[Show abstract][Hide abstract] 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;
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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 01/2014; · 2.45 Impact Factor
[Show abstract][Hide abstract] 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; · 4.16 Impact Factor
[Show abstract][Hide abstract] 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; · 4.16 Impact Factor
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: The development of diagnostic susceptibility tests for CEM-101, a new fluoroketolide, was addressed by structured studies to determine the optimal disk diffusion test concentration and effects of various testing conditions or supplements and to establish the quality control (QC) ranges for reference broth microdilution tests. The 15-microg CEM-101 disk was selected, and MIC ranges for a total of four QC organisms were proposed, with only three doubling dilutions each that included 95.6 to 99.7% of values reported from the eight-laboratory investigation.
Journal of clinical microbiology 04/2010; 48(4):1470-3. · 4.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: CEM-101 is a novel fluorinated macrolide-ketolide with potent activity against bacterial pathogens that are susceptible or resistant to other macrolide-lincosamide-streptogramin B (MLS(B))-ketolide agents. CEM-101 is being developed for oral and parenteral use in moderate to moderately severe community-acquired bacterial pneumonia. The objective of this study was to assess the activity of CEM-101 and comparators against contemporary respiratory tract infection (RTI) isolates. A worldwide sample of organisms was used, including Streptococcus pneumoniae [n=168; 59.3% erythromycin-resistant and 18 multidrug-resistant (MDR) serogroup 19A strains], Moraxella catarrhalis (n=21; 11 beta-lactamase positive), Haemophilus influenzae (n=100; 48 beta-lactamase positive), Haemophilus parainfluenzae and Haemophilus haemolyticus (n=12), and Legionella pneumophila (n=30). Testing and interpretation were performed using reference Clinical and Laboratory Standards Institute methods. CEM-101 was very potent against S. pneumoniae [minimum inhibitory concentration for 90% of the organisms (MIC90)=0.25 mg/L; highest MIC at 0.5 mg/L] and was 2- and > or =32-fold more active than telithromycin and clindamycin, respectively. CEM-101 also demonstrated potent activity against S. pneumoniae MDR-19A strains (MIC90=0.5 mg/L). CEM-101 was the most potent antimicrobial agent tested against L. pneumophila, with all MIC values at < or = 0.015 mg/L (telithromycin MIC90=0.03 mg/L). CEM-101 was as potent as azithromycin against Haemophilus spp. RTI pathogens (MIC90=2 mg/L), with no variations for beta-lactamase production. CEM-101 MIC values against M. catarrhalis were all at < or =0.5mg/L. Interestingly, CEM-101 potency was ca. 6 log(2) dilutions greater than telithromycin MIC results among 44 beta-haemolytic streptococci having telithromycin MICs > or = 2 mg/L. CEM-101 exhibited the greatest potency and widest spectrum of activity against RTI pathogens among the tested MLS(B)-ketolide agents (azithromycin, clarithromycin, erythromycin, telithromycin, clindamycin and quinupristin/dalfopristin) and was comparable overall with levofloxacin.
International journal of antimicrobial agents 03/2010; 35(6):537-43. · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fusidic acid (CEM-102) is an established antistaphylococcal agent that has been used in clinical practice for more than 4 decades. The activity of fusidic acid against 778 isolates of Staphylococcus aureus collected from U.S. (53.8% were methicillin-resistant S. aureus [MRSA]) and Canadian (46.5% were MRSA) medical centers was assessed to determine the intermethod accuracy of the Clinical and Laboratory Standards Institute (CLSI) and Etest methods. Broth microdilution MIC results were compared by scattergram analysis to zone diameters around commercially available 5- and 10-microg disks. Acceptable correlation (r = 0.74 to 0.76) was observed for the two disk concentrations, and applying breakpoints of < or = 1 microg/ml (> or = 22 mm) for susceptibility (S) and > or = 4 microg/ml (< or = 19 mm) for resistance (R) provided 99.9% absolute intermethod categorical agreement. Reference CLSI MIC versus Etest MIC results (r = 0.77; 728 strains) showed 55.4% identical results and agreement of 99.7% +/- one log2 dilution. The diagnostic susceptibility testing reagents (including Etest) for fusidic acid (CEM-102) performed at an excellent level of intermethod agreement for the proposed breakpoint criteria.
Journal of clinical microbiology 03/2010; 48(3):972-6. · 4.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fusidic acid (CEM-102) is a steroidal antimicrobial agent with focused Gram-positive activity that acts by preventing bacterial protein synthesis via interacting with elongation factor G. A collection of 114 wild-type isolates (> 80 species) was used to define the contemporary limits of fusidic acid spectrum against Gram-positive and Gram-negative species. Reference broth microdilution and anaerobic agar dilution methods were performed. Modifications of standardized test methods included adding 10% human serum and adjusting the medium pH to 5, 6, and 8. Synergy was assessed by the checkerboard method and time-kill studies. Mutational rates to resistance were determined at 4 x, 8 x, and 16 x MIC. Against Gram-positive pathogens, fusidic acid MIC values ranged from 0.06 to 32 microg/mL with the greatest potency against Staphylococcus aureus, Corynebacterium spp., and Micrococcus luteus (MIC results, 0.25, < or = 0.12, and < or = 0.5 microg/mL, respectively). Enterococci and streptococci were less susceptible (MIC ranges, 2-8 and 16-32 microg/mL, respectively). Fusidic acid activity against Gram-negative species was more limited (all MIC values, > or = 2 microg/mL) except for Empedobacter brevis, Moraxella catarrhalis and Neisseria meningitidis. A 4-fold increase in fusidic acid MIC results was observed when 10% serum was added to the broth. Decreasing medium pH to 5.0 to 6.0 negated the protein binding effects. Among the 8 antimicrobial combinations tested, gentamicin and rifampin enhanced the activity when combined with fusidic acid (no antagonism). Fusidic acid in vitro activity was most improved when combined with rifampin. Single-step mutational rates ranged from 1.2 x 10(-6) for 4x MIC to 9.8 x 10(-8) for 16 x MIC. In conclusion, these in vitro results for fusidic acid tested against contemporary strains confirm a persisting antimicrobial spectrum, especially against staphylococci and some other Gram-positive species.
[Show abstract][Hide abstract] ABSTRACT: We evaluated the susceptibility rates for piperacillin/tazobactam tested against Pseudomonas aeruginosa isolates from the Asia-Pacific (APAC), Europe (EU), Latin America (LA), and North America (NA) for 1997 to 2007. A total of 25 460 isolates were tested originating from APAC (4441), EU (7695), LA (4277), and NA (9047). All testing was performed by reference broth microdilution methods. The samples were collected from >110 medical centers and samples averaging >30 nations/year. For this analysis, results from 1997 to 2007, 1997 to 1999, 2005 to 2007, APAC, EU, LA, and NA were assessed against several broad-spectrum beta-lactams, including cefepime, ceftazidime, imipenem, meropenem, and piperacillin alone, for a total of 12 agents overall. Using P. aeruginosa breakpoints (< or =64 microg/mL), piperacillin/tazobactam had the broadest coverage (% susceptible) in 2 regions (EU, LA) and, overall, at 83.6% followed by meropenem (83.0%) > imipenem (79.7%) > piperacillin (79.5%) > cefepime (77.5%) > ceftazidime (75.8%). Other non-beta-lactam activity results were ciprofloxacin at only 71.5% susceptible, but tobramycin and polymyxin B had higher susceptibility rates (81.0% and 99.5%, respectively). Trends toward piperacillin/tazobactam resistance were noted between 1997 to 1999 and 2000 to 2007 in APAC (-11.6% susceptibility), NA (-4.0%), and EU (-2.3%). LA susceptibility rates were lowest overall but actually increased recently by +2.9% (current rate, 79.4% susceptible). For beta-lactamase inhibitor combinations, susceptibility rates were higher for piperacillin/tazobactam when compared in all regions with piperacillin alone (+2.6-7.1%) and greatest for LA isolates. In contrast, ticarcillin/clavulanate susceptibility rates were lower than ticarcillin tested alone in NA (-1.5%, antagonism), and this agent only inhibited 70.3% of isolates worldwide. In conclusion, piperacillin/tazobactam remained a very active beta-lactam when tested in vitro against clinical isolates of P. aeruginosa found in the SENTRY Program (1997-2007). Trends toward slightly decreased susceptibility were noted in all regions over the last decade (except LA); only polymyxins had susceptibility rates at >90%. Resistance surveillance programs should be sustained to document emerging resistance patterns of old and newer agents for difficult-to-treat pathogens such as P. aeruginosa.