Paul R Rhomberg

JMI Laboratories, North Liberty, Iowa, United States

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Publications (80)251.69 Total impact

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    ABSTRACT: Pexiganan, a 22-amino acid synthetic cationic peptide, is currently in Phase 3 clinical trials as a topical antimicrobial for the treatment of mild infections associated with diabetic foot ulcers. Bacterial isolates from the 2013 SENTRY Antimicrobial Surveillance Program designated as pathogens from diabetic foot infections (DFI) and Gram-negative and -positive pathogens from various infection types that harbored selected resistance mechanisms/phenotypes were tested against pexiganan in reference cation-adjusted Mueller-Hinton broth. The MIC50/90 against all organisms tested from DFI was 16/32 μg/mL. Echerichia coli, Klebsiella pneumoniae, Citrobacter koseri, Enterobacter cloacae, Acinetobacter spp. and Pseudomonas aeruginosa MIC values ranged from 8-16 μg/mL. Pexiganan MIC values among Staphylococcus aureus (MRSA and MSSA), β-hemolytic streptococci and E. faecium ranged from 8-32 μg/mL. Pexiganan activity was not adversely affected for Enterobacteriaceae or P. aeruginosa that produced β-lactamases or resistance mechanisms to other commonly used antimicrobials. Decreased susceptibility to vancomycin did not affect pexiganan activity against S. aureus nor against E. faecium. E. faecalis appears to be intrinsically less susceptible to pexiganan (MIC, 32-256 μg/mL). The "all organism" MIC90 of 32 μg/mL for pexiganan in this study was >250-fold below the pexiganan concentration in the cream/delivery vehicle being developed for topical use. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Antimicrobial Agents and Chemotherapy 01/2015; · 4.57 Impact Factor
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    ABSTRACT: MGCD290, a Hos2 fungal histone deacetylase inhibitor showed modest activity when tested alone (MIC range, 0.12-4 μg/ml; MIC50/90, 0.5/4 μg/ml) against C. glabrata (n=15; 14 fks mutants; 5 also fluconazole-resistant), C. albicans (8 fks mutants; 2 also fluconazole-resistant), C. tropicalis (4 fks mutants), and C. krusei (3 fks mutants). However, MGCD290 showed synergy or partial synergy for 33.3, 30.1, 36.7 and 80.0% of the isolates when tested with anidulafungin, caspofungin, micafungin and fluconazole, respectively. Favorable interactions were achieved with low concentrations of MGCD290 (0.015 to 0.25 μg/ml) and categorical shifts were observed in 2 of 8 (25.0%) isolates of C. albicans and 2 of 3 (66.7%) isolates of C. krusei. In addition, 4 of the 5 (80.0%) fluconazole- resistant isolates of C. glabrata. MGCD290 exerts a distinctly favorable influence on the MICs of fluconazole and the echinocandins, resulting in conversion from resistance to susceptibility regardless of fks mutations.
    Diagnostic Microbiology and Infectious Disease 11/2014; · 2.57 Impact Factor
  • Ronald N Jones, Nicole M Holliday, Paul R Rhomberg
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    ABSTRACT: Tedizolid, a novel oxazolidinone antibacterial with potent activity against a wide range of Gram-positive pathogens, was recently approved by regulatory authorities for the treatment of acute bacterial skin and skin structure infections. A commercial broth microdilution device (Sensititre®, Thermo Fisher Scientific) was validated using 285 selected Gram-positive isolates, and was documented to have 100.0% essential and categorical agreement compared to reference MIC results, with excellent MIC endpoint reproducibility. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
    Journal of Clinical Microbiology 11/2014; · 4.23 Impact Factor
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    ABSTRACT: Background: The importance of antifungal surveillance was highlighted by the increasing resistance among certain species and breakthrough infections. We evaluated 1,846 fungal clinical isolates against 9 antifungals using CLSI reference broth microdilution methods (BMD). Additionally, 1,206 isolates were tested using polysorbate-80 (P-80). Methods: 1,846 isolates collected in 2013 (31 countries) were tested by CLSI BMD and interpretive criteria. Echinocandins (EC), amphotericin B (AMB) and fluconazole (FLC) were also tested using 0.002% P-80 supplemented broth. Isolates were identified using MALDI-TOF MS and/or DNA sequencing. Results: EC, AMB and FLC were active against common Candida spp. (Table). EC-resistance ranged from 0.0 to 2.8% (anidulafungin for C. glabrata [CGLA]). 11.9 and 11.6% of the CGLA and C. tropicalis were resistant to FLC, respectively. Two A. fumigatus displayed elevated MIC values for itraconazole (≥4 µg/mL). All C. neoformanshad MIC < epidemiological cutoff values for azoles. P-80 lowered the MIC values for EC for all species, but not for FLC. AMB MIC values were lower and ranges broader (0.03-0.5 µg/mL) when compared with reference BMD (0.5-2 µg/mL). Conclusion: EC and azoles were potent against yeasts and moulds. P-80 use broadened MIC ranges for AMB; however, differences in the growth patterns in RPMI + P-80, requirement for new QC ranges and a possible effect in cell growth reported previously in bacteria might be an impediment to the use of P-80 for antifungal BMD testing. Organism (no. tested [no. tested with P-80]) MIC/MEC50/90 for CLSI BMD (with P-80) Anidulafungin Caspofungin Amphotericin B Fluconazole C. albicans (712 [475]) 0.015/0.06 (≤0.008/≤0.008) 0.03/0.03 (≤0.008/≤0.008) 1/1 (0.06/0.12) 0.12/0.25 (0.25/0.25) C. glabrata (252 [156]) 0.06/0.12 (0.015/0.015) 0.03/0.06 (≤0.008/≤0.008) 1/1 (0.12/0.12) 8/64 (4/32) C. parapsilosis (215 [149]) 2/2 (1/2) 0.25/0.5 (0.06/0.06) 1/1 (0.12/0.25) 1/2 (1/4) C. tropicalis (155 [90]) 0.015/0.03 (≤0.008/≤0.008) 0.03/0.03 (≤0.008/≤0.008) 1/1 (0.06/0.12) 0.5/32 (0.5/1) C. krusei (49 [29]) 0.06/0.06 (0.03/0.03) 0.12/0.25 (0.03/0.03) 1/2 (0.25/0.25) 32/64 (32/64) A. fumigatus (142 [94]) ≤0.008/0.03 (≤0.008/≤0.008) 0.03/0.03 (≤0.008/≤0.008) 2/2 (0.25/0.5) -/-
    IDWeek 2014 Meeting of the Infectious Diseases Society of America; 10/2014
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    ABSTRACT: Telavancin biological activity, determined by serum titers against a reference strain of Staphylococcus aureus, was maintained in the serum of subjects with severe renal impairment or end-stage renal disease (ESRD) suggesting that there is no apparent effect of renal function on in vitro activity of telavancin.
    Diagnostic Microbiology and Infectious Disease 09/2014; · 2.57 Impact Factor
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    ABSTRACT: The reference broth microdilution (BMD) antimicrobial susceptibility testing method for telavancin was revised to include dimethyl sulfoxide as solvent and diluent for frozen-form panel preparation, following the CLSI recommendations for water-insoluble agents. Polysorbate-80 (P-80) was also added to the test media to minimize proven drug losses associated with binding to plastic surfaces. 462 Gram-positive isolates, including a challenge set of organisms with reduced susceptibility to comparator agents, were selected and tested using the revised method for telavancin, and the MIC results were compared with those tested by the previously established method and several Sensititre™ dry-form BMD panel formulations. The revised method provided MIC results two- to eight-fold lower than the previous method when tested against staphylococci and enterococci, resulting in MIC50 values of 0.03 - 0.06 μg/ml for staphylococci, and 0.03 and 0.12 μg/ml for E. faecalis and E. faecium. Less significant MIC decreases (one to two log2 dilution steps) were observed when testing streptococci in broth supplemented with blood, which showed similar MIC50 values. However, S. pneumoniae had MIC50 results of 0.008 and 0.03 μg/ml when tested by the revised and previous methods, respectively. Highest essential agreement rates (≥94.0%) were noted for one candidate dry-form panel formulation compared to the revised test. The revised BMD method provides lower MIC results for telavancin, especially when tested against staphylococci and enterococci. This is secondary to the use of DMSO for panel production and presence of P-80, which ensure the proper telavancin testing concentration and result in a more accurate MIC determination. Moreover, earlier studies where the previous method was applied underestimated the in vitro drug potency.
    Antimicrobial Agents and Chemotherapy 07/2014; · 4.57 Impact Factor
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    ABSTRACT: The in vitro activity of isavuconazole and nine antifungal comparator agents was assessed using reference broth microdilution methods against 1,421 common and uncommon species of Candida from a 2012 global survey. Isolates were identified using CHROMagar, biochemical methods and sequencing of ITS and/or 28S regions. Candida spp. were classified as either susceptible or resistant and as wild type (WT) or non-WT using CLSI clinical breakpoints or epidemiological cutoff values, respectively, for the antifungal agents. Isolates included 1,421 organisms from 21 different species of Candida. Among Candida spp., resistance to all 10 tested antifungal agents was low (0.0-7.9 %). The vast majority of each species of Candida, with the exception of Candida glabrata, Candida krusei, and Candida guilliermondii (modal MICs of 0.5 µg/ml), were inhibited by ≤0.12 µg/ml of isavuconazole (99.0 %; range 94.3 % [Candida tropicalis] to 100.0 % [Candida lusitaniae and Candida dubliniensis]). C. glabrata, C. krusei, and C. guilliermondii were largely inhibited by ≤1 µg/ml of isavuconazole (89.7, 96.9 and 92.8 %, respectively). Decreased susceptibility to isavuconazole was most prominent with C. glabrata where the modal MIC for isavuconazole was 0.5 µg/ml for those strains that were SDD to fluconazole or WT to voriconazole, and was 4 µg/ml for those that were either resistant or non-WT to fluconazole or voriconazole, respectively. In conclusion, these data document the activity of isavuconazole and generally the low resistance levels to the available antifungal agents in a large, contemporary (2012), global collection of molecularly characterized species of Candida.
    Mycopathologia 06/2014; · 1.55 Impact Factor
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    ABSTRACT: The antifungal broth microdilution (BMD) method of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) was compared with Clinical and Laboratory Standards Institute (CLSI) BMD method M27-A3 for amphotericin B, flucytosine, anidulafungin, caspofungin, micafungin, fluconazole, isavuconazole, itraconazole, posaconazole, and voriconazole susceptibility testing of 357 isolates of Candida. The isolates were selected from global surveillance collections to represent both wildtype (WT) and non-WT MIC results for the azoles (12% of fluconazole and voriconazole results were non-WT) and the echinocandins (6% of anidulafungin and micafungin results were non-WT). The study collection included 114 isolates of C. albicans, 73 of C. glabrata, 76 of C. parapsilosis, 60 of C. tropicalis, and 34 of C. krusei. The overall essential agreement (EA) between EUCAST and CLSI results ranged from 78.9% (posaconazole) to 99.6% (flucytosine). The categorical agreement (CA) between methods and species of Candida was assessed using previously determined CLSI epidemiological cutoff values (ECVs). The overall CA between methods was 95.0% with 2.5% very major (VM) and major (M) discrepancies. The CA was >93% for all antifungal agents with the exception of caspofungin (84.6%), where 10% of the results were categorized as non-WT by the EUCAST method and WT by the CLSI method. Problem areas with low EA or CA include testing of amphotericin B, anidulafungin, and isavuconazole against C. glabrata, itraconazole and posaconazole against most species, and caspofungin against C. parapsilosis, C. tropicalis, and C. krusei. We confirm high level EA and CA (>90%) between the two methods for testing fluconazole, voriconazole, and micafungin against all five species. The results indicate that the EUCAST and CLSI methods produce comparable results for testing the systemically active antifungal agents against the five most common species of Candida; however, there are several areas where additional steps toward harmonization are warranted.
    Diagnostic microbiology and infectious disease 06/2014; · 2.45 Impact Factor
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    ABSTRACT: The amikacin fosfomycin inhalation system (AFIS) is a combination of 2 antibiotics and an in-line nebulizer delivery system that is being developed for adjunctive treatment of Gram-negative pneumonia in patients on mechanical ventilation. AFIS consists of a combination of amikacin and fosfomycin solutions in a 5:2 ratio (amikacin, 3 mL, 100 mg/mL and fosfomycin 3 mL, 40 mg/mL) and the PARI Investigational eFlow Inline System. In this antibiotic potentiation study, the antimicrobial activity of amikacin and fosfomycin, alone and in a 5:2 combination, were assessed against 62 Gram-negative pathogens from a worldwide antimicrobial surveillance collection (SENTRY). The 62 isolates of Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae had amikacin minimum inhibitory concentrations (MICs) of ≥ 32 μg/mL (Clinical and Laboratory Standards Institute [CLSI]: intermediate or resistant; European Committee on Antimicrobial Susceptibility Testing [EUCAST]: resistant). Each isolate was tested against amikacin (0.25 - 1024 μg/mL), fosfomycin (0.1 - 409.6 μg/mL), and amikacin/fosfomycin (5:2 ratio) using CLSI reference agar dilution methods.The median MIC values for amikacin and fosfomycin against the 62 isolates each decreased 2-fold with the amikacin/fosfomycin (5:2) combination, compared with either antibiotic alone. Interactions between amikacin and fosfomycin varied by isolate, and ranged from non-detectable to high potentiation. The amikacin/fosfomycin (5:2) combination reduced the amikacin concentration required to inhibit all 62 isolates from > 1024 to ≤ 256 μg/mL, and reduced the required fosfomycin concentration from 204.8 to 102.4 μg/mL. These results support continued development of the amikacin/fosfomycin combination for aerosolized administration, where high drug levels can be achieved.
    Antimicrobial Agents and Chemotherapy 04/2014; · 4.57 Impact Factor
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    ABSTRACT: The amikacin fosfomycin inhalation system (AFIS), a combination of antibiotics administered with an in-line nebulizer delivery system, is being developed for adjunctive treatment of ventilator-associated pneumonia (VAP). The in vitro characterization of amikacin/fosfomycin (5:2) described herein included determining resistance selection rates for pathogens that are representative of those commonly associated with VAP (including multi-drug resistant strains), and evaluating interactions with antibiotics commonly used intravenously to treat VAP.Spontaneous amikacin/fosfomycin (5:2) resistance was not observed for most tested strains (n=10/14). Four strains had spontaneously resistant colonies (frequencies were 4.25 x 10(-8) to 3.47 x 10(-10)); colonies had 2- to 8-fold increases in amikacin/fosfomycin (5:2) minimum inhibitory concentrations (MIC) compared with the original strains. After 7 days of serial passage, resistance (>4-fold increase from baseline MIC) occurred in fewer strains (n=4/14) passaged in the presence of amikacin/fosfomycin (5:2), compared with either amikacin (n=7/14) or fosfomycin (n=12/14) alone.Interactions between amikacin/fosfomycin (5:2) and 10 comparator antibiotics in checkerboard testing against 30 different Gram-positive or Gram-negative bacterial strains were synergistic (fractional inhibitory concentration [FIC] index ≤ 0.5) for 6.7% (n=10/150) of tested combinations. No antagonism was observed. Synergy was confirmed by time-kill methodology for amikacin/fosfomycin (5:2) plus cefepime (against E. coli), aztreonam (P. aeruginosa), daptomycin (E. faecalis), and azithromycin (S. aureus). Amikacin/fosfomycin (5:2) was bactericidal at 4-fold the MIC for 7 strains tested.The reduced incidence of developing resistance to amikacin/fosfomycin (5:2), compared with amikacin or fosfomycin alone, and lack of negative interactions with commonly used intravenous antibiotics, further support the development of AFIS for the treatment of VAP.
    Antimicrobial Agents and Chemotherapy 04/2014; · 4.57 Impact Factor
  • Helio S Sader, Paul R Rhomberg, Ronald N Jones
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    ABSTRACT: The post β-lactamase inhibitor effect (PBLIE) of tazobactam when combined with ceftolozane was evaluated by time-kill assays on two clinical Escherichia coli strains producing CTX-M-15 ± TEM-1. The organisms were exposed (2 hours) to 4/4 μg/ml of ceftolozane/tazobactam (4x MIC), 4 μg/ml of ceftolozane and media containing no drug, washed and re-suspended in media alone or containing ceftolozane/tazobactam or ceftolozane. PBLIE was determined as 1.3-2.1 hours, & a post antibiotic effect was measured as 0.8-0.9 hours.
    Antimicrobial Agents and Chemotherapy 01/2014; · 4.57 Impact Factor
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    ABSTRACT: BACKGROUND: Isavuconazole is a new broad-spectrum triazole with a favorable pharmacokinetic and safety profile.METHODS: We report the MIC distributions for isavuconazole and 111 isolates of Candida (C. albicans [42 isolates], C. glabrata (25), C. parapsilosis (22), C. tropicalis (14), and C. krusei (8)) as determined by both CLSI and EUCAST broth microdilution (BMD) methods; also the comparative activity of isavuconazole, itraconazole, fluconazole, posaconazole, voriconazole and the three echinocandins was assessed against a recent (2011) global collection of 1,358 isolates of Candida spp., 101 of Aspergillus spp., 54 of non-Candida yeasts, and 21 of non-Aspergillus moulds as determined by CLSI BMD methods.RESULTS: The overall essential agreement (EA; ± two log2 dilutions) between the CLSI and EUCAST methods was 99.1% (EA ± 1 log 2 dilution, 90.1% [range 80.0-100.0%]). The activity of isavuconazole against the larger collection of Candida spp. and Aspergillus spp. was comparable to that of posaconazole and voriconazole: MIC90 values for these 3 triazoles against Candida spp. was 0.5, 1 and 0.25 μg/ml, respectively and against Aspergillus spp. was 2, 1 and 1 μg/ml, respectively. Isavuconazole showed good activity against Cryptococcus neoformans (MIC90, 0.12 μg/ml) and other non-Candida yeasts (MIC90, 1 μg/ml), but was less potent against non-Aspergillus moulds (MIC90, >8 μg/ml). MIC values for isavuconazole and three mucormycetes isolates were 4, 1 and 2 μg/ml, respectively, whereas all three were inhibited by 1 μg/ml of posaconazole.CONCLUSIONS: Isavuconazole demonstrates broad-spectrum activity against this global collection of opportunistic fungi and both CLSI and EUCAST methods may be used to test this agent against Candida with highly comparable results.
    Journal of clinical microbiology 06/2013; · 4.23 Impact Factor
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    ABSTRACT: We evaluated the ability of four commercial minimum inhibitory concentration (MIC) testing systems (MicroScan, Vitek-2, Phoenix and Etest) to detect vancomycin MIC values of ≤1 - ≥2 in 200 MRSA strains compared to the Clinical and Laboratory Standards Institute broth microdilution (BMD) reference methods. Compared to BMD, absolute agreement (0 +/- dilution) was highest for Phoenix (66.2%) and MicroScan turbidity method (61.8%) followed by Vitek-2 at 54.3%. Etest produced MIC values 1-2 dilutions higher than BMD (36.7% agreement). Of interest, the MicroScan system (prompt method) was more likely to overcall an MIC value of 1 mg/liter (74.1%) whereas, Phoenix (76%) and Vitek-2 (20%) had a tendency to undercall an MIC of 2 mg/liter. The ability to correctly identify vancomycin MIC values of 1 and 2 has clinical implications and requires further evaluation.
    Journal of clinical microbiology 04/2013; · 4.23 Impact Factor
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    ABSTRACT: External laboratory proficiency programs are an important requirement for test quality assurance (EQA) and compliance to regulatory guidelines (Clinical Laboratory Improvement Amendments and inspections). The American Proficiency Institute (API) regularly distributes EQA sample challenges (test events) including an Educational Sample (ES) for antimicrobial susceptibility testing. Beginning in 2007, API has sent 3 ES samples annually, each a well-characterized (molecular/phenotypic methods) strain having an interesting/emerging mechanism of resistance. Hundreds of USA laboratories, usually serving small- to medium-size hospitals and clinics, participate in the API ungraded ES test event. Analysis of responses is made and reported electronically as ES critiques addressing contemporary susceptibility testing issues that affect patient therapy. Seven Gram-positive (+) and 8 Gram-negative (-) ES strains were tested over the 5 years (2007-2011) with organism identification (graded) accuracy of 95.3% (range, 91.0-99.2%) for Gram (-) and 97.0% (range, 94.2-100.0%) for Gram (+) challenges. Susceptibility testing categorical accuracy was generally greatest for the disk diffusion test (91.0/97.0%) compared to the MIC methods (commercial automated or manual) combined (89.9/96.1%, for Gram [-]/Gram [+], respectively). The most worrisome observations of these ES samples were as follows: 1) poor recognition of ESBL- and serine carbapenemase-producing strains (various types including Klebsiella pneumoniae carbapanemase) due to delayed application of Clinical and Laboratory Standards Institute [CLSI] guidelines; 2) overcalling of ESBL in organisms having wild-type non-ESBL enzymes (OXA series; OXA, 1/30) due to commercial system or participant interpretive error; and 3) occasional drug-bug discords noted in nonfermentative Gram (-) bacilli. In conclusion, the API ES series of ungraded susceptibility testing challenges (accuracy was >90%) has been well received by subscribers and has provided detailed educational opportunities to improve laboratory testing performance. ES samples have delivered guidance to enable laboratories to rapidly comply with CLSI document changes of interpretive breakpoints such as those for β-lactams when testing Enterobacteriaceae and Pseudomonas aeruginosa; the program was sustained into 2012 and beyond to document quality of susceptibility tests in USA laboratories.
    Diagnostic microbiology and infectious disease 03/2013; · 2.45 Impact Factor
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    ABSTRACT: OBJECTIVES: In spite of reported nephrotoxicity, polymyxins have been reinstated as the last-line therapy to treat infections caused by Gram-negative bacterial strains that are resistant to other agents. NAB739 has a cyclic portion identical to that of polymyxin B, but its linear peptide portion consists of threonyl-d-serinyl instead of diaminobutyryl-threonyl-diaminobutyryl. Therefore, NAB739 lacks both of the positive charges present in the linear part of polymyxin B. Here, we compare the antibacterial activity of NAB739 with that of polymyxin B against a representative collection of contemporary Gram-negative bacteria. METHODS: NAB739 and polymyxin B MIC values were determined for 310 clinical isolates by the reference broth microdilution method according to CLSI document M07-A9 (2012). RESULTS: MIC(90)s of NAB739 for the subset consisting of polymyxin-susceptible (MIC, ≤2 mg/L) clinical isolates of Escherichia coli (n = 51), Klebsiella pneumoniae (n = 50), Acinetobacter spp. (n = 49) and Pseudomonas aeruginosa (n = 49) were 2, 2, 8 and 16 mg/L, respectively. For polymyxin-non-susceptible strains of E. coli (n = 12), K. pneumoniae (n = 11), Acinetobacter spp. (n = 11) and P. aeruginosa (n = 14) the NAB739 MIC(90) was ≥64 mg/L. CONCLUSIONS: The MIC(90) of NAB739 for polymyxin-susceptible strains of E. coli and K. pneumoniae was identical to and 2-fold higher than that of polymyxin B, respectively. For polymyxin-susceptible strains of Acinetobacter spp. and P. aeruginosa, the MIC(90) of NAB739 was 4-fold and 8-fold higher than that of polymyxin B, respectively. For polymyxin-non-susceptible strains of all these species, the MIC(90) values of NAB739 were high and 2- to 4-fold higher than those of polymyxin B.
    Journal of Antimicrobial Chemotherapy 11/2012; · 5.34 Impact Factor
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    ABSTRACT: Accurate determination of in vitro activity for polymyxin class agents has consistently been a problem due to their physical-chemical characteristics that can be influenced by the constituents of reference and/or standardized susceptibility testing methods. We evaluated the impact of using polysorbate 80 (P-80), a surfactant, in reference broth microdilution (BMD) methods when testing polymyxin B and colistin against 247 clinical strains of Enterobacteriaceae (124 strains), Acinetobacter spp. (60 strains), and Pseudomonas aeruginosa (63 strains). All testing was performed in frozen-form BMD panels with and without 0.002% P-80. MIC results for both polymyxins were generally 4- to 8-fold lower when P-80 was added to the testing broth compared to Mueller-Hinton broth without the surfactant. Decreases were greatest in organisms having MIC values at ≤2 μg/mL and among Acinetobacter spp. Polymyxins should be tested with P-80 to more accurately assess the potencies of these agents necessary to treat multidrug-resistant Gram-negative bacilli.
    Diagnostic microbiology and infectious disease 10/2012; · 2.45 Impact Factor
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    ABSTRACT: Background: Telavancin (TLV) is approved in the US and Canada for the treatment of complicated skin and skin structure infections (cSSSI) in adults caused by susceptible Gram-positive organisms. In the analysis of the TLV phase 3 cSSSI clinical trials , lower cure rates were observed in patients with diminished renal function, especially those with severe impairment (CrCL < 30 mL/min). To identify a possible mechanism for this reduced efficacy, a study was conducted to determine antibacterial activity of serum in subjects with severe renal impairment, including end stage renal disease (ESRD), compared with normal renal function following IV TLV. Biologic activity was measured as serum inhibitory (SIT) and bactericidal titers (SBT) vs a reference strain of Staphylococcus aureus (SA). Methods: 15 adult men and women in each of three cohorts were recruited: normal renal function, severe impairment (CrCL< 30 mL/min), and receiving chronic hemodialysis (ESRD). A single 7.5 mg/kg dose of TLV was given over 1 hr, followed by sampling for SIT/SBT at: end of infusion, 2, 4, 6, 8, 12, 24, 30, 36 & 48 hr after start of infusion. ESRD subjects also had samples taken at 54, 60 & 72 hr. Serum titers were measured by serial 2-fold dilutions in sterile, pooled human serum tested against the SA susceptible strain (ATCC 29213). TLV MIC for the test organism using CLSI standard methods was 0.25-0.5 mg/mL, on different testing days. Results: Figure displays SIT over time. SBT were similar to SIT. Area under the SIT vs time curve from 0-48hr (AUIC48) demonstrated that values for subjects with severe renal impairment (3076) or ESRD (3377) were approximately double that found in subjects with normal renal function (1602), consistent with observed pharmacokinetic differences in these subjects. Despite use of a lower dose than in the Phase 3 studies, high titers and prolonged activity were observed, suggesting that other factors such as differences in safety/tolerability may have been responsible for lower cure rates. Conclusion: TLV produced high and prolonged bactericidal activity vs. S. aureus in subjects across renal function cohorts, including ESRD. This suggests that reduced serum antibacterial activity was not a likely cause of reduced efficacy observed in the cSSSI trials.
    IDWeek 2012 Meeting of the Infectious Diseases Society of America; 10/2012
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    ABSTRACT: CXA-101, a novel oxyimino-aminothiazolyl cephalosporin, CXA-201 (CXA-101 combined with tazobactam), and various comparators were susceptibility tested by broth microdilution methods against 1,301 well-characterized clinical strains collected worldwide, including ceftazidime-resistant members of the family Enterobacteriaceae and Klebsiella pneumoniae carbapenemase (KPC)- and extended-spectrum β-lactamase (ESBL)-producing strains of Pseudomonas aeruginosa and Bacteroides fragilis. CXA-201 was 2- to 32-fold more active than ceftazidime and piperacillin-tazobactam against ceftazidime-resistant Enterobacteriaceae species but less active than cefepime for some species. CXA-101 and CXA-201 were very active against P. aeruginosa (MIC50, 1 μg/ml for both compounds), including imipenem-resistant strains.
    Antimicrobial Agents and Chemotherapy 02/2011; 55(5):2390-4. · 4.57 Impact Factor
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    ABSTRACT: Telavancin is approved in the United States and Canada for the treatment of complicated skin and skin structure infections (cSSSI) in adults caused by susceptible Gram-positive organisms. The antimicrobial activity of telavancin and comparators was evaluated against 5,027 (2007-2008) Gram-positive bacteria responsible for SSSI in medical centers in Asia-Pacific, European, Latin American, and North American regions. Telavancin was active against Staphylococcus aureus (MIC₅₀(/)₉₀, 0.12/0.25 mg/l; 100.0% susceptible) and coagulase-negative staphylococci (MIC₅₀(/)₉₀, 0.12/0.25 mg/l). telavancin inhibited all Enterococcus faecalis, including four strains displaying a VanB phenotype, at ≤ 1 mg/L (MIC₅₀(/)₉₀, 0.25/0.5 mg/l), except for two isolates with a VanA phenotype (MIC, >2 mg/l). Vancomycin-susceptible and VanB vancomycin-resistant E. faecium were inhibited by telavancin at ≤ 0.25 mg/L, while this drug exhibited elevated MIC values (≥ 0.5 mg/l) against E. faecium of VanA phenotype (MIC₅₀(/)₉₀, 2/>2 mg/l). Telavancin was potent against β-haemolytic streptococci (MIC₅₀(/)₉₀, 0.03/0.12 mg/l; 100.0% susceptible) and viridans group streptococci (MIC₅₀(/)₉₀, 0.03/0.06 mg/l; 100.0% susceptible). These in vitro data document the activity of telavancin against contemporary Gram-positive isolates and support its clinical use for the treatment of cSSSI caused by the indicated pathogens.
    Journal of chemotherapy (Florence, Italy) 10/2010; 22(5):304-11. · 0.83 Impact Factor
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    ABSTRACT: As part of Meropenem Yearly Susceptibility Test Information Collection/USA Surveillance Programme, we monitored the occurrence of quinolone resistance in Escherichia coli over a 10-year period. A total of 271 E. coli isolates from our institution were tested over a 10-year period. Screening for quinolone resistance (qnr) gene was performed. A decline in susceptibility of E. coli isolates to quinolones and aminoglycosides was noted over the 10-year span (P < 0.0001), which was significantly reduced compared with the average susceptibility of all sites. Introduction of quinolone prophylaxis has led to a significant decline in susceptibility of E. coli to all quinolones. The organisms remain susceptible to carbapenems, cefepime, and piperacillin/tazobactam. Periodic surveillance allows for detection of resistance patterns and adjustment of empiric antibiotic choice in patients at high risk for infection.
    Diagnostic microbiology and infectious disease 07/2010; 67(3):266-9. · 2.45 Impact Factor

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  • 2002–2014
    • JMI Laboratories
      North Liberty, Iowa, United States
  • 2008–2011
    • Universidade Federal de São Paulo
      • School of Medicine
      San Paulo, São Paulo, Brazil
  • 2003
    • Christian Medical College Vellore
      Velluru, Tamil Nādu, India
  • 1997–2003
    • University of Iowa
      • • Department of Internal Medicine
      • • Department of Pathology
      • • Department of Obstetrics and Gynecology
      Iowa City, IA, United States