Activity of Simulated Human Dosage Regimens of Meropenem and Vaborbactam against Carbapenem-Resistant Enterobacteriaceae in an In Vitro Hollow-Fiber Model

ABSTRACT The objective of these studies was to evaluate the exposures of meropenem and vaborbactam that would produce antibacterial activity and prevent resistance development in carbapenem-resistant Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae strains when tested at an inoculum of 108 CFU/ml. Thirteen K. pneumoniae isolates, three Enterobacter cloacae isolates, and one Escherichia coli isolate were examined in an in vitro hollow-fiber model over 32 h. Simulated dosage regimens of 1 to 2 g of meropenem with 1 to 2 g of vaborbactam, with meropenem administered every 8 h by a 3-h infusion based on phase 1 or phase 3 patient pharmacokinetic data, were studied in the model. A dosage of 2 g of meropenem in combination with 2 g of vaborbactam was bactericidal against K. pneumoniae, E. cloacae, and E. coli strains, with meropenem-vaborbactam MICs of up to 8 mg/liter. When the vaborbactam exposure was adjusted to the levels observed in patients enrolled in phase 3 trials (24-h free AUC, ∼550 mg · h/liter, versus 320 mg · h/liter in the phase 1 studies), 2 g of meropenem with 2 g of vaborbactam was also bactericidal against strains with meropenem-vaborbactam MICs of 16 mg/liter. In addition, this level of vaborbactam also suppressed the development of resistance observed using phase 1 exposures. In this pharmacodynamic model, exposures similar to 2 g of meropenem in combination with 2 g of vaborbactam administered every 8 h by a 3-h infusion in phase 3 trials produced antibacterial activity and suppressed the development of resistance against carbapenem-resistant KPC-producing strains of Enterobacteriaceae.

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Pharmacokinetics/Pharmacodynamics of Vaborbactam, a Novel Beta-Lactamase Inhibitor, in Combination with Meropenem

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01659-18 ◽

2018 ◽

Vol 63 (1) ◽

Cited By ~ 16

Author(s):

David C. Griffith ◽

Mojgan Sabet ◽

Ziad Tarazi ◽

Olga Lomovskaya ◽

Michael N. Dudley

Keyword(s):

Hollow Fiber ◽

Infection Model ◽

Beta Lactamase ◽

Fiber Model ◽

Content Type ◽

Development Of Resistance ◽

Wide Range ◽

Tract Infections ◽

Lactamase Inhibitor

ABSTRACT Vaborbactam is a novel beta-lactamase inhibitor with activity against important beta-lactamases, in particular, serine carbapenemases, and is currently approved in combination with meropenem as Vabomere for the treatment of complicated urinary tract infections, including pyelonephritis. This combination is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing carbapenem-resistant Enterobacteriaceae. The objective of these studies was to evaluate vaborbactam pharmacokinetics (PK) and pharmacodynamics (PD) relationships for efficacy in a neutropenic mouse thigh infection model, as well as in an in vitro hollow-fiber infection model, in combination with a fixed exposure of meropenem using KPC-containing strains of Enterobacteriaceae. For both models, the meropenem dosage regimen was designed to simulate a 2-g dose administered every eight hours (q8h) by 3-h infusion. Vaborbactam dosage regimens were designed to produce a wide range of 24-h areas under the concentration-time curves (AUCs) in the thigh infection model. However, for the hollow-fiber model, the AUCs were limited to values of 192, 320, or 550 mg · h/liter. In both the animal and in vitro models, the PK-PD parameter that best described the antibacterial activity of vaborbactam, when administered in combination with meropenem at exposures equivalent to 2 g dosed q8h by 3-h infusion in humans, was the 24-h free vaborbactam AUC/meropenem-vaborbactam (with vaborbactam at 8 mg/liter) MIC ratio. The magnitude of this ratio for bacteriostasis was 9 to 12 and the magnitude to observe a 1-log kill was 18 to 38. In addition, a magnitude greater than 24 suppressed the development of resistance in the in vitro hollow-fiber model.

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In Vitro Activity of KBP-7072, a Novel Third-Generation Tetracycline, against 531 Recent Geographically Diverse and Molecularly Characterized Acinetobacter baumannii Species Complex Isolates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02375-19 ◽

2020 ◽

Vol 64 (5) ◽

Cited By ~ 3

Author(s):

Michael D. Huband ◽

Rodrigo E. Mendes ◽

Michael A. Pfaller ◽

Jill M. Lindley ◽

Gregory J. Strand ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Species Complex ◽

Phase 1 ◽

The United States ◽

Clinical Development ◽

Asia Pacific ◽

Third Generation ◽

Content Type ◽

Carbapenem Resistant

ABSTRACT KBP-7072 is a novel third-generation tetracycline (aminomethylcycline) antibacterial that overcomes common efflux and ribosomal protection resistance mechanisms that cause resistance in older-generation tetracyclines. KBP-7072 completed phase 1 clinical development studies for safety, tolerability, and pharmacokinetics (ClinicalTrials.gov identifier NCT02454361) and multiple ascending doses in healthy subjects (ClinicalTrials.gov identifier NCT02654626) in December 2015. Both oral and intravenous formulations of KBP-7072 are being developed. In this study, we evaluated the in vitro activities of KBP-7072 and comparator agents by CLSI document M07 (2018) broth microdilution against 531 recent geographically diverse and/or molecularly characterized Acinetobacter baumannii-A. calcoaceticus species complex (A. baumannii) isolates from the United States, Europe, Asia-Pacific (excluding China), and Latin America. A. baumannii isolates included carbapenem-resistant, colistin-resistant, tetracycline-resistant, and extended-spectrum-β-lactamase (ESBL)- and metallo-β-lactamase (MBL)-producing isolates. Overall, KBP-7072 (MIC50/90, 0.25/1 mg/liter) was comparable in activity to colistin (92.8%/92.8% susceptible [S] [CLSI/EUCAST]) against A. baumannii isolates, inhibiting 99.2% of isolates at ≤2 mg/liter and 97.6% of isolates at ≤1 mg/liter. KBP-7072 was equally active against A. baumannii isolates, including carbapenem-resistant, colistin-resistant, and tetracycline-resistant isolates, regardless of geographic location, and maintained activity against ESBL- and MBL-producing isolates. KBP-7072 outperformed comparator agents, including ceftazidime (40.3% S [CLSI]), gentamicin (48.2%/48.2% S [CLSI/EUCAST]), levofloxacin (39.5%/37.9% S [CLSI/EUCAST]), meropenem (42.0%/42.0% S [CLSI/EUCAST]), piperacillin-tazobactam (33.3% S [CLSI]), and all tetracycline-class comparator agents, which include doxycycline (67.3% S [CLSI]), minocycline (73.8% S [CLSI]), tetracycline (37.2% S [CLSI]), and tigecycline (79.5% inhibited by ≤2 mg/liter). The potent in vitro activity of KBP-7072 against recent geographically diverse, molecularly characterized, and drug-resistant A. baumannii isolates supports continued clinical development for the treatment of serious infections, including those caused by A. baumannii.

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Evaluation of Meropenem Regimens Suppressing Emergence of Resistance in Acinetobacter baumannii with Human Simulated Exposure in anIn VitroIntravenous-Infusion Hollow-Fiber Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03505-14 ◽

2014 ◽

Vol 58 (11) ◽

pp. 6773-6781 ◽

Cited By ~ 15

Author(s):

Xin Li ◽

Lin Wang ◽

Xian-Jia Zhang ◽

Yang Yang ◽

Wei-Tao Gong ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Hollow Fiber ◽

Dosage Interval ◽

Infection Model ◽

Bacterial Killing ◽

Content Type ◽

Dosage Regimens ◽

Drug Concentrations ◽

Emergence Of Resistance

ABSTRACTThe emergence of resistance to carbapenems inPseudomonas aeruginosacan be suppressed by optimizing the administration of meropenem. However, whether the same is true forAcinetobacter baumanniiis not fully understood. We assessed the bactericidal activity of meropenem and its potency to suppress the emergence of resistance inA. baumanniiwith human simulated exposure in anin vitrointravenous-infusion hollow-fiber infection model (HFIM). Two clinical strains of carbapenem-susceptible multidrug-resistantA. baumannii(CS-MDRAB), CSRA24 and CSRA91, were used, and their MICs and mutant prevention concentrations (MPCs) were determined. Six meropenem dosage regimens (0.5, 1.0, or 2.0 g given every 8 h [q8h] with a 0.5-h or 3-h infusion for seven consecutive days) were simulated and then evaluated in the HFIM. Both the total population and resistant subpopulations of the two strains were quantified. Drug concentrations were measured by high-performance liquid chromatography. All dosage regimens, except for the lowest dosage (0.5 g for both the 0.5-h and 3-h infusions), showed 3-log CFU/ml bacterial killing. Dosage regimens of 2.0 g with 0.5-h and 3-h infusions exhibited an obvious bactericidal effect and suppressed resistance. Selective amplification of subpopulations with reduced susceptibility to meropenem was suppressed with a percentage of the dosage interval in which meropenem concentrations exceeded the MPC (T>MPC) of ≥20% or with a ratio ofT>MPC to the percentage of the dosage interval in which drug concentrations are within the mutant selection window of ≥0.25. Ourin vitrodata support the use of a high dosage of meropenem (2.0 g q8h) for the treatment of severe infection caused by CS-MDRAB.

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Evaluation of Telavancin Alone and Combined with Ceftaroline or Rifampin against Methicillin-ResistantStaphylococcus aureusin anIn VitroBiofilm Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00567-18 ◽

2018 ◽

Vol 62 (8) ◽

Cited By ~ 3

Author(s):

Seyedehameneh Jahanbakhsh ◽

Nivedita B. Singh ◽

Juwon Yim ◽

Warren E. Rose ◽

Michael J. Rybak

Keyword(s):

Rapid Decrease ◽

Biofilm Reactor ◽

Content Type ◽

Development Of Resistance ◽

Dosage Regimens ◽

Enhanced Activity ◽

Dosing Regimens ◽

Mrsa Strains ◽

Reactor Models

ABSTRACTInfections caused by biofilm-producing methicillin-resistantStaphylococcus aureus(MRSA) bacteria are challenging due to increasing antibiotic resistance. Synergistic activities of lipopeptides and lipoglycopeptides with β-lactams have been demonstrated for MRSA, but little is known about biofilm-embedded organisms. Our objective was to evaluate two telavancin (TLV) dosage regimens (7.5 mg/kg of body weight and 10 mg/kg every 24 h [q24h]) alone and in combination with ceftaroline (CPT) (600 mg every 8 h [q8h]) or rifampin (RIF) (450 mg every 12 h [q12h]) against two biofilm-producing MRSA strains (494 and N315). Pharmacokinetic/pharmacodynamic CDC biofilm reactor models with polyurethane coupons were used to evaluate the efficacies of the antibiotic combinations over 72 h. Overall, there were no significant differences observed between the two TLV dosing regimens either alone or in combination with RIF or CPT against these strains. Both TLV dosing regimens and CPT alone demonstrated killing but did not reach bactericidal reduction at 72 h. However, both TLV regimens in combination with RIF demonstrated enhanced activity against both strains, with a rapid decrease in CFU/ml at 4 h that was bactericidal and maintained over the 72-h experiment (−Δ3.75 log10CFU/ml from baseline;P< 0.0001). Of interest, no enhanced activity was observed for TLV combined with CPT. No development of resistance was observed in any of the combination models. However, resistance to RIF developed as early as 24 h, with MIC values exceeding 32 mg/liter. Our results show that TLV plus RIF displayed therapeutic improvement against biofilm-producing MRSA. These results suggest that TLV at 7.5 and 10 mg/kg q24h are equally effective in eradicating biofilm-associated MRSA strainsin vitro.

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Assessment of Microbial Load of Un-pasteurized Fruit Juices and in vitro Antibacterial Potential of Honey Against Bacterial Isolates

The Open Microbiology Journal ◽

10.2174/1874285801509010026 ◽

2015 ◽

Vol 9 (1) ◽

pp. 26-32 ◽

Cited By ~ 4

Author(s):

Muhammad Naeem Iqbal ◽

Aftab Ahmad Anjum ◽

Muhammad Asad Ali ◽

Firasat Hussain ◽

Shahzad Ali ◽

...

Keyword(s):

Antibacterial Activity ◽

Viable Count ◽

Fruit Juices ◽

Microbial Load ◽

Resistant Bacteria ◽

Klebsiella Pneumonia ◽

Street Vendors ◽

Permissible Limits ◽

Development Of Resistance

The development of resistance in bacteria against commonly used antibiotics/drugs is of considerable medical significance. Aim of this study was to determine the microbial load of un-pasteurized packed fruit juices sold in Lahore city and to determine antibacterial activity of five different honey samples against isolated bacteria. Unpasteurized fruit juice samples (n=60) were collected from street vendors. All the samples were subjected to Total viable count (TVC), Staphylococcal count (SC) and Coliform count (CC). One hundred and ten strains of bacteria were isolated from various fruit juices and identified on the basis of cultural characters, morphology and biochemical characters. Mean TVCs, SCs and CCs of juices (6.80±1.91, 5.45±1.06 and 3.25±1.25 log10 CFU/ml respectively) were non-significant with standard permissible limits (p<0.05). Among all the fruit juices, 66.66% of samples had TVC more than 4 log10 CFU/ml, 51.66% of samples had SC more than 3 log10 CFU/ml and 46.66% of samples had CC more than 2 log10 CFU/ml. Among the bacillus isolates purified, were Bacillus alvei, Bacillus subtilis, Bacillus polymyxa, Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumonia, Escherichia coli and Enterobecter. All five different types of honey samples used in this study showed antibacterial activity against B. alvei, B. polymyxa, B. subtilis and S. aureus and no activity against P. aeruginosa, K. pneumonia, Enterobecter and E. coli. It is concluded that microbial load in unpasteurized fruit juices is significantly higher than standard permissible limits which insinuates its possible role in spoilage and food borne illnesses. Periodic monitoring of packed fruit juices should be carried out to make them safe for consumption. Honey can be used as an alternative for treatment of various infections, especially those caused by antibiotic resistant bacteria.

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Semimechanistic Pharmacokinetic/Pharmacodynamic Modeling of Fosfomycin and Sulbactam Combination against Carbapenem-Resistant Acinetobacter baumannii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02472-20 ◽

2021 ◽

Vol 65 (5) ◽

Author(s):

Sazlyna Mohd Sazlly Lim ◽

Aaron J. Heffernan ◽

Jason A. Roberts ◽

Fekade B. Sime

Keyword(s):

Acinetobacter Baumannii ◽

Treatment Options ◽

Pharmacodynamic Modeling ◽

Synergistic Activity ◽

Bacterial Burden ◽

Target Attainment ◽

Content Type ◽

Carbapenem Resistant ◽

Time Kill

ABSTRACT Due to limited treatment options for carbapenem-resistant Acinetobacter baumannii (CR-AB) infections, antibiotic combinations are now considered potential treatments for CR-AB. This study aimed to explore the utility of fosfomycin-sulbactam combination (FOS/SUL) therapy against CR-AB isolates. Synergism of FOS/SUL against 50 clinical CR-AB isolates was screened using the checkerboard method. Thereafter, time-kill studies against two CR-AB isolates were performed. The time-kill data were described using a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Monte Carlo simulations were then performed to estimate the probability of stasis, 1-log kill, and 2-log kill after 24 h of combination therapy. The FOS/SUL combination demonstrated a synergistic effect against 74% of isolates. No antagonism was observed. The MIC50 and MIC90 of FOS/SUL were decreased 4- to 8-fold, compared to the monotherapy MIC50 and MIC90. In the time-kill studies, the combination displayed bactericidal activity against both isolates and synergistic activity against one isolate at the highest clinically achievable concentrations. Our PK/PD model was able to describe the interaction between fosfomycin and sulbactam in vitro. Bacterial kill was mainly driven by sulbactam, with fosfomycin augmentation. FOS/SUL regimens that included sulbactam at 4 g every 8 h demonstrated a probability of target attainment of 1-log10 kill at 24 h of ∼69 to 76%, compared to ∼15 to 30% with monotherapy regimens at the highest doses. The reduction in the MIC values and the achievement of a moderate PTA of a 2-log10 reduction in bacterial burden demonstrated that FOS/SUL may potentially be effective against some CR-AB infections.

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Combating Carbapenem-ResistantAcinetobacter baumanniiby an Optimized Imipenem-plus-Tobramycin Dosage Regimen: Prospective Validation via Hollow-Fiber Infection and Mathematical Modeling

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02053-17 ◽

2018 ◽

Vol 62 (4) ◽

Cited By ~ 7

Author(s):

Cornelia B. Landersdorfer ◽

Rajbharan Yadav ◽

Kate E. Rogers ◽

Tae Hwan Kim ◽

Beom Soo Shin ◽

...

Keyword(s):

Mathematical Modeling ◽

Acinetobacter Baumannii ◽

Hollow Fiber ◽

Dosage Regimen ◽

Infection Model ◽

Bacterial Killing ◽

Content Type ◽

Carbapenem Resistant

ABSTRACTWe aimed to prospectively validate an optimized combination dosage regimen against a clinical carbapenem-resistantAcinetobacter baumannii(CRAB) isolate (imipenem MIC, 32 mg/liter; tobramycin MIC, 2 mg/liter). Imipenem at constant concentrations (7.6, 13.4, and 23.3 mg/liter, reflecting a range of clearances) was simulated in a 7-day hollow-fiber infection model (inoculum, ∼107.2CFU/ml) with and without tobramycin (7 mg/kg q24h, 0.5-h infusions). While monotherapies achieved no killing or failed by 24 h, this rationally optimized combination achieved >5 log10bacterial killing and suppressed resistance.

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694. In vitro Antibacterial Activity of Sulbactam–Durlobactam (ETX2514SUL) Against 121 Recent Acinetobacter baumannii Isolated from Patients in India

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.762 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S314-S314

Author(s):

Alita Miller ◽

Sarah McLeod ◽

Tarun Mathur ◽

Ian Morrissey

Keyword(s):

Antibacterial Activity ◽

Acinetobacter Baumannii ◽

Package Insert ◽

Multidrug Resistant ◽

Antibiotic Resistant ◽

Carbapenem Resistant ◽

In Vitro Antibacterial Activity ◽

Spectrum Activity ◽

Broad Spectrum Activity

Abstract Background The incidence of infections caused by multidrug-resistant Acinetobacter baumannii is increasing at an alarming rate in Southeast Asia and other parts of the world. Sulbactam (SUL) has intrinsic antibacterial activity against A. baumannii; however, the prevalence of β-lactamases in this species has limited its therapeutic use. Durlobactam (ETX2514, DUR) is a novel β-lactamase inhibitor with broad-spectrum activity against Ambler class A, C and D β-lactamases. DUR restores SUL in vitro activity against multidrug-resistant A. baumannii. Against >3,600 globally diverse, clinical isolates from 2012–2017, addition of 4 mg/L DUR reduced the SUL MIC90 from >32 to 2 mg/L. SUL-DUR is currently in Phase 3 clinical development for the treatment of infections caused by carbapenem-resistant Acinetobacter spp.The goal of this study was to determine the activity of SUL-DUR and comparator antibiotics (amikacin (AMK), ampicillin-sulbactam (AMP-SUL), cefoperazone-sulbactam (CFP-SUL) and meropenem (MEM)) against A. baumannii isolated from hospitalized patients in India. Methods A total of 121 clinical A. baumannii isolates from multiple hospital settings and infection sources were collected between 2016–2019 from six geographically diverse hospitals in India. Species identification was performed by MALDI-TOF. Susceptibility of these isolates to SUL-DUR (10µg/10µg) and comparator antibiotics was determined by disk diffusion using CLSI methodology and interpretive criteria, except for CFP-SUL, for which resistance was defined using breakpoints from the CFP-SUL package insert. Results As shown in Table 1, resistance of this collection of isolates to marketed agents was extremely high. In contrast, based on preliminary breakpoint criteria, only 11.5% of isolates were resistant to SUL-DUR. Conclusion The in vitro antibacterial activity of SUL-DUR was significantly more potent than comparator agents against multidrug-resistant A. baumannii isolates collected from diverse sites in India. These data support the continued development of SUL-DUR for the treatment of antibiotic-resistant infections caused by A. baumannii. Disclosures All authors: No reported disclosures.

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In Vitro Activity of Ceftazidime-Avibactam against Isolates from Respiratory and Blood Specimens from Patients with Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia, in a Phase 3 Clinical Trial

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02356-19 ◽

2020 ◽

Vol 64 (5) ◽

Cited By ~ 2

Author(s):

Gregory G. Stone ◽

Patricia A. Bradford ◽

Margaret Tawadrous ◽

Dianna Taylor ◽

Mary Jane Cadatal ◽

...

Keyword(s):

Nosocomial Pneumonia ◽

Bacterial Pathogen ◽

Multidrug Resistant ◽

Ventilator Associated Pneumonia ◽

Phase 3 ◽

Gram Positive ◽

Gram Negative ◽

Content Type ◽

Highly Active

ABSTRACT Nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP), is increasingly associated with multidrug-resistant Gram-negative pathogens. This study describes the in vitro activity of ceftazidime-avibactam, ceftazidime, and relevant comparator agents against bacterial pathogens isolated from patients with NP, including VAP, enrolled in a ceftazidime-avibactam phase 3 trial. Gram-positive pathogens were included if coisolated with a Gram-negative pathogen. In vitro susceptibility was determined at a central laboratory using Clinical and Laboratory Standards Institute broth microdilution methods. Of 817 randomized patients, 457 (55.9%) had ≥1 Gram-negative bacterial pathogen(s) isolated at baseline, and 149 (18.2%) had ≥1 Gram-positive pathogen(s) coisolated. The most common isolated pathogens were Klebsiella pneumoniae (18.8%), Pseudomonas aeruginosa (15.8%), and Staphylococcus aureus (11.5%). Ceftazidime-avibactam was highly active in vitro against 370 isolates of Enterobacteriaceae, with 98.6% susceptible (MIC90, 0.5 μg/ml) compared with 73.2% susceptible for ceftazidime (MIC90, >64 μg/ml). The percent susceptibility values for ceftazidime-avibactam and ceftazidime against 129 P. aeruginosa isolates were 88.4% and 72.9% (MIC90 values of 16 μg/ml and 64 μg/ml), respectively. Among ceftazidime-nonsusceptible Gram-negative isolates, ceftazidime-avibactam percent susceptibility values were 94.9% for 99 Enterobacteriaceae and 60.0% for 35 P. aeruginosa. MIC90 values for linezolid and vancomycin (permitted per protocol for Gram-positive coverage) were within their respective MIC susceptibility breakpoints against the Gram-positive pathogens isolated. This analysis demonstrates that ceftazidime-avibactam was active in vitro against the majority of Enterobacteriaceae and P. aeruginosa isolates from patients with NP, including VAP, in a phase 3 trial. (This study has been registered at ClinicalTrials.gov under identifier NCT01808092.)

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GC-072, a Novel Therapeutic Candidate for Oral Treatment of Melioidosis and Infections Caused by Select Biothreat Pathogens

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00834-19 ◽

2019 ◽

Vol 63 (12) ◽

Author(s):

Jeffry D. Shearer ◽

Michelle L. Saylor ◽

Christine M. Butler ◽

Anthony M. Treston ◽

Henry S. Heine ◽

...

Keyword(s):

Acute Phase ◽

Oral Treatment ◽

Lethal Dose ◽

Current Therapy ◽

Content Type ◽

Development Of Resistance ◽

Strong Candidate ◽

Oral Therapeutic ◽

Drug Resistant Strains

ABSTRACT Burkholderia pseudomallei, the etiological agent of melioidosis, is a Gram-negative bacterium with additional concern as a biothreat pathogen. The mortality rate from B. pseudomallei varies depending on the type of infection and extent of available health care; in the case of septicemia, left untreated, it can range from 50% to 90%. Current therapy for melioidosis is biphasic, consisting of parenteral acute-phase treatment for 2 weeks or longer, followed by oral eradication-phase treatment lasting several months. An effective oral therapeutic for outpatient treatment of acute-phase melioidosis is needed. GC-072 is a potent, 4-oxoquinolizine antibiotic with selective inhibitory activity against bacterial topoisomerases. GC-072 has demonstrated in vitro potency against susceptible and drug-resistant strains of B. pseudomallei and is also active against Burkholderia mallei, Bacillus anthracis, Yersinia pestis, and Francisella tularensis. GC-072 is bactericidal both extra- and intracellularly, with rapid killing noted within a few hours and reduced development of resistance compared to that for ceftazidime. GC-072, delivered intragastrically to mimic oral administration, promoted dose-dependent survival in mice using lethal inhalational models of B. pseudomallei infection following exposure to a 24- or 339-LD50 (50% lethal dose) challenge with B. pseudomallei strain 1026b. Overall, GC-072 appears to be a strong candidate for first-line oral treatment of melioidosis.

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