scholarly journals Does the Activity of the Combination of Imipenem and Colistin In Vitro Exceed the Problem of Resistance in Metallo-β-Lactamase-Producing Klebsiella pneumoniae Isolates?

2009 ◽  
Vol 53 (5) ◽  
pp. 2133-2135 ◽  
Author(s):  
Maria Souli ◽  
Panagiota Danai Rekatsina ◽  
Zoi Chryssouli ◽  
Irene Galani ◽  
Helen Giamarellou ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Bactericidal Activity ◽  
Clinical Isolates ◽  
Type Gene ◽  
Time Kill

ABSTRACT Using time-kill methodology, we investigated the interactions of an imipenem-colistin combination against 42 genetically distinct Klebsiella pneumoniae clinical isolates carrying a bla VIM-1-type gene. Irrespective of the imipenem MIC, the combination was synergistic (50%) or indifferent (50%) against colistin-susceptible strains, while it was antagonistic (55.6%) and rarely synergistic (11%) against non-colistin-susceptible strains (with synergy being observed only against strains with colistin MICs of 3 to 4 μg/ml). The combination showed improved bactericidal activity against isolates susceptible either to both agents or to colistin.

scholarly journals Synergistic Activities of Moxifloxacin Combined with Piperacillin-Tazobactam or Cefepime against Klebsiella pneumoniae, Enterobacter cloacae, and Acinetobacter baumannii Clinical Isolates

2004 ◽  
Vol 48 (3) ◽  
pp. 1055-1057 ◽  
Author(s):  
Rose Jung ◽  
Maroof Husain ◽  
Michael K. Choi ◽  
Douglas N. Fish
Keyword(s):  
Klebsiella Pneumoniae ◽  
Acinetobacter Baumannii ◽  
Bactericidal Activity ◽  
Enterobacter Cloacae ◽  
Clinical Isolates ◽  
Time Kill

ABSTRACT The bactericidal activity of moxifloxacin alone and in combination with cefepime or piperacillin-tazobactam against clinical isolates of Klebsiella pneumoniae, Enterobacter cloacae, and Acinetobacter baumannii was evaluated by using time-kill methods and antimicrobial concentrations of one-half and one times the MIC. Synergy was observed in 58 to 88% of the strains and resulted in bactericidal activity against 60 to 100% of the strains. Combinations including moxifloxacin demonstrated enhanced bactericidal activity compared with that of either agent tested alone.

scholarly journals In vitro Optimization of Ceftazidime/Avibactam for KPC-Producing Klebsiella pneumoniae

2021 ◽  
Vol 12 ◽  
Author(s):  
Yanqin Huang ◽  
Tiffany Wu ◽  
Omar Perez ◽  
Amisha P. Rana ◽  
Liang Chen ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Outer Membrane ◽  
Bactericidal Activity ◽  
Base Pair ◽  
Treatment Approach ◽  
Bacterial Regrowth ◽  
Base Pair Deletion ◽  
Outer Membrane Porin ◽  
Time Kill

Ceftazidime/avibactam is an important treatment option for infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp), however, resistance can emerge during treatment. The objective of the study was to define the ceftazidime/avibactam concentrations required to suppress bacterial regrowth in ceftazidime/avibactam susceptible isolates and identify active therapies against ceftazidime/avibactam-resistant KPC-Kp. Time-kill assays were performed against twelve ST258 KPC-Kp isolates that harbored blaKPC–2 or blaKPC–3. Nine KPC-Kp isolates (KPC-Kp 5A, 6A, 7A, 8A, 9A, 24A, 25A, 26A, and 27A) were susceptible to ceftazidime/avibactam, two (KPC-Kp 6B and 7B) were ceftazidime/avibactam resistant and meropenem susceptible, and one (KPC-Kp 1244) was resistant to both ceftazidime/avibactam and meropenem. Sequencing of the blaKPC genes revealed mutations in KPC-Kp 6B (D179Y substitution) and 7B (novel 21 base pair deletion) that both affected the Ω-loop encoding portion of the gene. Time-kill assays showed that against ceftazidime/avibactam-susceptible KPC-Kp, ceftazidime/avibactam concentrations ≥40/7.5 mg/L caused mean 5.42 log10CFU/mL killing and suppressed regrowth. However, regrowth occurred for some KPC-Kp isolates with a ceftazidime/avibactam concentration of 20/3.75 mg/L. Against ceftazidime/avibactam-resistant and meropenem-susceptible KPC-Kp 6B and 7B, bactericidal activity and synergy was observed for ceftazidime/avibactam in combination with meropenem ≤3.125 mg/L, while meropenem concentrations ≥50 mg/L were bactericidal as monotherapy. In contrast, clinically achievable concentrations of ceftazidime/avibactam were bactericidal against KPC-Kp 1244, which was ceftazidime/avibactam-resistant and meropenem-resistant due to outer membrane porin mutations and elevated blaKPC expression. Achieving high ceftazidime/avibactam concentrations may help to suppress bacterial regrowth in the presence of ceftazidime/avibactam. The optimal treatment approach for ceftazidime/avibactam-resistant KPC-Kp likely depends on the mechanism of resistance. Additional studies are warranted to confirm these findings.

scholarly journals Polymyxin B in Combination with Rifampin and Meropenem against Polymyxin B-Resistant KPC-Producing Klebsiella pneumoniae

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
John K. Diep ◽  
David M. Jacobs ◽  
Rajnikant Sharma ◽  
Jenna Covelli ◽  
Dana R. Bowers ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Bactericidal Activity ◽  
Population Analysis ◽  
Polymyxin B ◽  
Infection Model ◽  
Triple Combination Therapy ◽  
Content Type ◽  
Drug Regimens ◽  
Time Kill

ABSTRACT Safe and effective therapies are urgently needed to treat polymyxin-resistant KPC-producing Klebsiella pneumoniae infections and suppress the emergence of resistance. We investigated the pharmacodynamics of polymyxin B, rifampin, and meropenem alone and as polymyxin B-based double and triple combinations against KPC-producing K. pneumoniae isolates. The rates and extents of killing with polymyxin B (1 to 128 mg/liter), rifampin (2 to 16 mg/liter), and meropenem (10 to 120 mg/liter) were evaluated against polymyxin B-susceptible (PBs) and polymyxin B-resistant (PBr) clinical isolates using 48-h static time-kill studies. Additionally, humanized triple-drug regimens of polymyxin B (concentration at steady state [C ss] values of 0.5, 1, and 2 mg/liter), 600 mg rifampin every 12 or 8 h, and 1 or 2 g meropenem every 8 h dosed as an extended 3-h infusion were simulated over 48 h by using a one-compartment in vitro dynamic infection model. Serial bacterial counts were performed to quantify the pharmacodynamic effect. Population analysis profiles (PAPs) were used to assess the emergence of polymyxin B resistance. Monotherapy was ineffective against both isolates. Polymyxin B with rifampin demonstrated early bactericidal activity against the PBs isolate, followed by regrowth by 48 h. Bactericidal activity was sustained at all polymyxin B concentrations of ≥2 mg/liter in combination with meropenem. No two-drug combinations were effective against the PBr isolate, but all simulated triple-drug regimens showed early bactericidal activity against both strains by 8 h that was sustained over 48 h. PAPs did not reveal the emergence of resistant subpopulations. The triple-drug combination of polymyxin B, rifampin, and meropenem may be a viable consideration for the treatment of PBr KPC-producing K. pneumoniae infections. Further investigation is warranted to optimize triple-combination therapy.

scholarly journals In VitroInteractions of Antimicrobial Combinations with Fosfomycin against KPC-2-Producing Klebsiella pneumoniae and Protection of Resistance Development

2011 ◽  
Vol 55 (5) ◽  
pp. 2395-2397 ◽  
Author(s):  
Maria Souli ◽  
Irene Galani ◽  
Stefanos Boukovalas ◽  
Michael George Gourgoulis ◽  
Zoi Chryssouli ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Bactericidal Activity ◽  
Clinical Isolates ◽  
Resistance Development ◽  
Content Type ◽  
Fosfomycin Resistance ◽  
Time Kill ◽  
Antimicrobial Combinations

ABSTRACTUsing time-kill methodology, we investigated the interactions of fosfomycin with meropenem or colistin or gentamicin against 17 genetically distinctKlebsiella pneumoniaeclinical isolates carryingblaKPC-2. Synergy was observed with meropenem or colistin against 64.7 and 11.8% of tested isolates, while the combination with gentamicin resulted in indifference. All studied combinations showed improved bactericidal activity, compared to fosfomycin alone and prevented the development of fosfomycin resistance in 69.2, 53.8, and 81.8% of susceptible isolates, respectively.

scholarly journals Interplay among Different Fosfomycin Resistance Mechanisms in Klebsiella pneumoniae

2020 ◽  
Vol 65 (3) ◽  
Author(s):  
M. Ortiz-Padilla ◽  
I. Portillo-Calderón ◽  
B. de Gregorio-Iaria ◽  
J. Blázquez ◽  
J. Rodríguez-Baño ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Growth Curves ◽  
Resistant Mutant ◽  
Bactericidal Effect ◽  
Clinical Isolates ◽  
Growth Monitoring ◽  
Content Type ◽  
Fosfomycin Resistance ◽  
Time Kill

ABSTRACT The objectives of this study were to characterize the role of the uhpT, glpT, and fosA genes in fosfomycin resistance in Klebsiella pneumoniae and evaluate the use of sodium phosphonoformate (PPF) in combination with fosfomycin. Seven clinical isolates of K. pneumoniae and the reference strain (ATCC 700721) were used, and their genomes were sequenced. ΔuhpT, ΔglpT, and ΔfosA mutants were constructed from two isolates and K. pneumoniae ATCC 700721. Fosfomycin susceptibility testing was done by the gradient strip method. Synergy between fosfomycin and PPF was studied by checkerboard assay and analyzed using SynergyFinder. Spontaneous fosfomycin mutant frequencies at 64 and 512 mg/liter, in vitro activity using growth curves with fosfomycin gradient concentrations (0 to 256mg/liter), and time-kill assays at 64 and 307 mg/liter were evaluated with and without PPF (0.623 mM). The MICs of fosfomycin against the clinical isolates ranged from 16 to ≥1,024 mg/liter. The addition of 0.623 mM PPF reduced fosfomycin MIC between 2- and 8-fold. Deletion of fosA led to a 32-fold decrease. Synergistic activities were observed with the combination of fosfomycin and PPF (most synergistic area at 0.623 mM). The lowest fosfomycin-resistant mutant frequencies were found in ΔfosA mutants, with decreases in frequency from 1.69 × 10−1 to 1.60 × 10−5 for 64 mg/liter of fosfomycin. In the final growth monitoring and time-kill assays, fosfomycin showed a bactericidal effect only with the deletion of fosA and not with the addition of PPF. We conclude that fosA gene inactivation leads to a decrease in fosfomycin resistance in K. pneumoniae. The pharmacological approach using PPF did not achieve enough activity, and the effect decreased with the presence of fosfomycin-resistant mutations.

Emergence of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae in vivo

2019 ◽  
Vol 74 (11) ◽  
pp. 3211-3216 ◽  
Author(s):  
Stephan Göttig ◽  
Denia Frank ◽  
Eleonora Mungo ◽  
Anika Nolte ◽  
Michael Hogardt ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Selection Pressure ◽  
Galleria Mellonella ◽  
Phenotypic Characterization ◽  
Infection Model ◽  
Development Of Resistance ◽  
Time Kill

Abstract Objectives The β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is active against KPC-producing Enterobacterales. Herein, we present molecular and phenotypic characterization of ceftazidime/avibactam resistance in KPC-3-producing Klebsiella pneumoniae that emerged in vivo and in vitro. Methods Sequence analysis of blaKPC-3 was performed from clinical and in vitro-generated ceftazidime/avibactam-resistant K. pneumoniae isolates. Time–kill kinetics and the Galleria mellonella infection model were applied to evaluate the activity of ceftazidime/avibactam and imipenem alone and in combination. Results The ceftazidime/avibactam-resistant clinical K. pneumoniae isolate revealed the amino acid change D179Y in KPC-3. Sixteen novel mutational changes in KPC-3 among in vitro-selected ceftazidime/avibactam-resistant isolates were described. Time–kill kinetics showed the emergence of a resistant subpopulation under selection pressure with either imipenem or ceftazidime/avibactam. However, combined selection pressure with imipenem plus ceftazidime/avibactam prevented the development of resistance and resulted in bactericidal activity. Concordantly, the G. mellonella infection model revealed that monotherapy with ceftazidime/avibactam is prone to select for resistance in vivo and that combination therapy with imipenem results in significantly better survival. Conclusions Ceftazidime/avibactam is a valuable antibiotic against MDR and carbapenem-resistant Enterobacterales. Based on time–kill kinetics as well as an in vivo infection model we postulate a combination therapy of ceftazidime/avibactam and imipenem as a strategy to prevent the development of ceftazidime/avibactam resistance in KPC-producing Enterobacterales in vivo.

scholarly journals C3 Promotes Clearance of Klebsiella pneumoniae by A549 Epithelial Cells

2004 ◽  
Vol 72 (3) ◽  
pp. 1767-1774 ◽  
Author(s):  
Beatriz de Astorza ◽  
Guadalupe Cortés ◽  
Catalina Crespí ◽  
Carles Saus ◽  
José María Rojo ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Klebsiella Pneumoniae ◽  
Alveolar Epithelial Cells ◽  
Clinical Isolates ◽  
Complement Components ◽  
Innate Defense ◽  
Alveolar Epithelial

ABSTRACT The airway epithelium represents a primary site for contact between microbes and their hosts. To assess the role of complement in this event, we studied the interaction between the A549 cell line derived from human alveolar epithelial cells and a major nosocomial pathogen, Klebsiella pneumoniae, in the presence of serum. In vitro, we found that C3 opsonization of poorly encapsulated K. pneumoniae clinical isolates and an unencapsulated mutant enhanced dramatically bacterial internalization by A549 epithelial cells compared to highly encapsulated clinical isolates. Local complement components (either present in the human bronchoalveolar lavage or produced by A549 epithelial cells) were sufficient to opsonize K. pneumoniae. CD46 could competitively inhibit the internalization of K. pneumoniae by the epithelial cells, suggesting that CD46 is a receptor for the binding of complement-opsonized K. pneumoniae to these cells. We observed that poorly encapsulated strains appeared into the alveolar epithelial cells in vivo but that (by contrast) they were completely avirulent in a mouse model of pneumonia compared to the highly encapsulated strains. Our results show that bacterial opsonization by complement enhances the internalization of the avirulent microorganisms by nonphagocytic cells such as A549 epithelial cells and allows an efficient innate defense.

scholarly journals Carbapenem-Resistant Klebsiella pneumoniae Clinical Isolates: In Vivo Virulence Assessment in Galleria mellonella and Potential Therapeutics by Polycationic Oligoethyleneimine

Antibiotics ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 56
Author(s):  
Dalila Mil-Homens ◽  
Maria Martins ◽  
José Barbosa ◽  
Gabriel Serafim ◽  
Maria J. Sarmento ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Galleria Mellonella ◽  
Multidrug Resistant ◽  
In Vitro Models ◽  
Clinical Isolates ◽  
In Vivo Model ◽  
Virulence Potential ◽  
Hospital Acquired

Klebsiella pneumoniae, one of the most common pathogens found in hospital-acquired infections, is often resistant to multiple antibiotics. In fact, multidrug-resistant (MDR) K. pneumoniae producing KPC or OXA-48-like carbapenemases are recognized as a serious global health threat. In this sense, we evaluated the virulence of K. pneumoniae KPC(+) or OXA-48(+) aiming at potential antimicrobial therapeutics. K. pneumoniae carbapenemase (KPC) and the expanded-spectrum oxacillinase OXA-48 isolates were obtained from patients treated in medical care units in Lisbon, Portugal. The virulence potential of the K. pneumonia clinical isolates was tested using the Galleria mellonella model. For that, G. mellonella larvae were inoculated using patients KPC(+) and OXA-48(+) isolates. Using this in vivo model, the KPC(+) K. pneumoniae isolates showed to be, on average, more virulent than OXA-48(+). Virulence was found attenuated when a low bacterial inoculum (one magnitude lower) was tested. In addition, we also report the use of a synthetic polycationic oligomer (L-OEI-h) as a potential antimicrobial agent to fight infectious diseases caused by MDR bacteria. L-OEI-h has a broad-spectrum antibacterial activity and exerts a significantly bactericidal activity within the first 5-30 min treatment, causing lysis of the cytoplasmic membrane. Importantly, the polycationic oligomer showed low toxicity against in vitro models and no visible cytotoxicity (measured by survival and health index) was noted on the in vivo model (G. mellonella), thus L-OEI-h is foreseen as a promising polymer therapeutic for the treatment of MDR K. pneumoniae infections.

Meropenem/vaborbactam activity in vitro: a new option for Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae treatment

2021 ◽  
Author(s):  
Federica Romanelli ◽  
Stefania Stolfa ◽  
Anna Morea ◽  
Luigi Ronga ◽  
Raffaele Del Prete ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Turning Point ◽  
Treatment Strategies ◽  
Blood Cultures ◽  
Clinical Isolates ◽  
In Vitro Susceptibility ◽  
Klebsiella Pneumoniae Carbapenemase ◽  
Lactamase Inhibitor

Aim: Infections by Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae represent a major challenge because of limited treatment strategies. New β-lactam/β-lactamase inhibitor associations may help to deal with this challenge. The aim of this study is to evaluate the in vitro susceptibility of KPC-producing K. pneumoniae for meropenem/vaborbactam in comparison with ceftazidime/avibactam against. Materials and methods: Twenty-eight strains isolated from blood cultures were evaluated. Testing for susceptibility to meropenem/vaborbactam and ceftazidime/avibactam was performed by E-test gradient strip. Results: All the clinical isolates were susceptible to meropenem/vaborbactam, while one strain was resistant to ceftazidime/avibactam with a MIC of 32 μg/ml. The median MIC of ceftazidime/avibactam evaluated after standardization was higher compared with that of meropenem/vaborbactam. Conclusion: Meropenem/vaborbactam could be an important turning point in the treatment of KPC-producing K. pneumoniae infections, especially considering the emergence of ceftazidime/avibactam resistance.

scholarly journals In vitro antibacterial activity of LY333328, a new semisynthetic glycopeptide.

1997 ◽  
Vol 41 (10) ◽  
pp. 2165-2172 ◽  
Author(s):  
F Biavasco ◽  
C Vignaroli ◽  
R Lupidi ◽  
E Manso ◽  
B Facinelli ◽  
...  
Keyword(s):  
Structural Analog ◽  
Clinical Isolates ◽  
Alkyl Derivative ◽  
Minimal Bactericidal Concentration ◽  
Highly Active ◽  
In Vitro Antibacterial Activity ◽  
Resistant Strains ◽  
Vancomycin Resistant ◽  
Time Kill

LY333328 is a semisynthetic N-alkyl derivative of LY264826, a naturally occurring structural analog of vancomycin. LY333328 was evaluated for its in vitro inhibitory and bactericidal activities in comparison with those of the two currently available glycopeptides (vancomycin and teicoplanin). Glycopeptide-susceptible test strains included a total of 311 isolates (most of clinical origin) from the genera Staphylococcus, Enterococcus, Streptococcus, Aerococcus, Gemella, Lactococcus, Listeria, Corynebacterium, and Clostridium. Test strains resistant or intermediate to vancomycin and/or teicoplanin included 56 clinical isolates of Enterococcus (of the VanA, VanB, and VanC phenotypes) and 32 clinical isolates of Staphylococcus (S. haemolyticus, S. epidermidis, and S. aureus), 31 strains of gram-positive genera outside the spectrum of activity of vancomycin (Leuconostoc, Pediococcus, Lactobacillus, and Erysipelothrix), and laboratory-derived organisms obtained after exposure of susceptible Staphylococcus isolates to teicoplanin (6 strains) or laboratory-derived organisms with resistance determinants received from VanA enterococci (2 Enterococcus and 25 Listeria transconjugants). LY333328 was highly active against staphylococci, enterococci, and listeriae (whether they were clinical or laboratory-derived strains) resistant to the currently available glycopeptides. In particular, the MICs of LY333328 did not vary substantially between teicoplanin-susceptible and teicoplanin-resistant staphylococci and between vancomycin-susceptible and vancomycin-resistant enterococci. LY333328 demonstrated fairly good inhibitory activity even against most strains of Leuconostoc, Pediococcus, and Erysipelothrix (MIC range, 1 to 8 microg/ml), whereas it proved less active (although much more active than vancomycin or teicoplanin) against Lactobacillus strains. In minimal bactericidal concentration (MBC) and time-kill studies, LY333328 demonstrated excellent bactericidal activity; enterococci, in particular, which were largely tolerant of vancomycin and teicoplanin, were uniformly killed by LY333328, with MBC-to-MIC ratios of 4 to 8 for most vancomycin-susceptible and vancomycin-resistant strains. In attempts to select for resistant clones, no survivors stably growing in the presence of 10 microg of LY333328 per ml were obtained from the Staphylococcus and Enterococcus test strains exposed to the drug.

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