Micromyx LLC

Kalamazoo, MI, United States

Micromyx LLC

Kalamazoo, MI, United States

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Queenan A.M.,Janssen Research and Development | Pillar C.M.,Eurofins | Pillar C.M.,Micromyx LLC | Deane J.,Eurofins | And 6 more authors.
Diagnostic Microbiology and Infectious Disease | Year: 2012

Multidrug resistance among Acinetobacter spp. leaves few effective antibiotic options for treatment. To monitor antibiotic resistance in Acinetobacter spp., the US CAPITAL 2010 Surveillance data were evaluated by patient demographics, specimen source, and hospital ward. Isolates (N= 514) were collected from 65 sites across the USA and Puerto Rico. Isolates were centrally tested for susceptibility to carbapenems and key antimicrobials by broth microdilution. Colistin was the most effective agent tested, with 95% susceptibility. The overall susceptibility of Acinetobacter spp. was low (39% for piperacillin/tazobactam, 41% for levofloxacin, 45% for ceftazidime, 47-51% for the carbapenems, and 58% for tobramycin). Multidrug resistance (MDR), defined as resistance to ≥ 3 antimicrobial agent groups, was detected in 54% of the isolates. MDR isolates were most common among elderly patients (65%), lower respiratory tract isolates (62%), and inpatient/intensive care unit isolates (54-58%). These data update trends in the distribution and prevalence of the MDR phenotype in Acinetobacter spp. © 2012 Elsevier Inc.


Butler M.M.,Microbiotix, Inc | Shinabarger D.L.,Micromyx LLC | Citron D.M.,Alden Research Laboratory | Kelly C.P.,Beth Israel Deaconess Medical Center | And 6 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2012

Clostridium difficile infection (CDI) causes moderate to severe disease, resulting in diarrhea and pseudomembranous colitis. CDI is difficult to treat due to production of inflammation-inducing toxins, resistance development, and high probability of recurrence. Only two antibiotics are approved for the treatment of CDI, and the pipeline for therapeutic agents contains few new drugs. MBX-500 is a hybrid antibacterial, composed of an anilinouracil DNA polymerase inhibitor linked to a fluoroquinolone DNA gyrase/topoisomerase inhibitor, with potential as a new therapeutic for CDI treatment. Since MBX-500 inhibits three bacterial targets, it has been previously shown to be minimally susceptible to resistance development. In the present study, the in vitro and in vivo efficacies of MBX-500 were explored against the Gram-positive anaerobe, C. difficile. MBX-500 displayed potency across nearly 50 isolates, including those of the fluoroquinolone-resistant, toxin-overproducing NAP1/027 ribotype, performing as well as comparator antibiotics vancomycin and metronidazole. Furthermore, MBX-500 was a narrow-spectrum agent, displaying poor activity against many other gut anaerobes. MBX-500 was active in acute and recurrent infections in a toxigenic hamster model of CDI, exhibiting full protection against acute infections and prevention of recurrence in 70% of the animals. Hamsters treated with MBX-500 displayed significantly greater weight gain than did those treated with vancomycin. Finally, MBX-500 was efficacious in a murine model of CDI, again demonstrating a fully protective effect and permitting nearnormal weight gain in the treated animals. These selective anti-CDI features support the further development of MBX 500 for the treatment of CDI. Copyright © 2012, American Society for Microbiology. All Rights Reserved.


PubMed | University of South Australia, Micromyx LLC., Eurofins and Flinders University
Type: | Journal: The Journal of antibiotics | Year: 2016

Antibiotic-resistant bacteria is a major threat to human health and is predicted to become the leading cause of death from disease by 2050. Despite the recent resurgence of research and development in the area, few antibiotics have reached the market, with most of the recently approved antibiotics corresponding to new uses for old antibiotics, or structurally similar derivatives thereof. We have recently reported an in silico approach that led to the design of an entirely new class of antibiotics for the bacteria-specific mechanosensitive ion channel of large conductance: MscL. Here, we present the preclinical development of one such antibiotic, Ramizol, a first generation antibiotic belonging to that class. We present the lack of interaction between Ramizol and other mammalian channels adding credibility to its MscL selectivity. We determine the pharmacokinetic profile in a rat model and show <0.1% of Ramizol is absorbed systemically. We show this non-systemic nature of the antibiotic translates to over 70% survival of hamsters in a Clostridium difficile colitis model. Lastly, initial in vitro data indicate that resistance to Ramizol occurs at a low frequency. In conclusion, we establish the potential of Ramizol as an effective new treatment for C. difficile associated disease.The Journal of Antibiotics advance online publication, 18 May 2016; doi:10.1038/ja.2016.45.


PubMed | ViviSource Laboratories, Lawrence Livermore National Laboratory, Trius Therapeutics, Advanced Light Source and Micromyx LLC
Type: Journal Article | Journal: PloS one | Year: 2014

Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. However, growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highly conserved ATP-binding subunits of DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD), we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models.


Asbell P.A.,Mount Sinai School of Medicine | Sanfilippo C.M.,Bausch & Lomb | Pillar C.M.,Eurofins | Pillar C.M.,Micromyx LLC | And 5 more authors.
JAMA Ophthalmology | Year: 2015

Importance The Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) study is the only ongoing nationwide antibiotic resistance surveillance program specific to ocular pathogens. OBJECTIVE To report resistance rates and trends among common ocular isolates collected during the first 5 years of the ARMOR study. DESIGN, SETTING, AND PARTICIPANTS This antibiotic resistance surveillance studywas performed at an independent central laboratory. Clinical centers across the United States were invited to submit ocular isolates of Staphylococcus aureus, coagulase-negative staphylococci (CoNS), Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa. Isolates were collected from January 1, 2009, through December 31, 2013, and analyzed from January 16 toMay 15, 2015. MAIN OUTCOMES AND MEASURES Minimum inhibitory concentrations for various antibiotic classes were determined by broth microdilution according to the guidelines of the Clinical and Laboratory Standards Institute. Minimum inhibitory concentrations were interpreted as susceptible, intermediate, or resistant based on established break points. RESULTS A total of 3237 ocular isolates (1169 S aureus, 992 CoNS, 330 S pneumoniae, 357 H influenzae, and 389 P aeruginosa) were collected from 72 centers. Methicillin resistance was found among 493 S aureus isolates (42.2%; 95%CI, 39.3%-45.1%) and 493 CoNS isolates (49.7%; 95%CI, 46.5%-52.9%), and methicillin-resistant (MR) isolates had a high probability of concurrent resistance to fluoroquinolones, aminoglycosides, or macrolides (P <.001). Multidrug resistance to at least 3 additional antibiotic classes was found in 428MR S aureus isolates (86.8%) and 381 MRCoNS isolates (77.3%). All staphylococcal isolates were susceptible to vancomycin. Resistance among S pneumoniae isolates was highest for azithromycin (113 isolates [34.2%]) whereas resistance among P aeruginosa and H influenzae was low against the antibiotics tested. Staphylococcal isolates from elderly patients were more likely to be MR, as were S aureus isolates obtained from the southern United States (P <.001). Methicillin resistance among staphylococci did not increase during the 5-year study period (P ≤.22), and small decreases in resistance to ciprofloxacin among CoNS and MRCoNS and to tobramycin among CoNS (P ≤.03) were found. CONCLUSIONS AND RELEVANCE Methicillin resistancewas prevalent among staphylococcal isolates from ocular infections, with many strains demonstrating multidrug resistance. These findings are consistent with resistance trends reported for nonocular staphylococcal isolates. Overall ocular resistance did not increase during the 5-year study period. Continued surveillance of ocular isolates provides critical information to guide selection of topical antibacterials used for empirical management of ocular infections. © 2015 American Medical Association. All rights reserved.


Shinabarger D.L.,Micromyx LLC | Zurenko G.E.,Micromyx LLC | Hesje C.K.,Bausch & Lomb | Sanfilippo C.M.,Bausch & Lomb | And 2 more authors.
Journal of Chemotherapy | Year: 2011

This study examined the susceptibility of a variety of wild-type strains and efflux pump mutants to besifloxacin and the comparator agents sparfloxacin, ciprofloxacin, norfloxacin, moxifloxacin, tetracycline, and ethidium bromide. Organisms tested included Staphylococcus aureus (mepA or norA), Streptococcus pneumoniae (pmrA, patB), Escherichia coli (acrAB::Tn903, tolCr.TnlO), Haemophilus influenzae (acrAB) and Pseudomonas aeruginosa (mepAB-oprM, oprM::ΩHg r rpsL). The minimal inhibitory concentrations (MIC) of besifloxacin and comparators were also measured in the presence of the ef flux pump inhibitors reserpine, carbonyl cyanide m-chlorophenyl-hydrazone, or sodium orthovanadate. Overall, very few meaningful changes (>2-fold) in besifloxacin MIC values resulted from the presence of efflux pump mutations or efflux pump inhibitors. In summary, the novel fluoroquinolone besifloxacin is no exception to the observation that newer fluoroquinolones are generally less affected by efflux pump-mediated resistance than older fluoroquinolones. © E.S.I.F.T. srl - Firenze.


Pillar C.M.,Micromyx LLC | Stoneburner A.,Micromyx LLC | Shinabarger D.L.,Micromyx LLC | Abbeloos E.,Boehringer Ingelheim | Goby L.,Boehringer Ingelheim
Journal of Dairy Science | Year: 2014

Dry cow therapy is an important part of mastitis control. This therapy typically consists of an antibiotic or antibiotics administered at a single dose by intramammary infusion at dry off to treat or prevent infection by prevalent mastitis pathogens. A combination dry cow therapy consisting of the active components penicillin and framycetin is currently used in several countries. Despite its use, standardized methods for the susceptibility testing of this combination against mastitis pathogens have not been established. In this study, which used Clinical and Laboratory Standards Institute methodology, preliminary interpretive criteria for the broth microdilution minimum inhibitory concentration (MIC) testing of mastitis pathogens to penicillin combined with framycetin (2:1 wt/wt) were established based on the amount of drug achieved and maintained postadministration in the udder. Based on resulting MIC distributions of recent veterinary field isolates and a subset of isolates preselected for resistance to β-lactams or aminoglycosides and concentrations achieved postadministration, criteria for broth microdilution testing of the combination (susceptible, intermediate, resistant in micrograms per milliliter) were set as follows: Escherichia coli ≤8/4, 16/8, ≥32/16; Staphylococcus spp. ≤2/1, 4/2-8/4, >16/8; Streptococcus uberis and Streptococcus dysgalactiae <0.25/0.12, 0.5/0.25-2/1, >4/2. A disk diffusion test using disks containing 100. μg of framycetin and 10. IU of penicillin was also developed, and preliminary interpretive criteria (susceptible, intermediate, resistant in millimeters) were set based on correlation to broth MIC values and the minimization of interpretive errors between isolates tested concurrently by broth microdilution and disk diffusion as follows: E. coli ≥18, 16-17, ≤15; Staphylococcus spp. ≥21, 18-20, ≤17; Strep. uberis and Strep. dysgalactiae ≥21, 19-20, ≤18. In addition, ranges for the quality control of the testing of this combination by both broth microdilution and disk diffusion are provided. Based on these criteria and recent veterinary mastitis isolates, 96.0/96.8% of E. coli, 93.7/89.1% of Staph. aureus, 94.6/96.4% coagulase-negative staphylococci, 94.5/97.0% of Strep. uberis, and 96.7/100.0% Strep. dysgalactiae were susceptible to the combination by broth microdilution or disk diffusion, respectively. The availability of these methods will allow for the susceptibility testing of clinical isolates in the field and will also provide a way to monitor for resistance development as this combination is used going forward. © 2014 American Dairy Science Association.


PubMed | Micromyx LLC and The Medicines Company
Type: Journal Article | Journal: Diagnostic microbiology and infectious disease | Year: 2016

Methicillin-resistant Staphylococcus aureus (MRSA) infections constitute a threat to the public health due to their prevalence and associated mortality and morbidity. Several agents have been recently approved to treat MRSA skin infections including lipoglycopeptides (dalbavancin, oritavancin, and telavancin), ceftaroline, and tedizolid. This study compared the MIC, minimum bactericidal concentration (MBC), and time-kill of these agents alongside daptomycin, linezolid, and vancomycin against MRSA (n=15); meropenem, cefazolin, and nafcillin were also included against methicillin-susceptible S. aureus (MSSA [n=12]). MIC and MBC testing was conducted in accordance with Clinical and Laboratory Standards Institute guidelines, and time-kills were evaluated at multiples of the MIC and the free-drug maximum plasma concentration (fC


Dry cow therapy is an important part of mastitis control. This therapy typically consists of an antibiotic or antibiotics administered at a single dose by intramammary infusion at dry off to treat or prevent infection by prevalent mastitis pathogens. A combination dry cow therapy consisting of the active components penicillin and framycetin is currently used in several countries. Despite its use, standardized methods for the susceptibility testing of this combination against mastitis pathogens have not been established. In this study, which used Clinical and Laboratory Standards Institute methodology, preliminary interpretive criteria for the broth microdilution minimum inhibitory concentration (MIC) testing of mastitis pathogens to penicillin combined with framycetin (2:1 wt/wt) were established based on the amount of drug achieved and maintained postadministration in the udder. Based on resulting MIC distributions of recent veterinary field isolates and a subset of isolates preselected for resistance to -lactams or aminoglycosides and concentrations achieved postadministration, criteria for broth microdilution testing of the combination (susceptible, intermediate, resistant in micrograms per milliliter) were set as follows: Escherichia coli 8/4, 16/8, 32/16; Staphylococcus spp. 2/1, 4/2-8/4, >16/8; Streptococcus uberis and Streptococcus dysgalactiae <0.25/0.12, 0.5/0.25-2/1, >4/2. A disk diffusion test using disks containing 100 g of framycetin and 10 IU of penicillin was also developed, and preliminary interpretive criteria (susceptible, intermediate, resistant in millimeters) were set based on correlation to broth MIC values and the minimization of interpretive errors between isolates tested concurrently by broth microdilution and disk diffusion as follows: E. coli 18, 16-17, 15; Staphylococcus spp. 21, 18-20, 17; Strep. uberis and Strep. dysgalactiae 21, 19-20, 18. In addition, ranges for the quality control of the testing of this combination by both broth microdilution and disk diffusion are provided. Based on these criteria and recent veterinary mastitis isolates, 96.0/96.8% of E. coli, 93.7/89.1% of Staph. aureus, 94.6/96.4% coagulase-negative staphylococci, 94.5/97.0% of Strep. uberis, and 96.7/100.0% Strep. dysgalactiae were susceptible to the combination by broth microdilution or disk diffusion, respectively. The availability of these methods will allow for the susceptibility testing of clinical isolates in the field and will also provide a way to monitor for resistance development as this combination is used going forward.


PubMed | Micromyx LLC
Type: Journal Article | Journal: Journal of chemotherapy (Florence, Italy) | Year: 2011

This study examined the susceptibility of a variety of wild-type strains and efflux pump mutants to besifloxacin and the comparator agents sparfloxacin, ciprofloxacin, norfloxacin, moxifloxacin, tetracycline, and ethidium bromide. Organisms tested included Staphylococcus aureus (mepA or norA), Streptococcus pneumoniae (pmrA, patB), Escherichia coli (acrAB::Tn903, tolC::Tn10), Haemophilus influenzae (acrAB) and Pseudomonas aeruginosa (mepAB-oprM, oprM::Hg(r) rpsL). The minimal inhibitory concentrations (MIC) of besifloxacin and comparators were also measured in the presence of the efflux pump inhibitors reserpine, carbonyl cyanide mchlorophenyl- hydrazone, or sodium orthovanadate. Overall, very few meaningful changes (>2-fold) in besifloxacin MIC values resulted from the presence of efflux pump mutations or efflux pump inhibitors. In summary, the novel fluoroquinolone besifloxacin is no exception to the observation that newer fluoroquinolones are generally less affected by efflux pump-mediated resistance than older fluoroquinolones.

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