scholarly journals The Role of IgG Subclass in Antibody-Mediated Protection against Carbapenem-Resistant Klebsiella pneumoniae

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Michael P. Motley ◽  
Elizabeth Diago-Navarro ◽  
Kasturi Banerjee ◽  
Sean Inzerillo ◽  
Bettina C. Fries
Keyword(s):  
Monoclonal Antibodies ◽  
Klebsiella Pneumoniae ◽  
Capsular Polysaccharide ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Neutropenic Patients ◽  
Antibody Subclass

ABSTRACT Monoclonal antibodies (MAbs) have the potential to assist in the battle against multidrug-resistant bacteria such as carbapenem-resistant Klebsiella pneumoniae (CR-Kp). However, the characteristics by which these antibodies (Abs) function, such as the role of antibody subclass, must be determined before such modalities can be carried from the bench to the bedside. We performed a subclass switch on anticapsular monoclonal murine IgG3 (mIgG3) hybridomas and identified and purified a murine IgG1 (mIgG1) hybridoma line through sib selection. We then compared the ability of the mIgG1 and mIgG3 antibodies to control CR-Kp sequence type 258 (ST258) infection both in vitro and in vivo. We found by enzyme-limited immunosorbent assay (ELISA) and flow cytometry that mIgG3 has superior binding to the CR-Kp capsular polysaccharide (CPS) and superior agglutinating ability compared to mIgG1. The mIgG3 also, predictably, had better complement-mediated serum bactericidal activity than the mIgG1 and also promoted neutrophil-mediated killing at concentrations lower than that of the mIgG1. In contrast, the mIgG1 had marginally better activity in improving macrophage-mediated phagocytosis. Comparing their activities in a pulmonary infection model with wild-type as well as neutropenic mice, both antibodies reduced organ burden in a nonlethal challenge, regardless of neutrophil status, with mIgG1 having the highest overall burden reduction in both scenarios. However, at a lethal inoculum, both antibodies showed reduced efficacy in neutropenic mice, with mIgG3 retaining the most activity. These findings suggest the viability of monoclonal Ab adjunctive therapy in neutropenic patients that cannot mount their own immune response, while also providing some insight into the relative contributions of immune mediators in CR-Kp protection. IMPORTANCE Carbapenem-resistant Klebsiella pneumoniae is an urgent public health threat that causes life-threatening infections in immunocompromised hosts. Its resistance to nearly all antibiotics necessitates novel strategies to treat it, including the use of monoclonal antibodies. Monoclonal antibodies are emerging as important adjuncts to traditional pharmaceuticals, and studying how they protect against specific bacteria such as Klebsiella pneumoniae is crucial to their development as effective therapies. Antibody subclass is often overlooked but is a major factor in how an antibody interacts with other mediators of immunity. This paper is the first to examine how the subclass of anticapsular monoclonal antibodies can affect efficacy against CR-Kp. Additionally, this work sheds light on the viability of monoclonal antibody therapy in neutropenic patients, who are most vulnerable to CR-Kp infection.

scholarly journals The Role of IgG Subclass in Antibody-Mediated Protection against Carbapenem-Resistant Klebsiella pneumoniae

2020 ◽  
Author(s):  
Michael P. Motley ◽  
Elizabet Diago-Navarro ◽  
Kasturi Banerjee ◽  
Sean Inzerillo ◽  
Bettina C. Fries
Keyword(s):  
Monoclonal Antibodies ◽  
Klebsiella Pneumoniae ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Lethal Challenge ◽  
Carbapenem Resistant ◽  
Neutropenic Patients ◽  
Antibody Subclass

ABSTRACTMonoclonal antibodies (Abs) have the potential to assist in the battle against multidrug-resistant bacteria such as Carbapenem-Resistant Klebsiella pneumoniae (CR-Kp). However, the characteristics by which these Abs function, such as the role of antibody subclass, must be determined before such modalities can be carried from the bench to the bedside. We performed a subclass switch on anti-capsular monoclonal murine IgG3 (mIgG3) hybridomas and identified and purified a murine IgG1 (mIgG1) hybridoma line through sib selection. We then compared the ability of the mIgG1 and mIgG3 antibodies to control CR-Kp ST258 infection both in vitro and in vivo. We found by ELISA and flow cytometry that mIgG3 has superior binding to CR-Kp CPS and superior agglutinating ability compared to mIgG1. The mIgG3 also predictably had better complement-mediated serum bactericidal activity than the mIgG1 and also promoted neutrophil-mediated killing at concentrations lower than the mIgG1. In contrast, the mIgG1 had marginally better activity in improving macrophage-mediated phagocytosis. Comparing their activities in a pulmonary infection model with wild type as well as neutropenic mice, both antibodies reduced organ burden in a non-lethal challenge, regardless of neutrophil status, with mIgG1 having the highest overall burden reduction in both scenarios. However, at a lethal inoculum, both antibodies showed reduced efficacy in neutropenic mice, with mIgG3 retaining the most activity. These findings suggest the viability of monoclonal Ab adjunctive therapy in neutropenic patients that cannot mount their own immune response, while also providing some insight into the relative contributions of immune mediators in CR-Kp protection.ImportanceCarbapenem-resistant Klebsiella pneumoniae is an urgent public health threat that causes life-threatening infections in immunocompromised hosts. Its resistance to nearly all antibiotics necessitates novel strategies to treat it, including the use of monoclonal antibodies. Monoclonal antibodies are emerging as important adjuncts to traditional pharmaceuticals, and studying how they protect against specific bacteria such as Klebsiella pneumoniae is crucial to their development as effective therapies. Antibody subclass is often overlooked but is a major factor in how an antibody interacts with other mediators of immunity. This paper is the first to examine how the subclass of anti-capsular monoclonal antibodies can affect efficacy against CR-Kp. Additionally, this work sheds light on the viability of monoclonal antibody therapy in neutropenic patients, who are most vulnerable to CR-Kp infection.

scholarly journals Colistin Heteroresistance Is Largely Undetected among Carbapenem-Resistant Enterobacterales in the United States

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Victor I. Band ◽  
Sarah W. Satola ◽  
Richard D. Smith ◽  
David A. Hufnagel ◽  
Chris Bower ◽  
...  
Keyword(s):  
United States ◽  
Klebsiella Pneumoniae ◽  
Diagnostic Testing ◽  
Cladistic Analysis ◽  
The United States ◽  
Clinical Diagnostics ◽  
Infection Model ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Clinical Diagnostic

ABSTRACT Heteroresistance is a form of antibiotic resistance where a bacterial strain is comprised of a minor resistant subpopulation and a majority susceptible subpopulation. We showed previously that colistin heteroresistance can mediate the failure of colistin therapy in an in vivo infection model, even for isolates designated susceptible by clinical diagnostics. We sought to characterize the extent of colistin heteroresistance among the highly drug-resistant carbapenem-resistant Enterobacterales (CRE). We screened 408 isolates for colistin heteroresistance. These isolates were collected between 2012 and 2015 in eight U.S. states as part of active surveillance for CRE. Colistin heteroresistance was detected in 10.1% (41/408) of isolates, and it was more common than conventional homogenous resistance (7.1%, 29/408). Most (93.2%, 38/41) of these heteroresistant isolates were classified as colistin susceptible by standard clinical diagnostic testing. The frequency of colistin heteroresistance was greatest in 2015, the last year of the study. This was especially true among Enterobacter isolates, of which specific species had the highest rates of heteroresistance. Among Klebsiella pneumoniae isolates, which were the majority of isolates tested, there was a closely related cluster of colistin-heteroresistant ST-258 isolates found mostly in Georgia. However, cladistic analysis revealed that, overall, there was significant diversity in the genetic backgrounds of heteroresistant K. pneumoniae isolates. These findings suggest that due to being largely undetected in the clinic, colistin heteroresistance among CRE is underappreciated in the United States. IMPORTANCE Heteroresistance is an underappreciated phenomenon that may be the cause of some unexplained antibiotic treatment failures. Misclassification of heteroresistant isolates as susceptible may lead to inappropriate therapy. Heteroresistance to colistin was more common than conventional resistance and was overwhelmingly misclassified as susceptibility by clinical diagnostic testing. Higher proportions of colistin heteroresistance observed in certain Enterobacter species and clustering among heteroresistant Klebsiella pneumoniae strains may inform colistin treatment recommendations. Overall, the rate of colistin nonsusceptibility was more than double the level detected by clinical diagnostics, suggesting that the prevalence of colistin nonsusceptibility among CRE may be higher than currently appreciated in the United States.

scholarly journals Fighting Antibiotic-Resistant Klebsiella pneumoniae with “Sweet” Immune Targets

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Roberto Adamo ◽  
Immaculada Margarit
Keyword(s):  
Klebsiella Pneumoniae ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Therapeutic Approaches ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Surface Polysaccharides ◽  
Resistant Strains ◽  
Murine Monoclonal Antibodies

ABSTRACT Antibiotics and vaccines have greatly impacted human health in the last century by dramatically reducing the morbidity and mortality associated with infectious diseases. The recent challenge posed by the emergence of multidrug-resistant bacteria could possibly be addressed by novel immune prophylactic and therapeutic approaches. Among the newly threatening pathogens, Klebsiella pneumoniae is particularly worrisome in the nosocomial setting, and its surface polysaccharides are regarded as promising antigen candidates. The majority of Klebsiella carbapenem-resistant strains belong to the sequence type 158 (ST258) lineage, with two main clades expressing capsular polysaccharides CPS1 and CPS2. In a recent article, S. D. Kobayashi and colleagues (mBio 9:e00297-18, 2018, https://doi.org/10.1128/mBio.00297-18) show that CPS2-specific IgGs render ST258 clade 2 bacteria more sensitive to human serum and phagocytic killing. E. Diago-Navarro et al. (mBio 9:e00091-18, 2018, https://doi.org/10.1128/mBio.00091-18) generated two murine monoclonal antibodies recognizing distinct glycotopes of CPS2 that presented functional activity against multiple ST258 strains. These complementary studies represent a step toward the control of this dangerous pathogen.

scholarly journals Serum Antibody Responses against Carbapenem-Resistant Klebsiella pneumoniae in Infected Patients

mSphere ◽  
2021 ◽  
Vol 6 (2) ◽  
Author(s):  
Kasturi Banerjee ◽  
Michael P. Motley ◽  
Elizabeth Diago-Navarro ◽  
Bettina C. Fries
Keyword(s):  
Klebsiella Pneumoniae ◽  
Capsular Polysaccharide ◽  
Serum Antibody ◽  
Antibody Responses ◽  
Capsular Polysaccharides ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Reactive Properties

ABSTRACT Capsular polysaccharide (CPS) heterogeneity within carbapenem-resistant Klebsiella pneumoniae (CR-Kp) strain sequence type 258 (ST258) must be considered when developing CPS-based vaccines. Here, we sought to characterize CPS-specific antibody responses elicited by CR-Kp-infected patients. Plasma and bacterial isolates were collected from 33 hospital patients with positive CR-Kp cultures. Isolate capsules were typed by wzi sequencing. Reactivity and measures of efficacy of patient antibodies were studied against 3 prevalent CR-Kp CPS types (wzi29, wzi154, and wzi50). High IgG titers against wzi154 and wzi50 CPS were documented in 79% of infected patients. Patient-derived (PD) IgGs agglutinated CR-Kp and limited growth better than naive IgG and promoted phagocytosis of strains across the serotype isolated from their donors. Additionally, poly-IgG from wzi50 and wzi154 patients promoted phagocytosis of nonconcordant CR-Kp serotypes. Such effects were lost when poly-IgG was depleted of CPS-specific IgG. Additionally, mice infected with wzi50, wzi154, and wzi29 CR-Kp strains preopsonized with wzi50 patient-derived IgG exhibited lower lung CFU than controls. Depletion of wzi50 antibodies (Abs) reversed this effect in wzi50 and wzi154 infections, whereas wzi154 Ab depletion reduced poly-IgG efficacy against wzi29 CR-Kp. We are the first to report cross-reactive properties of CPS-specific Abs from CR-Kp patients through both in vitro and in vivo models. IMPORTANCE Carbapenem-resistant Klebsiella pneumoniae is a rapidly emerging public health threat that can cause fatal infections in up to 50% of affected patients. Due to its resistance to nearly all antimicrobials, development of alternate therapies like antibodies and vaccines is urgently needed. Capsular polysaccharides constitute important targets, as they are crucial for Klebsiella pneumoniae pathogenesis. Capsular polysaccharides are very diverse and, therefore, studying the host’s capsule-type specific antibodies is crucial to develop effective anti-CPS immunotherapies. In this study, we are the first to characterize humoral responses in infected patients against carbapenem-resistant Klebsiella pneumoniae expressing different wzi capsule types. This study is the first to report the efficacy of cross-reactive properties of CPS-specific Abs in both in vitro and in vivo models.

scholarly journals An IncR Plasmid Harbored by a Hypervirulent Carbapenem-Resistant Klebsiella pneumoniae Strain Possesses Five Tandem Repeats of the blaKPC-2::NTEKPC-Id Fragment

2018 ◽  
Vol 63 (3) ◽  
Author(s):  
Ning Dong ◽  
Lizhang Liu ◽  
Rong Zhang ◽  
Kaichao Chen ◽  
Miaomiao Xie ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Klebsiella Pneumoniae ◽  
Tandem Repeats ◽  
Dna Recombination ◽  
Multidrug Resistant ◽  
Plasmid Evolution ◽  
Content Type ◽  
Carbapenem Resistant

ABSTRACT Completed sequences of three plasmids from a carbapenem-resistant hypervirulent Klebsiella pneumoniae isolate, SH9, were obtained. In addition to the pLVPK-like virulence-conferring plasmid (pVir-CR-HvKP_SH9), the two multidrug-resistant plasmids (pKPC-CR-HvKP4_SH9 and pCTX-M-CR-HvKP4_SH9) were predicted to originate from a single pKPC-CR-HvKP4-like multireplicon plasmid through homologous recombination. Interestingly, the blaKPC-2 gene was detectable in five tandem repeats exhibiting the format of an NTEKPC-Id-like transposon (IS26-ΔTn3-ISKpn8-blaKPC-2-ΔISKpn6-korC-orf-IS26). The data suggest an important role of DNA recombination in mediating active plasmid evolution.

scholarly journals Novel, Broadly Reactive Anticapsular Antibodies against Carbapenem-ResistantKlebsiella pneumoniaeProtect from Infection

mBio ◽  
2018 ◽  
Vol 9 (2) ◽  
Author(s):  
Elizabeth Diago-Navarro ◽  
Michael P. Motley ◽  
Gonzalo Ruiz-Peréz ◽  
Winnie Yu ◽  
Julianne Austin ◽  
...  
Keyword(s):  
At Risk ◽  
Klebsiella Pneumoniae ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Risk Of Infection ◽  
Treatment Alternative ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Polysaccharide Capsule ◽  
Valuable Treatment

ABSTRACTCarbapenem-resistant (CR) sequence type 258 (ST258)Klebsiella pneumoniaehas become an urgent health care threat, causing an increasing number of high-mortality infections. Its resistance to numerous antibiotics and threat to immunocompromised patients necessitate finding new therapies to combat these infections. Previous successes in the laboratory, as well as the conservation of capsular polysaccharide (CPS) among the members of the ST258 clone, suggest that monoclonal antibody (MAb) therapy targeting the outer polysaccharide capsule ofK. pneumoniaecould serve as a valuable treatment alternative for afflicted patients. Here, we isolated several IgG antibodies from mice inoculated with a mixture of CRK. pneumoniaeCPS conjugated to anthrax protective antigen. Two of these MAbs, 17H12 and 8F12, bind whole and oligosaccharide epitopes of the CPS of clade 2 ST258 CRK. pneumoniae, which is responsible for the most virulent CRK. pneumoniaeinfections in the United States. These antibodies were shown to agglutinate all clade 2 strains and were also shown to promote extracellular processes killing these bacteria, including biofilm inhibition, complement deposition, and deployment of neutrophil extracellular traps. Additionally, they promoted opsonophagocytosis and intracellular killing of CRK. pneumoniaeby human-derived neutrophils and cultured murine macrophages. Finally, when mice were intratracheally infected with preopsonized clade 2 CRK. pneumoniae, these MAbs reduced bacterial dissemination to organs. Our data suggest that broadly reactive anticapsular antibodies and vaccines against clade 2 ST258 CRK. pneumoniaeare possible. Such MAbs and vaccines would benefit those susceptible populations at risk of infection with this group of multidrug-resistant bacteria.IMPORTANCECarbapenem-resistantKlebsiella pneumoniaeis an enteric bacterium that has been responsible for an increasing number of deadly outbreaks and hospital-acquired infections. The pathogen’s resistance to numerous antibiotics, including new drugs, leaves few therapeutic options available for infected patients, who often are too sick to fight the infection themselves. Immunotherapy utilizing monoclonal antibodies has been successful in other medical fields, and antibodies targeting the outer polysaccharide capsule of these bacteria could be a valuable treatment alternative. This study presents two anticapsular antibodies, 17H12 and 8F12, that were found to be protective against the most virulent carbapenem-resistantK. pneumoniaeclinical strains. These antibodies are shown to promote the killing of these strains through several extracellular and intracellular processes and prevent the spread of infection in mice from the lungs to distal organs. Thus, they could ultimately treat or protect patients infected or at risk of infection by this multidrug-resistant bacterium.

scholarly journals Population Structure of KPC-Producing Klebsiella pneumoniae Isolates from Midwestern U.S. Hospitals

2014 ◽  
Vol 58 (8) ◽  
pp. 4961-4965 ◽  
Author(s):  
Meredith S. Wright ◽  
Federico Perez ◽  
Lauren Brinkac ◽  
Michael R. Jacobs ◽  
Keith Kaye ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Capsular Polysaccharide ◽  
Sequence Type ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Content Type ◽  
Strain Diversity ◽  
Carbapenem Resistant ◽  
Genetic Context ◽  
Over Time

ABSTRACTGenome sequencing of carbapenem-resistantKlebsiella pneumoniaeisolates from regional U.S. hospitals was used to characterize strain diversity and theblaKPCgenetic context. A phylogeny based on core single-nucleotide variants (SNVs) supports a division of sequence type 258 (ST258) into two distinct groups. The primary differences between the groups are in the capsular polysaccharide locus (cps) and their plasmid contents. A strict association between clade and KPC variant was found. TheblaKPCgene was found on variants of two plasmid backbones. This study indicates that highly similarK. pneumoniaesubpopulations coexist within the same hospitals over time.

scholarly journals The Role of ZntA in Klebsiella pneumoniae Zinc Homeostasis

2022 ◽  
Author(s):  
Eve A. Maunders ◽  
Katherine Ganio ◽  
Andrew J. Hayes ◽  
Stephanie L. Neville ◽  
Mark R. Davies ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Urinary Tract ◽  
Klebsiella Pneumoniae ◽  
Zinc Homeostasis ◽  
Healthcare Associated Infections ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Tract Infections ◽  
Healthcare Associated

Klebsiella pneumoniae is a leading cause of healthcare-associated infections, including pneumonia, urinary tract infections, and sepsis. Treatment of K. pneumoniae infections is becoming increasingly challenging due to high levels of antibiotic resistance and the rising prevalence of carbapenem-resistant, extended-spectrum β-lactamases producing strains.

scholarly journals Role of efflux pumps inhibitor in decreasing antibiotic resistance of Klebsiella pneumoniae in a tertiary hospital in North India

2015 ◽  
Vol 9 (08) ◽  
pp. 815-820 ◽  
Author(s):  
Joel Filgona ◽  
Tuhina Banerjee ◽  
Shampa Anupurba
Keyword(s):  
Klebsiella Pneumoniae ◽  
Efflux Pumps ◽  
Tertiary Hospital ◽  
Multidrug Resistant ◽  
North India ◽  
Resistant Bacteria ◽  
Disk Diffusion Test ◽  
Carbapenem Resistant ◽  
Agar Dilution

Introduction: The contribution of efflux systems to drug resistance in Enterobacteriaceae is becoming increasingly appreciated. This study phenotypically analyzed the role of efflux mechanisms in resistance to ertapenem, doripenem, and tigecycline among clinical isolates of carbapenem-resistant Klebsiella pneumoniae (CRKP). Methodology: Multidrug-resistant and carbapenem non-susceptible K. pneumoniae isolates were determined by disk diffusion test. Further susceptibility of these isolates to carbapenems, ceftriaxone, cefoperazone, ceftazidime, tigecycline, and colistin was determined by agar dilution assay, and CRKP was identified. While modified Hodge test was used to confirm carbapenemase production, the contribution of efflux mechanisms was determined by a minimum inhibitory concentration (MIC) reduction assay, and typing was done by enterobacterial repetitive intergenic consensus (ERIC) polymerase chain reaction (PCR). Results: Of the 238 isolates of K. pneumoniae, 174 were multidrug resistant and 74 were CRKP. Forty of the CRKP were positive for carbapenemase production, while 43, 11, and 2 of the CRKP isolates had elevated MIC of ≥ 32 µg/mL for ertapenem, doripenem, and tigecycline, respectively. Twofold or higher MIC reduction to ertapenem, doripenem, and tigecycline was observed in 6, 28, and 27 isolates, respectively; however, non-susceptibility to ertapenem, doripenem and tigecycline was abolished in 2, 11, and 18 K. pneumoniae isolates, respectively. Nine clones of CRKP widely distributed within the hospital were obtained from ERIC PCR. Conclusions: Although colistin retained better activity against CRKP, efflux pumps contributed to increased MIC in ertapenem, doripenem, and tigecycline. Therefore, efflux systems are important aspects that should be explored in the fight against multidrug-resistant bacteria.  

scholarly journals In VitroActivity of MK-7655, a Novel β-Lactamase Inhibitor, in Combination with Imipenem against Carbapenem-Resistant Gram-Negative Bacteria

2012 ◽  
Vol 56 (7) ◽  
pp. 3753-3757 ◽  
Author(s):  
Elizabeth B. Hirsch ◽  
Kimberly R. Ledesma ◽  
Kai-Tai Chang ◽  
Michael S. Schwartz ◽  
Mary R. Motyl ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Optimal Dose ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Bacterial Burden ◽  
Bacterial Strains ◽  
Significant Treatment ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Lactamase Inhibitor

ABSTRACTCarbapenem-resistant bacteria represent a significant treatment challenge due to the lack of active antimicrobials available. MK-7655 is a novel β-lactamase inhibitor under clinical development. We investigated the combined killing activity of imipenem and MK-7655 against four imipenem-resistant bacterial strains, using a mathematical model previously evaluated in our laboratory. Time-kill studies (TKS) were conducted with imipenem and MK-7655 against a KPC-2-producingKlebsiella pneumoniaeisolate (KP6339) as well as 3Pseudomonas aeruginosaisolates (PA24226, PA24227, and PA24228) with OprD porin deletions and overexpression of AmpC. TKS were performed using 25 clinically achievable concentration combinations in a 5-by-5 array. Bacterial burden at 24 h was determined in triplicate by quantitative culture and mathematically modeled using a three-dimensional response surface. Mathematical model assessments were evaluated experimentally using clinically relevant dosing regimens of imipenem, with or without MK-7655, in a hollow-fiber infection model (HFIM). The combination of imipenem and MK-7655 was synergistic for all strains. Interaction indices were as follows: for KP6339, 0.50 (95% confidence interval [CI], 0.42 to 0.58); for PA24226, 0.60 (95% CI, 0.58 to 0.62); for PA24227, 0.70 (95% CI, 0.66 to 0.74); and for PA24228, 0.55 (95% CI, 0.49 to 0.61). In the HFIM, imipenem plus MK-7655 considerably reduced the bacterial burden at 24 h, while failure with imipenem alone was seen against all isolates. Sustained suppression of bacterial growth at 72 h was achieved with simulated doses of 500 mg imipenem plus 500 mg MK-7655 in 2 (KP6339 and PA24227) strains, and it was achieved in an additional strain (PA24228) when the imipenem dose was increased to 1,000 mg. Additional studies are being conducted to determine the optimal dose and combinations to be used in clinical investigations.

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