scholarly journals The Combination of Colistin and Doripenem Is Synergistic against Klebsiella pneumoniae at Multiple Inocula and Suppresses Colistin Resistance in anIn VitroPharmacokinetic/Pharmacodynamic Model

2012 ◽  
Vol 56 (10) ◽  
pp. 5103-5112 ◽  
Author(s):  
Zakuan Z. Deris ◽  
Heidi H. Yu ◽  
Kathryn Davis ◽  
Rachel L. Soon ◽  
Jovan Jacob ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Population Analysis ◽  
Multidrug Resistant ◽  
Pharmacodynamic Model ◽  
Resistant Isolate ◽  
Colistin Resistance ◽  
Bacterial Killing ◽  
Content Type

ABSTRACTMultidrug-resistant (MDR)Klebsiella pneumoniaemay require combination therapy. We systematically investigated bacterial killing with colistin and doripenem mono- and combination therapy against MDRK. pneumoniaeand emergence of colistin resistance. A one-compartmentin vitropharmacokinetic/pharmacodynamic model was employed over a 72-h period with two inocula (∼106and ∼108CFU/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 responses were examined by determining 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/liter) plus doripenem (steady-state peak concentration [Cmax] of 2.5 or 25 mg/liter over 8 h; 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 106-CFU/ml inoculum and 14, 11, and 12 of 16 cases at the 108-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 at 2 mg/liter plus doripenem (Cmax, 25 mg/liter) at the low inoculum improved bacterial killing. This investigation provides important information for optimization of colistin-doripenem combinations.

scholarly journals Synergistic Killing of Multidrug-Resistant Pseudomonas aeruginosa at Multiple Inocula by Colistin Combined with Doripenem in an In Vitro Pharmacokinetic/Pharmacodynamic Model

2011 ◽  
Vol 55 (12) ◽  
pp. 5685-5695 ◽  
Author(s):  
Phillip J. Bergen ◽  
Brian T. Tsuji ◽  
Jurgen B. Bulitta ◽  
Alan Forrest ◽  
Jovan Jacob ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Combination Therapy ◽  
Limit Of Detection ◽  
Population Analysis ◽  
Multidrug Resistant ◽  
Pharmacodynamic Model ◽  
Bacterial Killing ◽  
Content Type ◽  
High Inoculum

ABSTRACTCombination therapy may be required for multidrug-resistant (MDR)Pseudomonas aeruginosa. The aim of this study was to systematically investigate bacterial killing and emergence of colistin resistance with colistin and doripenem combinations against MDRP. aeruginosa. Studies were conducted in a one-compartmentin vitropharmacokinetic/pharmacodynamic model for 96 h at two inocula (∼106and ∼108CFU/ml) against a colistin-heteroresistant reference strain (ATCC 27853) and a colistin-resistant MDR clinical isolate (19147 n/m). Four combinations utilizing clinically achievable concentrations were investigated. Microbiological response was examined by log changes and population analysis profiles. Colistin (constant concentrations of 0.5 or 2 mg/liter) plus doripenem (peaks of 2.5 or 25 mg/liter every 8 h; half-life, 1.5 h) substantially increased bacterial killing against both strains at the low inoculum, while combinations containing colistin at 2 mg/liter increased activity against ATCC 27853 at the high inoculum; only colistin at 0.5 mg/liter plus doripenem at 2.5 mg/liter failed to improve activity against 19147 n/m at the high inoculum. Combinations were additive or synergistic against ATCC 27853 in 16 and 11 of 20 cases (4 combinations across 5 sample points) at the 106- and 108-CFU/ml inocula, respectively; the corresponding values for 19147 n/m were 16 and 9. Combinations containing doripenem at 25 mg/liter resulted in eradication of 19147 n/m at the low inoculum and substantial reductions in regrowth (including to below the limit of detection at ∼50 h) at the high inoculum. Emergence of colistin-resistant subpopulations of ATCC 27853 was substantially reduced and delayed with combination therapy. This investigation provides important information for optimization of colistin-doripenem combinations.

scholarly journals Synergistic Activity of Colistin and Rifampin Combination against Multidrug-Resistant Acinetobacter baumannii in anIn VitroPharmacokinetic/Pharmacodynamic Model

2013 ◽  
Vol 57 (8) ◽  
pp. 3738-3745 ◽  
Author(s):  
Hee Ji Lee ◽  
Phillip J. Bergen ◽  
Jurgen B. Bulitta ◽  
Brian Tsuji ◽  
Alan Forrest ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Population Analysis ◽  
Multidrug Resistant ◽  
Synergistic Activity ◽  
Colistin Resistance ◽  
Bacterial Killing ◽  
Content Type ◽  
High Inoculum ◽  
Combination Regimens

ABSTRACTCombination 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 MDRA. baumannii. Studies were conducted over 72 h in anin vitropharmacokinetic (PK)/pharmacodynamic (PD) model at inocula of ∼106and ∼108CFU/ml using two MDR clinical isolates ofA. 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 [Cmax] 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 106-CFU/ml inoculum and 8 and 7 of 8 cases with the 2- and 5-mg/liter colistin regimens at the 108-CFU/ml inoculum. For FADDI-AB156, killing by the combination was ∼2.5 to 7.5 and ∼2.5 to 5 log10CFU/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 MDRA. baumannii.

scholarly journals In VitroPharmacodynamics of Polymyxin B and Tigecycline Alone and in Combination against Carbapenem-Resistant Acinetobacter baumannii

2013 ◽  
Vol 58 (2) ◽  
pp. 874-879 ◽  
Author(s):  
Mao Hagihara ◽  
Seth T. Housman ◽  
David P. Nicolau ◽  
Joseph L. Kuti
Keyword(s):  
Combination Therapy ◽  
Acinetobacter Baumannii ◽  
Population Analysis ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Bacterial Killing ◽  
Content Type ◽  
Model Free ◽  
Carbapenem Resistant

ABSTRACTCarbapenem-resistantAcinetobacter baumanniiis increasing in prevalence. Polymyxin B and tigecycline are among the most active antibiotics used against this pathogenin vitro. Pastin vitrostudies, however, neglected the importance of simulating exposures observed in humans to determine their antibacterial effects. In this study, four carbapenem-resistantA. baumanniiisolates were evaluated using anin vitropharmacodynamic model. Free-drug exposures using 1 mg/kg of body weight of polymyxin B every 12 h (q12h), 100 and 200 mg tigecycline q12h, and the combination of these regimens were simulated. The microbiological responses to these treatments were measured by the change in log10CFU/ml over 24 h and the area under the bacterial killing and regrowth curve (AUBC). Resistance was assessed by a population analysis profile (PAP) conducted after 24 h of treatment. Polymyxin B achieved a reduction on the order of −2.05 ± 0.68 log10CFU/ml against theseA. baumanniiisolates, while all isolates grew to control levels with tigecycline monotherapy. Combination therapy with polymyxin B plus 200 mg tigecycline q12h achieved a greater reduction in bacterial density than did therapy with polymyxin B alone (−3.31 ± 0.71 versus −2.05 ± 0.68 log10CFU/ml,P< 0.001) but not significantly different than combination therapy with 100 mg tigecycline q12h (−2.45 ± 1.00 log10CFU/ml,P= 0.370). Likewise, combination therapy with polymyxin B plus 200 mg tigecycline q12h significantly reduced the AUBC compared to that with polymyxin B alone (62.8 ± 8.9 versus 79.4 ± 10.5 log10CFU/ml,P< 0.05). No changes in the PAP from baseline were observed for either antibiotic alone. In this study, combination therapy with simulated exposures of polymyxin B and tigecycline at an aggressive dose of 200 mg q12h produced synergistic or additive effects on humans against these multidrug-resistantA. baumanniistrains.

scholarly journals In VitroSynergy of Colistin Combinations against Colistin-Resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae Isolates

2012 ◽  
Vol 56 (9) ◽  
pp. 4856-4861 ◽  
Author(s):  
Céline Vidaillac ◽  
Lothaire Benichou ◽  
Raphaël E. Duval
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Klebsiella Pneumoniae ◽  
Acinetobacter Baumannii ◽  
Population Analysis ◽  
Multidrug Resistant ◽  
Colistin Resistance ◽  
Content Type ◽  
Checkerboard Assay ◽  
Time Kill

ABSTRACTColistin resistance, although uncommon, is increasingly being reported among Gram-negative clinical pathogens, and an understanding of its impact on the activity of antimicrobials is now evolving. We evaluated the potential for synergy of colistin plus trimethoprim, trimethoprim-sulfamethoxazole (1/19 ratio), or vancomycin against 12 isolates ofAcinetobacter baumannii(n= 4),Pseudomonas aeruginosa(n= 4), andKlebsiella pneumoniae(n= 4). The strains included six multidrug-resistant clinical isolates,K. pneumoniaeATCC 700603,A. baumanniiATCC 19606,P. aeruginosaATCC 27853, and their colistin-resistant derivatives (KPm1, ABm1, and PAm1, respectively). Antimicrobial susceptibilities were assessed by broth microdilution and population analysis profiles. The potential for synergy of colistin combinations was evaluated using a checkerboard assay, as well as static time-kill experiments at 0.5× and 0.25× MIC. The MIC ranges of vancomycin, trimethoprim, and trimethoprim-sulfamethoxazole (1/19) were ≥128, 4 to ≥128, and 2/38 to >128/2,432 μg/ml, respectively. Colistin resistance demonstrated little impact on vancomycin, trimethoprim, or trimethoprim-sulfamethoxazole MIC values. Isolates with subpopulations heterogeneously resistant to colistin were observed to various degrees in all tested isolates. In time-kill assays, all tested combinations were synergistic against KPm1 at 0.25× MIC and 0.5× MIC and ABm1 and PAm1 at 0.5× MIC. In contrast, none of the tested combinations demonstrated synergy against any colistin-susceptibleP. aeruginosaisolates and clinical strains ofK. pneumoniaeisolates. Only colistin plus trimethoprim or trimethoprim-sulfamethoxazole was synergistic and bactericidal at 0.5× MIC againstK. pneumoniaeATCC 700603. Colistin resistance seems to promote thein vitroactivity of unconventional colistin combinations. Additional experiments are warranted to understand the clinical significance of these observations.

scholarly journals Activity of Telavancin against Staphylococcus aureus Strains with Various Vancomycin Susceptibilities in an In Vitro Pharmacokinetic/Pharmacodynamic Model with Simulated Endocardial Vegetations

2009 ◽  
Vol 53 (7) ◽  
pp. 2928-2933 ◽  
Author(s):  
Steven N. Leonard ◽  
Céline Vidaillac ◽  
Michael J. Rybak
Keyword(s):  
Staphylococcus Aureus ◽  
Combination Therapy ◽  
In Vitro Model ◽  
Therapeutic Potential ◽  
Population Analysis ◽  
Pharmacodynamic Model ◽  
Bacterial Killing ◽  
Vitro Model

ABSTRACT We investigated the activity of telavancin, a novel lipoglycopeptide, alone and combined with gentamicin or rifampin (rifampicin) against strains of Staphylococcus aureus with various vancomycin susceptibilities. Strains tested included methicillin (meticillin)-resistant S. aureus (MRSA) 494, methicillin-sensitive S. aureus (MSSA) 1199, heteroresistant glycopeptide-intermediate S. aureus (hGISA) 1629, which was confirmed by a population analysis profile, and glycopeptide-intermediate S. aureus (GISA) NJ 992. Regimens of 10 mg/kg telavancin daily and 1 g vancomycin every 12 h were investigated alone and combined with 5 mg/kg gentamicin daily or 300 mg rifampin every 8 h in an in vitro model with simulated endocardial vegetations over 96 h. Telavancin demonstrated significantly greater killing than did vancomycin (P < 0.01) for all isolates except MRSA 494 (P = 0.07). Telavancin absolute reductions, in log10 CFU/g, at 96 h were 2.8 ± 0.5 for MRSA 494, 2.8 ± 0.3 for MSSA 1199, 4.2 ± 0.2 for hGISA 1629, and 4.1 ± 0.3 for GISA NJ 992. Combinations of telavancin with gentamicin significantly enhanced killing compared to telavancin alone against all isolates (P < 0.001) except MRSA 494 (P = 0.176). This enhancement was most evident against hGISA 1629, where killing to the level of detection (2 log10 CFU/g) was achieved at 48 h (P < 0.001). The addition of rifampin to telavancin resulted in significant (P < 0.001) enhancement of killing against only MSSA 1199. No changes in telavancin susceptibilities were observed. These results suggest that telavancin may have therapeutic potential, especially against strains with reduced susceptibility to vancomycin. Combination therapy, particularly with gentamicin, may improve bacterial killing against certain strains.

scholarly journals Therapeutic Efficacy of Novel Antimicrobial Peptide AA139-Nanomedicines in a Multidrug-Resistant Klebsiella pneumoniae Pneumonia-Septicemia Model in Rats

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Hessel van der Weide ◽  
Unai Cossío ◽  
Raquel Gracia ◽  
Yvonne M. te Welscher ◽  
Marian T. ten Kate ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Therapeutic Efficacy ◽  
Antimicrobial Agents ◽  
Polymeric Nanoparticles ◽  
Multidrug Resistant ◽  
Antimicrobial Activities ◽  
Bacterial Killing ◽  
Gram Negative ◽  
Content Type

ABSTRACT Antimicrobial peptides (AMPs) have seen limited clinical use as antimicrobial agents, largely due to issues relating to toxicity, short biological half-life, and lack of efficacy against Gram-negative bacteria. However, the development of novel AMP-nanomedicines, i.e., AMPs entrapped in nanoparticles, has the potential to ameliorate these clinical problems. The authors investigated two novel nanomedicines based on AA139, an AMP currently in development for the treatment of multidrug-resistant Gram-negative infections. AA139 was entrapped in polymeric nanoparticles (PNPs) or lipid-core micelles (MCLs). The antimicrobial activity of AA139-PNP and AA139-MCL was determined in vitro. The biodistribution and limiting doses of AA139-nanomedicines were determined in uninfected rats via endotracheal aerosolization. The early bacterial killing activity of the AA139-nanomedicines in infected lungs was assessed in a rat model of pneumonia-septicemia caused by extended-spectrum β-lactamase-producing Klebsiella pneumoniae. In this model, the therapeutic efficacy was determined by once-daily (q24h) administration over 10 days. Both AA139-nanomedicines showed equivalent in vitro antimicrobial activities (similar to free AA139). In uninfected rats, they exhibited longer residence times in the lungs than free AA139 (∼20% longer for AA139-PNP and ∼80% longer for AA139-MCL), as well as reduced toxicity, enabling a higher limiting dose. In rats with pneumonia-septicemia, both AA139-nanomedicines showed significantly improved therapeutic efficacy in terms of an extended rat survival time, although survival of all rats was not achieved. These results demonstrate potential advantages that can be achieved using AMP-nanomedicines. AA139-PNP and AA139-MCL may be promising novel therapeutic agents for the treatment of patients suffering from multidrug-resistant Gram-negative pneumonia-septicemia.

scholarly journals Evolution of Colistin Resistance in the Klebsiella pneumoniae Complex Follows Multiple Evolutionary Trajectories with Variable Effects on Fitness and Virulence Characteristics

2020 ◽  
Vol 65 (1) ◽  
pp. e01958-20
Author(s):  
Axel B. Janssen ◽  
Dennis J. Doorduijn ◽  
Grant Mills ◽  
Malbert R. C. Rogers ◽  
Marc J. M. Bonten ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Lipid A ◽  
Multidrug Resistant ◽  
Sensu Stricto ◽  
Colistin Resistance ◽  
Content Type ◽  
Evolutionary Trajectories ◽  
Resistant Strains ◽  
Phosphate Groups

ABSTRACTThe increasing prevalence of multidrug-resistant Klebsiella pneumoniae has led to a resurgence in the use of colistin as a last-resort drug. Colistin is a cationic antibiotic that selectively acts on Gram-negative bacteria through electrostatic interactions with anionic phosphate groups of the lipid A moiety of lipopolysaccharides (LPSs). Colistin resistance in K. pneumoniae is mediated through loss of these phosphate groups, their modification by cationic groups, and by the hydroxylation of acyl groups of lipid A. Here, we study the in vitro evolutionary trajectories toward colistin resistance in four clinical K. pneumoniae complex strains and their impact on fitness and virulence characteristics. Through population sequencing during in vitro evolution, we found that colistin resistance develops through a combination of single nucleotide polymorphisms, insertions and deletions, and the integration of insertion sequence elements, affecting genes associated with LPS biosynthesis and modification and capsule structures. Colistin resistance decreased the maximum growth rate of one K. pneumoniaesensu stricto strain, but not those of the other three K. pneumoniae complex strains. Colistin-resistant strains had lipid A modified through hydroxylation, palmitoylation, and l-Ara4N addition. K. pneumoniaesensu stricto strains exhibited cross-resistance to LL-37, in contrast to the Klebsiella variicola subsp. variicola strain. Virulence, as determined in a Caenorhabditis elegans survival assay, was increased in two colistin-resistant strains. Our study suggests that nosocomial K. pneumoniae complex strains can rapidly develop colistin resistance through diverse evolutionary trajectories upon exposure to colistin. This effectively shortens the life span of this last-resort antibiotic for the treatment of infections with multidrug-resistant Klebsiella.

scholarly journals In VivoEmergence of Colistin Resistance in Klebsiella pneumoniae Producing KPC-Type Carbapenemases Mediated by Insertional Inactivation of the PhoQ/PhoPmgrBRegulator

2013 ◽  
Vol 57 (11) ◽  
pp. 5521-5526 ◽  
Author(s):  
Antonio Cannatelli ◽  
Marco Maria D'Andrea ◽  
Tommaso Giani ◽  
Vincenzo Di Pilato ◽  
Fabio Arena ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Genomic Analysis ◽  
Negative Regulator ◽  
Resistant Isolate ◽  
Comparative Genomic ◽  
Colistin Resistance ◽  
Content Type ◽  
Insertional Inactivation ◽  
Resistant Mutants

ABSTRACTColistin is one of the few agents that retain activity against extensively drug-resistant strains ofKlebsiella pneumoniaeproducing 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 themgrBgene, encoding a negative regulator of the PhoQ/PhoP signaling system, is a genetic mechanism for acquired colistin resistance. The role ofmgrBinactivation in acquired colistin resistance was confirmed by complementation experiments with wild-typemgrB, which restored colistin susceptibility in KKBO-4, and by construction of anmgrBdeletion mutant from KKBO-1, which exhibited a colistin-resistant phenotype. InsertionalmgrBinactivation was also detected in 60% of colistin-resistant mutants selected from KKBO-1in 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 themgrBgene, upregulated transcription ofphoP,phoQ, andpmrK(which is part of thepmrHFIJKLMoperon) was detected. These findings confirmed the MgrB regulatory role inK. pneumoniaeand were in agreement with the known association between upregulation of the PhoQ/PhoP system and activation of thepmrHFIJKLMoperon, which eventually leads to resistance to polymyxins by modification of the lipopolysaccharide target.

scholarly journals In VitroPharmacodynamics of Simulated Pulmonary Exposures of Tigecycline Alone and in Combination againstKlebsiella pneumoniaeIsolates Producing a KPC Carbapenemase

2011 ◽  
Vol 55 (4) ◽  
pp. 1420-1427 ◽  
Author(s):  
Dora E. Wiskirchen ◽  
Pornpan Koomanachai ◽  
Anthony M. Nicasio ◽  
David P. Nicolau ◽  
Joseph L. Kuti
Keyword(s):  
Multidrug Resistant ◽  
Pharmacodynamic Model ◽  
High Dose ◽  
Prolonged Infusion ◽  
Bacterial Killing ◽  
Epithelial Lining Fluid ◽  
Multidrug Resistant Organisms ◽  
Time Kill ◽  
Additional Reduction

ABSTRACTMultidrug-resistantKlebsiella pneumoniaestrains that produce a serine carbapenemase (KPC) are emerging worldwide, with few therapeutic options that retain consistent susceptibility. The objective of this study was to determine the effect of combination therapy with tigecycline versus tigecycline alone against KPC-producing isolates (KPC isolates). Anin vitropharmacodynamic model was used to simulate adult steady-state epithelial lining fluid concentrations of tigecycline (50 mg every 12 h) given alone and in combination with either meropenem (2 g by 3-hour infusion every 8 h) or rifampin (600 mg every 12 h). Five KPC isolates with various phenotypic profiles were exposed over 48 h. Time-kill curves were constructed, and the areas under the bacterial killing and regrowth curves (AUBCs) were calculated. No regimens tested were able to maintain bactericidal reductions in CFU over 48 h. The AUBCs for tigecycline and meropenem monotherapies at 48 h ranged from 375.37 to 388.11 and from 348.62 to 383.83 (CFU-h/ml), respectively. The combination of tigecycline plus meropenem significantly reduced the AUBCs at 24 and 48 h for isolates with tigecycline MICs of ≤2 μg/ml and meropenem MICs of ≤16 μg/ml (P< 0.001) but added no additional activity when the meropenem MIC was 64 μg/ml (P= 0.5). Rifampin provided no additional reduction in CFU or AUBC over tigecycline alone (P= 0.837). The combination of tigecycline with high-dose, prolonged-infusion meropenem warrants further study as a potential treatment option for these multidrug-resistant organisms.

scholarly journals Doripenem MICs andompK36Porin Genotypes of Sequence Type 258, KPC-Producing Klebsiella pneumoniae May Predict Responses to Carbapenem-Colistin Combination Therapy among Patients with Bacteremia

2014 ◽  
Vol 59 (3) ◽  
pp. 1797-1801 ◽  
Author(s):  
Ryan K. Shields ◽  
M. Hong Nguyen ◽  
Brian A. Potoski ◽  
Ellen G. Press ◽  
Liang Chen ◽  
...  
Keyword(s):  
Amino Acids ◽  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Sequence Type ◽  
Content Type

ABSTRACTTreatment failures of a carbapenem-colistin regimen among patients with bacteremia due to sequence type 258 (ST258), KPC-2-producingKlebsiella pneumoniaewere significantly more likely if both agents were inactivein vitro, as defined by a colistin MIC of >2 μg/ml and the presence of either a majorompK36porin mutation (guanine and alanine insertions at amino acids 134 and 135 [ins aa 134–135 GD], IS5promoter insertion [P= 0.007]) or a doripenem MIC of >8 μg/ml (P= 0.01). MajorompK36mutations among KPC-K. pneumoniaestrains are important determinants of carbapenem-colistin responsesin vitroandin vivo.

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