resistance. Against both isolates, combinations resulted in substantially greater killing at the low inoculum; combinations containing 2 and 5 mg/liter Colistin increased killing at the high inoculum. Combinations were additive or synergistic at 6, 24, 48, and 72 h with all Colistin concentrations against FADDI-AB030 and FADDI-AB156 in, respectively, 8 and 11 of 12 cases (i.e., all 3 combinations) at the 10 6 -CFU/ml inoculum and 8 and 7 of 8 cases with the 2- and 5-mg/liter Colistin regimens at the 10 8 -CFU/ml inoculum. For FADDI-AB156, killing by the combination was ∼2.5 to 7.5 and ∼2.5 to 5 log 10 CFU/ml greater at the low inoculum (all Colistin concentrations) and high inoculum (2 and 5 mg/liter Colistin), respectively. Emergence of Colistin-resistant subpopulations was completely suppressed in the Colistin-susceptible isolate with all combinations at both inocula. Our study provides important information for optimizing Colistin-rifampin combinations against Colistin-susceptible and -resistant MDR A. baumannii.
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the combination of Colistin and doripenem is synergistic against klebsiella pneumoniae at multiple inocula and suppresses Colistin resistance in an in vitro pharmacokinetic pharmacodynamic model
Antimicrobial Agents and Chemotherapy, 2012Co-Authors: Zakuan Zainy Deris, Heidi H Yu, Kathryn Erin Davis, Rachel L Soon, Jovan Jacob, Caron K Ku, Anima Poudyal, Phillip J. BergenAbstract:Multidrug-resistant (MDR) Klebsiella pneumoniae may require combination therapy. We systematically investigated bacterial killing with Colistin and doripenem mono- and combination therapy against MDR K. pneumoniae and emergence of Colistin resistance. A one-compartment in vitro pharmacokinetic/pharmacodynamic model was employed over 72 h at two inocula (∼10 6 and ∼10 8 CFU/mL); a Colistin-heteroresistant reference strain (ATCC 13883) and three clinical isolates (Colistin-susceptible FADDI-KP032 [doripenem-resistant], Colistin-heteroresistant FADDI-KP033, and Colistin-resistant FADDI-KP035) were included. Four combinations utilizing clinically achievable concentrations were investigated. Microbiological response was examined by log changes and population analysis profiles (for emergence of Colistin resistance) over 72 h. Against Colistin-susceptible and -heteroresistant isolates, combinations of Colistin (constant concentration regimens of 0.5 or 2 mg/L) plus doripenem ( C max of 2.5 or 25 mg/L 8-hourly; half-life 1.5 h) generally resulted in substantial improvements in bacterial killing at both inocula. Combinations were additive or synergistic against ATCC 13883, FADDI-KP032 and FADDI-KP033 in 9, 9 and 14 of 16 cases (4 combinations at 6, 24, 48, and 72 h) at the 10 6 CFU/mL inoculum and 14, 11 and 12 of 16 cases at the 10 8 CFU/mL inoculum, respectively. Combinations at the highest dosage regimens resulted in undetectable bacterial counts at 72 h in 5 of 8 cases (4 isolates at 2 inocula). Emergence of Colistin-resistant subpopulations in Colistin-susceptible and -heteroresistant isolates was virtually eliminated with combination therapy. Against the Colistin-resistant isolate, Colistin 2 mg/L plus doripenem C max 25 mg/L at the low inoculum improved bacterial killing. This investigation provides important information for optimization of Colistin-doripenem combinations.
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Colistin methanesulfonate is an inactive prodrug of Colistin against pseudomonas aeruginosa
Antimicrobial Agents and Chemotherapy, 2006Co-Authors: Phillip J. Bergen, Craig R Rayner, Roger L NationAbstract:There is a dearth of information on the pharmacodynamics of "Colistin," despite its increasing use as a last line of defense for treatment of infections caused by multidrug-resistant gram-negative organisms. The antimicrobial activities of Colistin and Colistin methanesulfonate (CMS) were investigated by studying the time-kill kinetics of each against a type culture of Pseudomonas aeruginosa in cation-adjusted Mueller-Hinton broth. The appearance of Colistin from CMS spiked at 8.0 and 32 mg/liter was measured by high-performance liquid chromatography, which generated Colistin concentration-time profiles. These concentration-time profiles were subsequently mimicked in other incubations, independent of CMS, by incrementally spiking Colistin. When the cultures were spiked with CMS at either concentration, there was a substantial delay in the onset of the killing effect which was not evident until the concentrations of Colistin generated from the hydrolysis of CMS had reached approximately 0.5 to 1 mg/liter (i.e., approximately 0.5 to 1 times the MIC for Colistin). The time course of the killing effect was similar when Colistin was added incrementally to achieve the same Colistin concentration-time course observed from the hydrolysis of CMS. Given that the killing kinetics of CMS can be accounted for by the appearance of Colistin, CMS is an inactive prodrug of Colistin with activity against P. aeruginosa. This is the first study to demonstrate the formation of Colistin in microbiological media containing CMS and to demonstrate that CMS is an inactive prodrug of Colistin. These findings have important implications for susceptibility testing involving "Colistin," in particular, for MIC measurement and for microbiological assays and pharmacokinetic and pharmacodynamic studies.
Gian Maria Rossolini - One of the best experts on this subject based on the ideXlab platform.
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Synergistic activity of Colistin in combination with N-acetylcysteine against Colistin-resistant Acinetobacter Baumannii grown in biofilms
Cystic fibrosis, 2018Co-Authors: Francesco Sergio, Simona Pollini, Selene Boncompagni, Tiziana Di Maggio, Stefano Aliberti, Francesco Blasi, Lucia Pallecchi, Gian Maria RossoliniAbstract:Objectives:Acinetobacter baumannii is a leading cause of hospital-acquired pneumonia often recalcitrant to antibiotics. Colistin is a last-resort drug to treat infections caused by XDR A baumannii. Nebulized Colistin alone or with iv Colistin was used to treat respiratory infections by those strains. High N-acetylcysteine (NAC) concentrations by topical route potentiated Colistin activity against a collection of Colistin-resistant A baumannii in planktonic phase. Methods: Two XDR A baumannii Colistin resistance phenotype clinical isolates were investigated (Z165, Z167). Biofilm susceptibility testing was performed using Nunc-TSP lid system. Biofilms grew in cation-adjusted Mueller Hinton broth for 7 days and exposed to NAC/Colistin combo. Three NAC concentrations (1.6, 3.2, 8mg/ml) and Colistin concentrations (2, 8, 32mcg/ml) were tested alone and in combo. Biofilm mass was determined by biofilm disruption and viable cell count (enumeration of CFUs) at time 0 (before exposure to the combo) and after 24 hours. Results: Biofilms were formed by mean of 6.08±0.49 and 5.89±1.06 log CFU/ml, for Z165 and Z167, respectively. Antibiofilm activity was not observed with NAC alone or Colistin ≤8µg/ml alone. Colistin 32mcg/ml eradicated both biofilms. Relevant antibiofilm NAC/Colistin combo activity was demonstrated for both tested strains. NAC potentiated Colistin activity in a concentration-dependent way, a relevant antibiofilm activity was seen with Colistin 8mcg/ml+NAC 1.6mg/ml (reduction>3 log CFU/ml vs controls). Conclusions: Nebulized NAC/Colistin combo is a valid option for biofilm-associated infections due to Colistin-resistant A baumannii strains.
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Synergistic Activity of Colistin in Combination With Resveratrol Against Colistin-Resistant Gram-Negative Pathogens
Frontiers in microbiology, 2018Co-Authors: Antonio Cannatelli, Lucia Pallecchi, Silvia Principato, Olga Lorenza Colavecchio, Gian Maria RossoliniAbstract:OBJECTIVES: In this study, we investigated the antimicrobial activity of resveratrol in combination with Colistin, a last-resort agent for the treatment of severe infections caused by multidrug resistant Gram-negative pathogens. METHODS: The synergistic activity and the bactericidal activity of Colistin in combination with resveratrol was investigated by checkerboard assays and time-kill assays, respectively. A total of 21 strains were investigated, including 16 strains of different species (Klebsiella pneumoniae, n = 6, Escherichia coli, n = 6; Citrobacter braakii, n = 1; Stenotrophomonas malthophilia, n = 1; Enterobacter cloaceae, n = 1; Acinetobacter baumannii, n = 1) with acquired Colistin resistance, three Colistin-susceptible K. pneumoniae precursors, and two strains of intrinsically Colistin-resistant species (Serratia marcescens, n = 1; Proteus mirabilis, n = 1). Mechanisms of acquired Colistin resistance included chromosomal mutations (i.e. mgrB, pmrAB) and plasmid genes (mcr-1, mcr-1.2). RESULTS: Resveratrol did not show any significant intrinsic antimicrobial activity. Overall, a relevant synergistic antimicrobial activity of resveratrol in combination with Colistin was observed with all tested strains, except for the three Colistin-susceptible K. pneumoniae strains, and for two mcr-1-positive E. coli strains. In time-kill assays, performed with 15 selected strains, the combination of Colistin 2 mg/L plus resveratrol 128 mg/L was bactericidal with 11 strains, and bacteriostatic for the remaining ones. CONCLUSIONS: Resveratrol was found to potentiate Colistin activity against a wide panel of Colistin-resistant strains, regardless of species and resistance mechanisms, which would deserve further investigation for potential clinical applications.
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in vivo emergence of Colistin resistance in klebsiella pneumoniae producing kpc type carbapenemases mediated by insertional inactivation of the phoq phop mgrb regulator
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Antonio Cannatelli, Gian Maria Rossolini, Marco Maria Dandrea, Tommaso Giani, Vincenzo Di Pilato, Fabio Arena, Simone Ambretti, Paolo GaibaniAbstract:Colistin is one of the few agents that retain activity against extensively drug-resistant strains of Klebsiella pneumoniae producing KPC-type carbapenemases (KPC-KP). However, resistance to Colistin is increasingly reported among KPC-KP. Comparative genomic analysis of a pair of sequential KPC-KP isolates from the same patient including a Colistin-susceptible isolate (KKBO-1) and a Colistin-resistant isolate (KKBO-4) selected after Colistin exposure revealed that insertional inactivation of the mgrB gene, encoding a negative regulator of the PhoQ/PhoP signaling system, is a genetic mechanism for acquired Colistin resistance. The role of mgrB inactivation in acquired Colistin resistance was confirmed by complementation experiments with wild-type mgrB, which restored Colistin susceptibility in KKBO-4, and by construction of an mgrB deletion mutant from KKBO-1, which exhibited a Colistin-resistant phenotype. Insertional mgrB inactivation was also detected in 60% of Colistin-resistant mutants selected from KKBO-1 in vitro, following plating on Colistin-containing medium, confirming the role (although not unique) of this mechanism in the emergence of acquired Colistin resistance. In Colistin-resistant mutants carrying insertional inactivation or deletion of the mgrB gene, upregulated transcription of phoP, phoQ, and pmrK (which is part of the pmrHFIJKLM operon) was detected. These findings confirmed the MgrB regulatory role in K. pneumoniae and were in agreement with the known association between upregulation of the PhoQ/PhoP system and activation of the pmrHFIJKLM operon, which eventually leads to resistance to polymyxins by modification of the lipopolysaccharide target.
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Synergistic activity of Colistin plus rifampin against Colistin-resistant kpc-producing klebsiella pneumoniae
Antimicrobial agents and chemotherapy, 2013Co-Authors: Carlo Tascini, Gian Maria Rossolini, Tommaso Giani, Enrico Tagliaferri, Alessandro Leonildi, Sarah Flammini, Beatrice Casini, Russell E. Lewis, Simone Ferranti, Francesco MenichettiAbstract:ABSTRACT Infections caused by carbapenem-resistant KPC-producing Klebsiella pneumoniae are responsible for high rates of mortality and represent a major therapeutic challenge, especially when the isolates are also resistant to Colistin. We used the checkerboard method to evaluate the synergistic activity of 10 antibiotic combinations against 13 Colistin-resistant KPC-producing K. pneumoniae isolates (Colistin MIC range of 8 to 128 mg/liter). Colistin plus rifampin was the only combination that demonstrated consistent synergistic bacteriostatic activity against 13/13 strains tested, reducing the Colistin MIC below the susceptibility breakpoint (MIC ≤ 2 mg/liter) in 7/13 strains at rifampin concentrations ranging from 4 to 16 mg/liter. Bactericidal synergistic activity was also documented for 8/13 tested strains. Other antimicrobial combinations with carbapenems, gentamicin, and tigecycline showed variously synergistic results. Colistin plus rifampin also exhibited bacteriostatic synergistic activity against 4/4 Colistin-susceptible KPC-producing K. pneumoniae isolates (Colistin MIC range of 0.5 to 2 mg/liter) and 4/4 ertapenem-resistant extended-spectrum beta-lactamase (ESBL)-producing K. pneumoniae isolates (ertapenem MIC range of 16 to 32 mg/liter). Collectively, our data suggest that Colistin plus rifampin is the most consistently synergistic combination against KPC-producing K. pneumoniae isolates, including Colistin-resistant strains. Colistin-rifampin combinations may have a role in the treatment of multidrug-resistant K. pneumoniae and may possibly slow the selection of heteroresistant subpopulations during Colistin therapy.
Jeanmarc Rolain - One of the best experts on this subject based on the ideXlab platform.
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Efflux pump inhibitor CCCP to rescue Colistin susceptibility in mcr-1 plasmid-mediated Colistin-resistant strains and Gram-negative bacteria
Journal of Antimicrobial Chemotherapy, 2018Co-Authors: Sophie A. Baron, Jeanmarc RolainAbstract:Objectives: Efflux in bacteria is a ubiquitous mechanism associated with resistance to antimicrobials agents. Efflux pump inhibitors (EPIs) have been developed to inhibit efflux mechanisms and could be a good alternative to reverse Colistin resistance, but only CCCP has shown good activity. The aim of our study was to identify CCCP activity in a collection of 93 Gram-negative bacteria with known and unknown Colistin resistance mechanisms including isolates with mcr-1 plasmid-mediated Colistin resistance. Methods: Colistin MIC was evaluated with and without CCCP and the fold decrease of Colistin MIC was calculated for each strain. In order to evaluate the effect of this combination, a time-kill study was performed on five strains carrying different Colistin resistance mechanisms. Results: Overall, CCCP was able to reverse Colistin resistance for all strains tested. The effect of CCCP was significantly greater on intrinsically Colistin-resistant bacteria (i.e. Proteus spp., Serratiamarcescens, Morganella morganii and Providencia spp.) than on other Enterobacteriaceae (P
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emergence of Colistin resistant bacteria in humans without Colistin usage a new worry and cause for vigilance
International Journal of Antimicrobial Agents, 2016Co-Authors: Abiola Olumuyiwa Olaitan, Serge Morand, Jeanmarc RolainAbstract:Abstract Colistin is currently regarded as one of the ‘last-resort’ antibiotics used for the treatment of critical infections caused by multidrug-resistant Gram-negative pathogens. There have been numerous reports of the emergence of Colistin resistance in patients, most of whom had previously received Colistin therapy or with acquisition via nosocomial transmission. However, there are also ample reports of Colistin resistance in humans who have not received the drug previously or without nosocomial transmission. We have also observed a similar occurrence in our study involving Colistin resistance from several countries along with a similar phenomenon being reported by researchers. The observation of Colistin resistance in humans without prior Colistin exposure is of particularly great clinical importance and concern because of the current importance of Colistin in clinical medicine. Colistin use and Colistin-resistant bacteria in animals have been recently reported, suggesting that animals could also be a source of transmission of Colistin-resistant bacteria to humans. This is a real worry and calls for clinicians to be aware and vigilant of this phenomenon and of the possibility of independent resistance to Colistin in some patients.
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Emergence of Colistin-resistant bacteria in humans without Colistin usage: a new worry and cause for vigilance
International Journal of Antimicrobial Agents, 2016Co-Authors: Abiola Olumuyiwa Olaitan, Serge Morand, Jeanmarc RolainAbstract:Colistin is currently regarded as one of the `last-resort' antibiotics used for the treatment of critical infections caused by multidrug-resistant Gram-negative pathogens. There have been numerous reports of the emergence of Colistin resistance in patients, most of whom had previously received Colistin therapy or with acquisition via nosocomial transmission. However, there are also ample reports of Colistin resistance in humans who have not received the drug previously or without nosocomial transmission. We have also observed a similar occurrence in our study involving Colistin resistance from several countries along with a similar phenomenon being reported by researchers. The observation of Colistin resistance in humans without prior Colistin exposure is of particularly great clinical importance and concern because of the current importance of Colistin in clinical medicine. Colistin use and Colistin-resistant bacteria in animals have been recently reported, suggesting that animals could also be a source of transmission of Colistin-resistant bacteria to humans. This is a real worry and calls for clinicians to be aware and vigilant of this phenomenon and of the possibility of independent resistance to Colistin in some patients. (C) 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
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Loss of LPS is involved in the virulence and resistance to Colistin of Colistin-resistant Acinetobacter nosocomialis mutants selected in vitro
The Journal of antimicrobial chemotherapy, 2015Co-Authors: Xavier Vila-farrés, Ernest Giralt, Jeanmarc Rolain, Mario Ferrer-navarro, Anna Elena Callarisa, Sara Marti, Paula Espinal, Sushim K. Gupta, Jordi VilaAbstract:OBJECTIVES Acinetobacter nosocomialis has increasingly been reported as an opportunistic pathogen causing nosocomial infections. Although it is more susceptible to all antimicrobial agents than Acinetobacter baumannii, MDR clinical isolates have also been described. In addition, several studies have shown a high percentage of resistance to Colistin. Therefore, in the present study we investigated the mechanism of resistance to Colistin in this microorganism. METHODS Colistin-resistant strains were selected from the original Colistin-susceptible A. nosocomialis strain following multi-step mutant selection. Comparative genomic and proteomic analyses of both Colistin-susceptible and Colistin-resistant A. nosocomialis strains were performed. In addition, virulence was investigated using the Caenorhabditis elegans assay. RESULTS The Colistin-resistant mutants selected showed a lower resistance profile for other types of antibacterial agents together with a significant decrease in virulence. The LT50 (i.e. time required to kill 50% of the nematodes) for the Colistin-susceptible strain (WT) was 7 days compared with 9 days for the Colistin-resistant strain (256) (P
Jian Li - One of the best experts on this subject based on the ideXlab platform.
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antimicrobial activity and toxicity of the major lipopeptide components of polymyxin b and Colistin last line antibiotics against multidrug resistant gram negative bacteria
ACS Infectious Diseases, 2015Co-Authors: Kade D Roberts, Mohammad Abul Kalam Azad, Andrew S Horne, Philip E Thompson, Tony Velkov, Roger L Nation, Jiping Wang, Jian LiAbstract:Polymyxin B and Colistin are currently used as a “last-line” treatment for multidrug-resistant Gram-negative bacteria. However, very little is known about the pharmacological differences between polymyxin B1, polymyxin B2, Colistin A, and Colistin B, the major cyclic lipopeptide components present in polymyxin B and Colistin products. Here, we report on the in vitro and in vivo antimicrobial activity and toxicity of these major lipopeptide components. All four lipopeptides had comparable minimum inhibitory concentrations (MICs) ( −3) and nephrotoxicity (mild to moderate histological damage) in mouse models. However, polymyxin B1 and Colistin A showed significantly higher (>3-fold) in vitro apoptotic effect on human kidney proximal tubular HK-2 cells than polymyxin B2 and Colistin B, respectively. Compared to the commercial polymyxin and Colistin ...
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Colistin: understanding and applying recent pharmacokinetic advances.
Pharmacotherapy, 2014Co-Authors: Jessica K. Ortwine, Jian Li, Keith S. Kaye, Jason M. PogueAbstract:Colistin, the most widely used polymyxin antibiotic, was originally introduced in the late 1950s before the establishment of the present-day drug approval process. Originally shelved due to toxicity concerns, Colistin, in the form of its inactive prodrug Colistin methanesulfonate, has undergone a renaissance in the past 15 years. Unfortunately, this is not because of an improved adverse-effect profile but because Colistin is among the only remaining antibiotics with activity against multidrug-resistant gram-negative bacilli. Pharmacokinetic and pharmacodynamic data are limited to guide the appropriate use of Colistin; however, important advances have occurred over the past 5 years. Since its reintroduction, published reports regarding Colistin have produced discordant results in terms of both efficacy and safety. Because the efficacy and toxicity of Colistin are dose dependent, the impact of discordant dosing recommendations cannot be understated. This review highlights the issues leading to differing and often conflicting dosing recommendations, reviews the recent pharmacokinetic advances, and provides recommendations for the optimal use of Colistin.
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synergistic activity of Colistin and rifampin combination against multidrug resistant acinetobacter baumannii in an in vitro pharmacokinetic pharmacodynamic model
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Phillip J. Bergen, Roger L Nation, Jurgen B Bulitta, Brian T Tsuji, Alan Forrest, Jian LiAbstract:ABSTRACT Combination therapy may be required for multidrug-resistant (MDR) Acinetobacter baumannii. This study systematically investigated bacterial killing and emergence of Colistin resistance with Colistin and rifampin combinations against MDR A. baumannii. Studies were conducted over 72 h in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model at inocula of ∼10 6 and ∼10 8 CFU/ml using two MDR clinical isolates of A. baumannii, FADDI-AB030 (Colistin susceptible) and FADDI-AB156 (Colistin resistant). Three combination regimens achieving clinically relevant concentrations (constant Colistin concentration of 0.5, 2, or 5 mg/liter and a rifampin maximum concentration [ C max ] of 5 mg/liter every 24 hours; half-life, 3 h) were investigated. Microbiological response was measured by serial bacterial counts. Population analysis profiles assessed emergence of Colistin resistance. Against both isolates, combinations resulted in substantially greater killing at the low inoculum; combinations containing 2 and 5 mg/liter Colistin increased killing at the high inoculum. Combinations were additive or synergistic at 6, 24, 48, and 72 h with all Colistin concentrations against FADDI-AB030 and FADDI-AB156 in, respectively, 8 and 11 of 12 cases (i.e., all 3 combinations) at the 10 6 -CFU/ml inoculum and 8 and 7 of 8 cases with the 2- and 5-mg/liter Colistin regimens at the 10 8 -CFU/ml inoculum. For FADDI-AB156, killing by the combination was ∼2.5 to 7.5 and ∼2.5 to 5 log 10 CFU/ml greater at the low inoculum (all Colistin concentrations) and high inoculum (2 and 5 mg/liter Colistin), respectively. Emergence of Colistin-resistant subpopulations was completely suppressed in the Colistin-susceptible isolate with all combinations at both inocula. Our study provides important information for optimizing Colistin-rifampin combinations against Colistin-susceptible and -resistant MDR A. baumannii.
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use of high performance liquid chromatography to study the pharmacokinetics of Colistin sulfate in rats following intravenous administration
Antimicrobial Agents and Chemotherapy, 2003Co-Authors: Jian Li, Roger L Nation, Robert W. Milne, John D. Turnidge, Timothy C. Smeaton, Kingsley CoulthardAbstract:The pharmacokinetics of Colistin was investigated using specific high-performance liquid chromatography (HPLC) to measure the concentrations of Colistin and Colistin A and B in plasma and urine in five rats after administration of an intravenous bolus of 1 mg of Colistin sulfate/kg of body weight. There were differences in the pharmacokinetic behaviors of unbound Colistin A and B. This is the first report of the use of HPLC to study the pharmacokinetics of Colistin and its two major components.