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1.
Laurent Bouillaut Shonna McBride Joseph A. Sorg Diane J. Schmidt José M. Suarez Saul Tzipori Carmela Mascio Laurent Chesnel A. L. Sonenshein 《Antimicrobial agents and chemotherapy》2015,59(7):4199-4205
The increasing incidence and severity of infection by Clostridium difficile have stimulated attempts to develop new antimicrobial therapies. We report here the relative abilities of two antibiotics (metronidazole and vancomycin) in current use for treating C. difficile infection and of a third antimicrobial, surotomycin, to kill C. difficile cells at various stages of development and to inhibit the production of the toxin proteins that are the major virulence factors. The results indicate that none of the drugs affects the viability of spores at 8× MIC or 80× MIC and that all of the drugs kill exponential-phase cells when provided at 8× MIC. In contrast, none of the drugs killed stationary-phase cells or inhibited toxin production when provided at 8× MIC and neither vancomycin nor metronidazole killed stationary-phase cells when provided at 80× MIC. Surotomycin, on the other hand, did kill stationary-phase cells when provided at 80× MIC but did so without inducing lysis. 相似文献
2.
Carl N. Kraus Matthew W. Lyerly Robert J. Carman 《Antimicrobial agents and chemotherapy》2015,59(5):2525-2530
Clostridium difficile infection (CDI) is a gastrointestinal disease caused by C. difficile, a spore-forming bacterium that in its spore form is tolerant to standard antimicrobials. Ramoplanin is a glycolipodepsipeptide antibiotic that is active against C. difficile with MICs ranging from 0.25 to 0.50 μg/ml. The activity of ramoplanin against the spores of C. difficile has not been well characterized; such activity, however, may hold promise, since posttreatment residual intraluminal spores are likely elements of disease relapse, which can impact more than 20% of patients who are successfully treated. C. difficile spores were found to be stable in deionized water for 6 days. In vitro spore counts were consistently below the level of detection for 28 days after even brief (30-min) exposure to ramoplanin at concentrations found in feces (300 μg/ml). In contrast, suppression of spore counts was not observed for metronidazole or vancomycin at human fecal concentrations during treatment (10 μg/ml and 500 μg/ml, respectively). Removal of the C. difficile exosporium resulted in an increase in spore counts after exposure to 300 μg/ml of ramoplanin. Therefore, we propose that rather than being directly sporicidal, ramoplanin adheres to the exosporium for a prolonged period, during which time it is available to attack germinating cells. This action, in conjunction with its already established bactericidal activity against vegetative C. difficile forms, supports further evaluation of ramoplanin for the prevention of relapse after C. difficile infection in patients. 相似文献
3.
Manoj Kumar Tarun Mathur Tarani K. Barman G. Ramkumar Ashish Bhati Gunjan Shukla Vandana Kalia Manisha Pandya V. Samuel Raj Dilip J. Upadhyay Chetana Vaishnavi Anjan Chakrabarti Biswajit Das Pradip K. Bhatnagar 《Antimicrobial agents and chemotherapy》2012,56(11):5986-5989
The MIC90 of RBx 14255, a novel ketolide, against Clostridium difficile was 4 μg/ml (MIC range, 0.125 to 8 μg/ml), and this drug was found to be more potent than comparator drugs. An in vitro time-kill kinetics study of RBx 14255 showed time-dependent bacterial killing for C. difficile. Furthermore, in the hamster model of C. difficile infection, RBx 14255 demonstrated greater efficacy than metronidazole and vancomycin, making it a promising candidate for C. difficile treatment. 相似文献
4.
D. M. Citron K. L. Tyrrell C. V. Merriam E. J. C. Goldstein 《Antimicrobial agents and chemotherapy》2010,54(4):1627-1632
The in vitro activities of ceftaroline, a novel, parenteral, broad-spectrum cephalosporin, and four comparator antimicrobials were determined against anaerobic bacteria. Against Gram-positive strains, the activity of ceftaroline was similar to that of amoxicillin-clavulanate and four to eight times greater than that of ceftriaxone. Against Gram-negative organisms, ceftaroline showed good activity against β-lactamase-negative strains but not against the members of the Bacteroides fragilis group. Ceftaroline showed potent activity against a broad spectrum of anaerobes encountered in respiratory, skin, and soft tissue infections.With the continuing emergence of novel patterns of resistance to commonly used antimicrobial agents, alternative therapies are needed to treat serious infections. Ceftaroline is a novel, parenteral, broad-spectrum cephalosporin that exhibits bactericidal activity against Gram-positive organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus, and multidrug-resistant Streptococcus pneumoniae (MDRSP) strains, as well as common Gram-negative pathogens (8, 12, 14, 16, 18-22). Ceftaroline is currently in development for the treatment of complicated skin and skin structure infections and community-acquired pneumonia.Anaerobic bacteria are common pathogens in a variety of pleuropulmonary infections, including aspiration pneumonia, lung abscesses, and empyema (1, 3, 6, 15). However, many laboratories do not culture for anaerobes (9), diminishing awareness of the role of anaerobes in these infections. The main anaerobic pathogens isolated from these infections include Prevotella melaninogenica (∼25%), Prevotella intermedia (∼30%), Fusobacterium species (∼39%), Gram-positive cocci (∼30%), and Veillonella species (∼35%) (7). Cephalosporins such as cefoxitin have been used for the therapy of aspiration pneumonias. Although cefoxitin is active against most respiratory anaerobes, it has poor activity against the newer resistant strains of members of the family Enterobacteriaceae and MRSA. The activity of ceftaroline against Gram-positive anaerobes is similar to that of amoxicillin-clavulanate, and non-β-lactamase-producing Gram-negative strains generally have low ceftaroline MICs (present study), suggesting that ceftaroline might have an adequate spectrum of activity for therapy for some cases of aspiration pneumonia.To investigate the broader potential of ceftaroline, we compared its in vitro activity against 623 unique clinical isolates of anaerobic bacteria representing 5 Gram-negative bacterial genera and 17 Gram-positive bacterial genera to the activities of ceftriaxone, metronidazole, clindamycin, and amoxicillin-clavulanate.The reference agar dilution procedure described in CLSI document M11-A7 was used (5). The organisms were recovered from a variety of clinical specimens and were stored at −70°C in 20% skim milk. Identification was accomplished by standard phenotypic methods or by partial 16S rRNA gene sequencing for strains that could not be identified phenotypically (13, 17). Quality control strains Bacteroides fragilis ATCC 25285, Clostridium difficile ATCC 700057, and Staphylococcus aureus ATCC 29213 were included on each day of testing.The antimicrobial agents were obtained as follows: ceftaroline was from Forest Laboratories, Inc. (New York, NY); ceftriaxone, vancomycin, and metronidazole were from Sigma-Aldrich, Inc. (St. Louis, MO); and amoxicillin and clavulanate were from GlaxoSmithKline (Research Triangle Park, NC). The agar dilution plates were prepared on the day of testing.The strains were taken from the freezer and transferred twice to ensure purity and good growth. Cell paste from 48-h cultures was suspended in brucella broth to achieve the turbidity of a 0.5 McFarland standard, and the mixture was applied to plates with a Steers replicator to deliver approximately 105 CFU/spot. The plates were incubated for 44 h at 37°C in an anaerobic chamber. The MIC was the lowest concentration that completely inhibited growth or that resulted in a marked reduction in growth compared with that for the drug-free growth control (5).A summary showing the MIC range, MIC50, MIC90, and percent susceptibility is presented in Table Table1.1. The cumulative ceftaroline MIC distributions for all groups of strains are displayed in Table Table22.
Open in a separate windowaNA, not applicable.bValues in parentheses are the breakpoints for susceptibility, resistance (in μg/ml).cBacteroides caccae (n = 6), B. distasonis (n = 3), B. merdae (n = 1), B. ovatus (n = 5), B. uniformis (n = 4), and B. vulgatus (n = 7).dPrevotella bergensis (n = 2), P. corporis (n = 1), P. denticola (n = 5), P. disiens (n = 5), P. loescheii (n = 3), P. nanceiensis (n = 2), P. oris (n = 1), and P. tannerae (n = 1).eAnaerococcus prevotii (n = 12) and A. tetradius (n = 8).fPeptostreptococcus anaerobius (n = 17) and P. stomatis (n = 6).gAnaerococcus lactolyticus (n = 1), Anaerococcus murdochii (n = 1), Anaerococcus octavius (n = 1), Anaerococcus vaginalis (n = 5), Anaerococcus species, no PCR match (n = 3), Gemella morbillorum (n = 1), Gemella sanguinis (n = 1), Peptoniphilus harei (n = 7), and Peptoniphilus lacrimalis (n = 2).hActinomyces israelii (n = 1), A. meyeri (n = 2), A. neuii subsp. anitratus (n = 2), A. odontolyticus (n = 3), and A. turicensis (n = 5).iAtopobium parvulum (n = 1), Collinsella aerofaciens (n = 4), Eubacterium contortum (n = 1), Eubacterium cylindroides (n = 1), Eubacterium limosum (n = 8), Eubacterium saburreum (n = 2), Mogibacterium timidum (n = 3), Slackia exigua (n = 4), and Solobacterium moorei (n = 1).jLactobacillus casei (n = 3) and L. rhamnosus (n = 7).kClostridium aldenense (n = 4), C. bolteae (n = 5), C. citroniae (n = 3), C. hathewayi (n = 4), and C. clostridioforme (n = 4).lClostridium barati (n = 1), C. bifermentans (n = 1), C. butyricum (n = 2), C. cadaveris (n = 2), C. celerecrescens (n = 1), C. difficile (n = 4), C. glycolicum (n = 2), C. hylemonae (n = 2), C. paraputrificum (n = 2), C. sordellii (n = 1), C. sphenoides (n = 1), C. subterminale (n = 1), C. symbiosum (n = 2), and C. tertium (n = 2).
Open in a separate windowaBacteroides thetaiotaomicron (n = 20), B. caccae (n = 6), B. distasonis (n = 3), B. merdae (n = 1), B. ovatus (n = 5), B. uniformis (n = 4), and B. vulgatus (n = 7).bPrevotella bivia (n = 20), P. buccae (n = 20), P. melaninogenica (n = 18), P. intermedia (n = 20), P. bergensis (n = 2), P. corporis (n = 1), P. denticola (n = 5), P. disiens (n = 5), P. loescheii (n = 3), P. nanceiensis (n = 2), P. oris (n = 1), and P. tannerae (n = 1).cPorphyromonas asaccharolytica (n = 21) and P. somerae (n = 10).dFusobacterium nucleatum (n = 22) and F. necrophorum (n = 22).eFinegoldia magna (n = 19), Parvimonas micra (n = 22), Peptostreptococcus anaerobius (n = 17), Peptostreptococcus stomatis (n = 6), Anaerococcus prevotii (n = 12), Anaerococcus tetradius (n = 8), Anaerococcus lactolyticus (n = 1), Anaerococcus murdochii (n = 1), Anaerococcus octavius (n = 1), Anaerococcus vaginalis (n = 5), Anaerococcus species, no PCR match (n = 3), Gemella morbillorum (n = 1), Gemella sanguinis (n = 1), Peptoniphilus asaccharolyticus (n = 21), Peptoniphilus harei (n = 7), and Peptoniphilus lacrimalis (n = 2).fPropionibacterium acnes (n = 21), Propionibacterium avidum (n = 11), Actinomyces israelii (n = 1), Actinomyces meyeri (n = 2), Actinomyces neuii subsp. anitratus (n = 2), Actinomyces odontolyticus (n = 3), and Actinomyces turicensis (n = 5).gLactobacillus casei (n = 3) and L. rhamnosus (n = 7).hAtopobium parvulum (n = 1), Collinsella aerofaciens (n = 4), Eubacterium contortum (n = 1), Eubacterium cylindroides (n = 1), Eubacterium limosum (n = 8), Eubacterium saburreum (n = 2), Mogibacterium timidum (n = 3), Slackia exigua (n = 4), and Solobacterium moorei (n = 1).iClostridium aldenense (n = 4), C. bolteae (n = 5), C. citroniae (n = 3), C. hathewayi (n = 4), and C. clostridioforme (n = 4).jClostridium barati (n = 1), C. bifermentans (n = 1), C. butyricum (n = 2), C. cadaveris (n = 2), C. celerecrescens (n = 1), C. difficile (n = 4), C. glycolicum (n = 2), C. hylemonae (n = 2), C. paraputrificum (n = 2), C. sordellii (n = 1), C. sphenoides (n = 1), C. subterminale (n = 1), C. symbiosum (n = 2), and C. tertium (n = 2).The ceftaroline MIC50s for B. fragilis and other B. fragilis group species were 16 and 64 μg/ml, respectively, and the MIC90s were >64 μg/ml for both for B. fragilis and other B. fragilis group species. Ceftaroline was effective against all other Gram-negative, non-β-lactamase-producing strains and had activity similar to that of ceftriaxone. For Prevotella species, the ceftaroline MICs varied according to β-lactamase production, with the MIC50 and the MIC90 being 1 and 32 μg/ml, respectively. Most Porphyromonas species were susceptible to ceftaroline at ≤0.5 μg/ml; four β-lactamase-positive strains of Porphyromonas somerae (previously Porphyromonas levii), however, had ceftaroline MICs of 8 to 16 μg/ml. Fusobacterium nucleatum and Fusobacterium necrophorum, including two β-lactamase-positive strains, had a ceftaroline MIC50 and a ceftaroline MIC90 of 0.015 and 0.125 μg/ml, respectively. The bile-resistant Fusobacterium varium strains were susceptible to ceftaroline, with the highest MIC observed being 0.5 μg/ml, whereas Fusobacterium mortiferum had high MICs of ceftaroline (MIC90, 32 μg/ml), ceftriaxone (MIC90, >64 μg/ml), and amoxicillin-clavulanate (MIC90, 8 μg/ml). All Veillonella species were inhibited by ≤1 μg/ml ceftaroline.Almost all of the Gram-negative species were susceptible to metronidazole; four strains of Veillonella species and one strain of Prevotella nanceiensis, however, showed elevated MICs of 4 to 8 μg/ml. Clindamycin resistance was present in 37% of B. fragilis strains, 43% of Bacteroides thetaiotaomicron strains, 45% of B. fragilis group species, 21% of Prevotella species, and 19% of Porphyromonas asaccharolytica strains. Resistance to amoxicillin-clavulanate at >8/4 μg/ml was present in one B. fragilis strain and one Bacteroides ovatus strain, both of which were also resistant to imipenem; however, 19% of the B. fragilis group species showed an intermediate-susceptible amoxicillin-clavulanate MIC.Ceftaroline exhibited excellent activity against Gram-positive strains. The MIC50 and MIC90 for 127 strains of Gram-positive cocci were 0.125 and 0.5 μg/ml, respectively; and the MIC50 and MIC90 for 44 strains of Propionibacterium acnes, Propionibacterium avidum, and Actinomyces species were 0.015 and 0.25 μg/ml, respectively. The MIC50 and MIC90 for 106 strains of Clostridium species were 0.5 and 2 μg/ml, respectively, with higher MICs of 8 to 16 μg/ml being noted for 4 strains of Clostridium difficile, 1 strain of Clostridium celerecrescens, and 1 strain of Clostridium tertium. The MIC50 and MIC90 for 10 strains of vancomycin-resistant lactobacilli were 0.5 and 1 μg/ml, respectively. All “Eubacterium” group Gram-positive rods except Eggerthella lenta were inhibited by ≤0.25 μg/ml; the MIC50 and MIC90 for Eggerthella lenta were 8 and 16 μg/ml, respectively. Ceftaroline was four- to eightfold more active than ceftriaxone against Gram-positive organisms, with the MICs being the most similar to those of amoxicillin-clavulanate.Clindamycin resistance was present in 37% of the Finegoldia magna strains and 40% of the strains in the Anaerococcus prevotii and Anaerococcus tetradius groups. All strains of Actinomyces, Propionibacterium, and Lactobacillus were resistant to metronidazole, as were one strain of anaerobic Gemella morbillorum and one strain of Gemella sanguinis. All except two Gram-positive strains were susceptible to amoxicillin-clavulanate; the exceptions were two strains of Peptostreptococcus anaerobius (MICs, 32 μg/ml).Ceftaroline has been demonstrated to have excellent activity against strains commonly encountered in skin and respiratory infections, including MRSA, group A Streptococcus, MDRSP, and non-extended-spectrum β-lactamase (ESBL)-producing members of the family Enterobacteriaceae (8, 12, 14, 16, 18-22). The present study is the first to focus on the activity of ceftaroline against anaerobes and expands the known spectrum of species against which ceftaroline shows activity. The findings reported here are consistent with those of a limited study by Sader et al. (21).Although ceftaroline has a low level of activity against most Bacteroides isolates, its use in combination with a β-lactamase inhibitor might overcome this resistance and increase the clinical potential of the use of ceftaroline against intra-abdominal infections and some skin and soft tissue infections. Many skin infections contain anaerobes that are predominantly Gram-positive anaerobic cocci and relatively few Bacteroides species (2, 10), suggesting that ceftaroline may have activity in these instances as well.Our study confirmed the increasing resistance to clindamycin currently being reported by many investigators. Of particular interest was the resistance demonstrated by 2 of 19 strains of P. asaccharolytica, a species previously thought to be very susceptible to clindamycin (11). Additionally, four strains of P. somerae were β-lactamase producers, which is of interest because most studies do not report MICs for Porphyromonas and, to date, β-lactamase-producing strains have been a rare finding. We also noted an increase in the number of B. fragilis group strains with amoxicillin-clavulanate MICs reaching the intermediate level, similar to the increase in the ampicillin-sulbactam MICs reported in the CLSI M11-A7 supplement, which includes an antibiogram for the B. fragilis group (4).Except for Bacteroides species and β-lactamase-producing Prevotella isolates, ceftaroline showed potent activity against a broad spectrum of anaerobic bacteria frequently recovered from a variety of clinical infections. 相似文献
TABLE 1.
Summary of ceftaroline and comparator agent MICs, by species or groupOrganism | No. of isolates | MIC (μg/ml) | % susceptible | % resistant | ||
---|---|---|---|---|---|---|
Range | 50% | 90% | ||||
Gram-negative bacteria | ||||||
Bacteroides fragilis | 30 | |||||
Ceftaroline | 4->64 | 16 | 64 | NAa | NA | |
Ceftriaxone (≤16, ≥64)b | 4->64 | 32 | 64 | 27 | 43 | |
Clindamycin (≤2, ≥8) | 0.06->128 | 1 | 128 | 63 | 37 | |
Metronidazole (≤8, ≥32) | 0.25-2 | 1 | 2 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | 0.5-64 | 0.5 | 2 | 93 | 7 | |
Bacteroides thetaiotaomicron | 20 | |||||
Ceftaroline | 32->64 | 64 | >64 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 64->64 | >64 | >64 | 0 | 100 | |
Clindamycin (≤2, ≥8) | 0.06->128 | 4 | 128 | 45 | 45 | |
Metronidazole (≤8, ≥32) | 0.5-1 | 1 | 1 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | 0.5-8 | 2 | 4 | 95 | 0 | |
Bacteroides fragilis group spp.c | 26 | |||||
Ceftaroline | 2->64 | 64 | >64 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 4->64 | >64 | >64 | 23 | 58 | |
Clindamycin (≤2, ≥8) | 0.06->128 | 4 | >128 | 42 | 50 | |
Metronidazole (≤8, ≥32) | 0.5-2 | 1 | 2 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | 0.125-32 | 2 | 8 | 77 | 4 | |
Prevotella bivia | 20 | |||||
Ceftaroline | 0.125->64 | 2 | 64 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 0.125->64 | 2 | >64 | 75 | 15 | |
Clindamycin (≤2, ≥8) | 0.03->128 | ≤0.03 | >128 | 85 | 15 | |
Metronidazole (≤8, ≥32) | ≤0.03-4 | 1 | 2 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-4 | 0.25 | 4 | 100 | 0 | |
Prevotella buccae | 20 | |||||
Ceftaroline | 0.125->64 | 0.5 | 64 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 0.125->64 | 0.25 | 64 | 50 | 30 | |
Clindamycin (≤2, ≥8) | ≤0.03->128 | ≤0.03 | >128 | 80 | 20 | |
Metronidazole (≤8, ≥32) | 0.25-1 | 0.5 | 1 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | 0.06-4 | 0.06 | 1 | 100 | 0 | |
Prevotella melaninogenica | 18 | |||||
Ceftaroline | ≤0.008-32 | 2 | 32 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 0.03-32 | 2 | 32 | 78 | 0 | |
Clindamycin (≤2, ≥8) | ≤0.03->128 | ≤0.03 | >128 | 72 | 28 | |
Metronidazole (≤8, ≥32) | 0.06-2 | 0.5 | 1 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-2 | 0.125 | 2 | 100 | 0 | |
Prevotella intermedia | 20 | |||||
Ceftaroline | ≤0.008-64 | 1 | 16 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 0.03-64 | 1 | 16 | 80 | 10 | |
Clindamycin (≤2, ≥8) | ≤0.03->128 | ≤0.03 | 16 | 85 | 15 | |
Metronidazole (≤8, ≥32) | 0.125-2 | 0.25 | 1 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-1 | 0.06 | 0.5 | 100 | 0 | |
Prevotella spp.d | 20 | |||||
Ceftaroline | ≤0.008-32 | 2 | 32 | NA | NA | |
Ceftriaxone (≤16, ≥64) | ≤0.008-64 | 1 | 8 | 90 | 5 | |
Clindamycin (≤2, ≥8) | ≤0.03->128 | ≤0.03 | 128 | 70 | 30 | |
Metronidazole (≤8, ≥32) | 0.06-8 | 0.5 | 2 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-2 | 0.125 | 1 | 100 | 0 | |
Porphyromonas asaccharolytica | 21 | |||||
Ceftaroline | ≤0.008-0.5 | 0.015 | 0.03 | NA | NA | |
Ceftriaxone (≤16, ≥64) | ≤0.008-1 | 0.06 | 0.06 | 100 | 0 | |
Clindamycin (≤2, ≥8) | ≤0.03->128 | ≤0.03 | >128 | 81 | 19 | |
Metronidazole (≤8, ≥32) | ≤0.03-0.25 | 0.06 | 0.125 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-≤0.03 | ≤0.03 | ≤0.03 | 100 | 0 | |
Porphyromonas somerae | 10 | |||||
Ceftaroline | ≤0.008-16 | 0.015 | 16 | NA | NA | |
Ceftriaxone (≤16, ≥64) | ≤0.008-64 | 0.015 | 64 | 80 | 20 | |
Clindamycin (≤2, ≥8) | ≤0.03->128 | ≤0.03 | >128 | 80 | 20 | |
Metronidazole (≤8, ≥32) | 0.25-0.5 | 0.5 | 0.5 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-0.5 | ≤0.03 | 0.125 | 100 | 0 | |
Fusobacterium nucleatum | 22 | |||||
Ceftaroline | ≤0.008-0.125 | ≤0.008 | 0.125 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 0.015-1 | 0.125 | 0.5 | 100 | 0 | |
Clindamycin (≤2, ≥8) | ≤0.03-0.5 | 0.06 | 0.06 | 100 | 0 | |
Metronidazole (≤8, ≥32) | ≤0.03-0.25 | ≤0.03 | 0.25 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-0.5 | ≤0.03 | 0.06 | 100 | 0 | |
Fusobacterium necrophorum | 22 | |||||
Ceftaroline | 0.015-0.06 | 0.03 | 0.06 | NA | NA | |
Ceftriaxone (≤16, ≥64) | ≤0.008-0.125 | 0.015 | 0.03 | 100 | 0 | |
Clindamycin (≤2, ≥8) | ≤0.03-0.25 | ≤0.03 | 0.06 | 100 | 0 | |
Metronidazole (≤8, ≥32) | 0.06-0.25 | 0.125 | 0.25 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-1 | 0.125 | 0.5 | 100 | 0 | |
Fusobacterium mortiferum | 10 | |||||
Ceftaroline | 1-64 | 8 | 32 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 16->64 | >64 | >64 | 10 | 90 | |
Clindamycin (≤2, ≥8) | ≤0.03-0.25 | 0.06 | 1 | 100 | 0 | |
Metronidazole (≤8, ≥32) | 0.25-2 | 0.5 | 1 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | 0.25-8 | 4 | 8 | 80 | 0 | |
Fusobacterium varium | 10 | |||||
Ceftaroline | 0.015-0.5 | 0.25 | 0.5 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 0.15-8 | 1 | 8 | 100 | 0 | |
Clindamycin (≤2, ≥8) | 0.06-64 | 2 | 4 | 90 | 10 | |
Metronidazole (≤8, ≥32) | 0.25-0.5 | 0.25 | 0.5 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | 0.125-2 | 1 | 2 | 100 | 0 | |
Veillonella spp. | 19 | |||||
Ceftaroline | 0.015-1 | 0.125 | 0.5 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 0.03-8 | 4 | 8 | 79 | 16 | |
Clindamycin (≤2, ≥8) | ≤0.03->128 | 0.125 | 128 | 79 | 21 | |
Metronidazole (≤8, ≥32) | 1-8 | 2 | 8 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-8 | 0.25 | 4 | 95 | 0 | |
Gram-positive bacteria | ||||||
Anaerococcus prevotii-Anaerococcus tetradiuse | 20 | |||||
Ceftaroline | ≤0.008-2 | 0.03 | 0.125 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 0.03-32 | 0.25 | 0.5 | 95 | 0 | |
Clindamycin (≤2, ≥8) | ≤0.03->128 | 0.5 | 128 | 60 | 40 | |
Metronidazole (≤8, ≥32) | 0.125-4 | 1 | 2 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-8 | ≤0.03 | 0.125 | 95 | 0 | |
Finegoldia magna | 19 | |||||
Ceftaroline | 0.03-1 | 0.25 | 0.5 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 2-8 | 4 | 8 | 100 | 0 | |
Clindamycin (≤2, ≥8) | 0.06->128 | 2 | >128 | 53 | 37 | |
Metronidazole (≤8, ≥32) | 0.06-1 | 0.5 | 1 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-0.25 | 0.125 | 0.25 | 100 | 0 | |
Parvimonas micra | 22 | |||||
Ceftaroline | 0.015-0.5 | 0.06 | 0.25 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 0.125-2 | 0.5 | 1 | 100 | 0 | |
Clindamycin (≤2, ≥8) | 0.06-128 | 0.25 | 16 | 86 | 14 | |
Metronidazole (≤8, ≥32) | 0.125-1 | 0.25 | 0.25 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-1 | 0.125 | 0.5 | 100 | 0 | |
Peptoniphilus asaccharolyticus | 21 | |||||
Ceftaroline | ≤0.008-0.25 | 0.06 | 0.25 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 0.03-1 | 0.125 | 0.25 | 100 | 0 | |
Clindamycin (≤2, ≥8) | ≤0.03->128 | 0.125 | >128 | 76 | 24 | |
Metronidazole (≤8, ≥32) | 0.125-2 | 1 | 1 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-0.06 | ≤0.03 | 0.06 | 100 | 0 | |
Peptostreptococcus anaerobius-Peptostreptococcus stomatisf | 23 | |||||
Ceftaroline | 0.125-8 | 0.5 | 4 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 0.5-16 | 2 | 8 | 100 | 0 | |
Clindamycin (≤2, ≥8) | ≤0.03-32 | ≤0.03 | 0.25 | 96 | 4 | |
Metronidazole (≤8, ≥32) | 0.125-1 | 0.5 | 1 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-32 | 0.125 | 0.5 | 91 | 9 | |
Anaerobic Gram-positive coccig | 22 | |||||
Ceftaroline | ≤0.008-8 | 0.06 | 1 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 0.03-64 | 0.25 | 16 | 91 | 5 | |
Clindamycin (≤2, ≥8) | ≤0.03->128 | 0.125 | 64 | 73 | 27 | |
Metronidazole (≤8, ≥32) | 0.25->64 | 1 | 4 | 91 | 9 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-4 | 0.06 | 0.5 | 100 | 0 | |
Actinomyces spp.h | 13 | |||||
Ceftaroline | ≤0.008-0.25 | 0.015 | 0.25 | NA | NA | |
Ceftriaxone (≤16, ≥64) | ≤0.008-0.5 | 0.125 | 0.5 | 100 | 0 | |
Clindamycin (≤2, ≥8) | ≤0.03->128 | 0.06 | 128 | 77 | 23 | |
Metronidazole (≤8, ≥32) | >32->32 | >32 | >32 | 0 | 100 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-0.5 | 0.06 | 0.5 | 100 | 0 | |
Propionibacterium acnes | 20 | |||||
Ceftaroline | ≤0.008-0.125 | ≤0.008 | 0.06 | NA | NA | |
Ceftriaxone (≤16, ≥64) | ≤0.008-0.125 | 0.015 | 0.06 | 100 | 0 | |
Clindamycin (≤2, ≥8) | 0.125->128 | 0.125 | 0.125 | 95 | 5 | |
Metronidazole (≤8, ≥32) | >32->32 | >32 | >32 | 0 | 100 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-0.25 | ≤0.03 | 0.06 | 100 | 0 | |
Propionibacterium avidum | 11 | |||||
Ceftaroline | 0.015-0.25 | 0.25 | 0.25 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 0.03-0.5 | 0.25 | 0.5 | 100 | 0 | |
Clindamycin (≤2, ≥8) | 0.125-0.5 | 0.25 | 0.25 | 100 | 0 | |
Metronidazole (≤8, ≥32) | >32->32 | >32 | >32 | 0 | 100 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-0.25 | 0.25 | 0.25 | 100 | 0 | |
Eggerthella lenta | 17 | |||||
Ceftaroline | 2-16 | 8 | 16 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 16->64 | >64 | >64 | 6 | 94 | |
Clindamycin (≤2, ≥8) | 0.06-8 | 0.5 | 2 | 94 | 6 | |
Metronidazole (≤8, ≥32) | 0.5-1 | 0.5 | 1 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | 0.5-1 | 1 | 1 | 100 | 0 | |
“Eubacterium” groupi | 25 | |||||
Ceftaroline | 0.015-0.25 | 0.125 | 0.25 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 0.03-16 | 0.5 | 2 | 100 | 0 | |
Clindamycin (≤2, ≥8) | ≤0.03->128 | 0.06 | 2 | 92 | 8 | |
Metronidazole (≤8, ≥32) | 0.125-4 | 0.5 | 1 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-0.5 | 0.125 | 0.25 | 100 | 0 | |
Lactobacillus casei-Lactobacillus rhamnosus groupj | 10 | |||||
Ceftaroline | 0.25-8 | 0.5 | 1 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 8->64 | 32 | 64 | 40 | 30 | |
Clindamycin (≤2, ≥8) | 0.25-2 | 1 | 2 | 100 | 0 | |
Metronidazole (≤8, ≥32) | >64->64 | >64 | >64 | 0 | 100 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | 0.25-2 | 0.5 | 1 | 100 | 0 | |
Clostridium perfringens | 20 | |||||
Ceftaroline | ≤0.008-0.5 | 0.125 | 0.25 | NA | NA | |
Ceftriaxone (≤16, ≥64) | ≤0.008-4 | 0.5 | 2 | 100 | 0 | |
Clindamycin (≤2, ≥8) | ≤0.03-2 | 0.25 | 1 | 100 | 0 | |
Metronidazole (≤8, ≥32) | 0.5-4 | 2 | 4 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-0.125 | 0.03 | 0.125 | 100 | 0 | |
Clostridium ramosum | 21 | |||||
Ceftaroline | 1-2 | 1 | 1 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 0.25-0.5 | 0.25 | 0.5 | 100 | 0 | |
Clindamycin (≤2, ≥8) | 1->128 | 4 | 8 | 24 | 43 | |
Metronidazole (≤8, ≥32) | 0.5-2 | 1 | 1 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-0.25 | 0.06 | 0.25 | 100 | 0 | |
Clostridium innocuum | 21 | |||||
Ceftaroline | 0.5-4 | 1 | 2 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 8-32 | 8 | 16 | 95 | 0 | |
Clindamycin (≤2, ≥8) | 0.125->128 | 0.5 | >128 | 86 | 14 | |
Metronidazole (≤8, ≥32) | 0.5-4 | 1 | 4 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | 0.125-1 | 0.5 | 0.5 | 100 | 0 | |
Clostridium clostridioforme groupk | 20 | |||||
Ceftaroline | 0.25-2 | 1 | 2 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 2->64 | 4 | 32 | 75 | 10 | |
Clindamycin (≤2, ≥8) | ≤0.03-4 | 0.5 | 2 | 95 | 0 | |
Metronidazole (≤8, ≥32) | ≤0.03-0.25 | 0.06 | 0.25 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | 0.25-1 | 0.5 | 0.5 | 100 | 0 | |
Clostridium spp., otherl | 24 | |||||
Ceftaroline | 0.015-16 | 0.5 | 16 | NA | NA | |
Ceftriaxone (≤16, ≥64) | 0.015->64 | 2 | 64 | 75 | 21 | |
Clindamycin (≤2, ≥8) | ≤0.03->128 | 2 | 128 | 54 | 38 | |
Metronidazole (≤8, ≥32) | 0.125-4 | 0.5 | 4 | 100 | 0 | |
Amoxicillin-clavulanate (≤4/2, ≥16/8) | ≤0.03-2 | 0.125 | 1 | 100 | 0 |
TABLE 2.
Ceftaroline MIC distributions for Gram-negative and Gram-positive anaerobesOrganism group and organism | Total | Cumulative % of isolates with the following ceftaroline MIC (μg/ml): | ||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
≤0.008 | 0.015 | 0.03 | 0.06 | 0.125 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 32 | 64 | >64 | ||
Gram-negative anaerobes | ||||||||||||||||
Bacteroides fragilis | 30 | 7 | 37 | 63 | 73 | 100 | ||||||||||
Bacteroides fragilis group, othera | 46 | 4 | 7 | 9 | 20 | 37 | 57 | 100 | ||||||||
Prevotella speciesb | 98 | 3.1 | 4.1 | 12 | 18 | 27 | 37 | 43 | 50 | 55 | 63 | 74 | 82 | 91 | 96 | 100 |
Porphyromonas speciesc | 31 | 13 | 71 | 81 | 84 | 87 | 90 | 100 | ||||||||
Fusobacterium nucleatum/Fusobacterium necrophorumd | 44 | 25 | 50 | 77 | 89 | 100 | ||||||||||
Fusobacterium mortiferum | 10 | 10 | 20 | 70 | 80 | 90 | 100 | |||||||||
Fusobacterium varium | 10 | 20 | 30 | 80 | 100 | |||||||||||
Veillonella species | 19 | 5 | 32 | 84 | 89 | 95 | 100 | |||||||||
Total | 288 | |||||||||||||||
Gram-positive anaerobes | ||||||||||||||||
All Gram-positive coccie | 127 | 10 | 20 | 30 | 47 | 61 | 82 | 92 | 96 | 97 | 98 | 100 | ||||
Propionibacterium and Actinomyces speciesf | 44 | 43 | 57 | 64 | 77 | 82 | 100 | |||||||||
Lactobacillus casei-Lactobacillus rhamnosus groupg | 10 | 20 | 80 | 90 | 100 | |||||||||||
Eggerthella lenta | 17 | 6 | 12 | 88 | 100 | |||||||||||
“Eubacterium” group, otherh | 25 | 8 | 20 | 28 | 92 | 100 | ||||||||||
Clostridium perfringens | 20 | 15 | 35 | 60 | 90 | 100 | ||||||||||
Clostridium ramosum | 21 | 90 | 100 | |||||||||||||
Clostridium innocuum | 21 | 29 | 67 | 95 | 100 | |||||||||||
Clostridium clostridioforme groupi | 20 | 15 | 35 | 80 | 100 | |||||||||||
Clostridium species, otherj | 24 | 4 | 8 | 21 | 46 | 54 | 67 | 75 | 83 | 100 | ||||||
Total | 329 |
5.
In Vitro Susceptibility of Clostridium difficile Isolates to Cefotaxime, Moxalactam, and Cefoperazone 下载免费PDF全文
Ronald A. Greenfield Terrence A. Kurzynski William A. Craig 《Antimicrobial agents and chemotherapy》1982,21(5):846-847
The in vitro susceptibility of 20 isolates of Clostridium difficile to cefotaxime, moxalactam, and cefoperazone was determined by a standard agar dilution method. The median minimal inhibitory concentrations were 64, 32, and 32 mug/ml for cefotaxime, moxalactam, and cefoperazone, respectively. 相似文献
6.
Butler MM Shinabarger DL Citron DM Kelly CP Dvoskin S Wright GE Feng H Tzipori S Bowlin TL 《Antimicrobial agents and chemotherapy》2012,56(9):4786-4792
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 near-normal weight gain in the treated animals. These selective anti-CDI features support the further development of MBX 500 for the treatment of CDI. 相似文献
7.
Jamie S. Huang Zhi-Dong Jiang Kevin W. Garey Todd Lasco Herbert L. DuPont 《Antimicrobial agents and chemotherapy》2013,57(6):2690-2693
The relationship between rifamycin drug use and the development of resistant strains of Clostridium difficile was studied at a large university hospital in Houston, TX, between May 2007 and September 2011. In 49 of 283 (17.3%) patients with C. difficile infection (CDI), a rifamycin-resistant strain of C. difficile was identified that compares to a rate of 8% using the same definitions in 2006-2007 (P = 0.59). The 49 patients infected by a resistant organism were matched by date of admission to 98 control patients with CDI from whom a rifamycin-susceptible C. difficile strain was isolated. Cases and controls did not differ according to demographic and clinical characteristics and showed similar but low rates of prior rifamycin use. Similar rates of rifamycin resistance were seen in cases of hospital-acquired CDI (38/112 [34%]) versus community-acquired CDI (7/20 [35%]). At a university hospital in which rifaximin was commonly used, infection by rifamycin-resistant strains of C. difficile was not shown to relate to prior use of a rifamycin drug or to acquiring the infection in the hospital, although the rate of overall resistance appeared to be rising. 相似文献
8.
Fran?ois Wasels Sarah A. Kuehne Stephen T. Cartman Patrizia Spigaglia Fabrizio Barbanti Nigel P. Minton Paola Mastrantonio 《Antimicrobial agents and chemotherapy》2015,59(3):1794-1796
Point mutations conferring resistance to fluoroquinolones were introduced in the gyr genes of the reference strain Clostridium difficile 630. Only mutants with the substitution Thr-82→Ile in GyrA, which characterizes the hypervirulent epidemic clone III/027/NAP1, were resistant to all fluoroquinolones tested. The absence of a fitness cost in vitro for the most frequent mutations detected in resistant clinical isolates suggests that resistance will be maintained even in the absence of antibiotic pressure. 相似文献
9.
Hans H. Locher Peter Seiler Xinhua Chen Susanne Schroeder Philippe Pfaff Michel Enderlin Axel Klenk Elvire Fournier Christian Hubschwerlen Daniel Ritz Ciaran P. Kelly Wolfgang Keck 《Antimicrobial agents and chemotherapy》2014,58(2):892-900
Clostridium difficile is a leading cause of health care-associated diarrhea with significant morbidity and mortality, and new options for the treatment of C. difficile-associated diarrhea (CDAD) are needed. Cadazolid is a new oxazolidinone-type antibiotic that is currently in clinical development for treatment of CDAD. Here, we report the in vitro and in vivo antibacterial evaluation of cadazolid against C. difficile. Cadazolid showed potent in vitro activity against C. difficile with a MIC range of 0.125 to 0.5 μg/ml, including strains resistant to linezolid and fluoroquinolones. In time-kill kinetics experiments, cadazolid showed a bactericidal effect against C. difficile isolates, with >99.9% killing in 24 h, and was more bactericidal than vancomycin. In contrast to metronidazole and vancomycin, cadazolid strongly inhibited de novo toxin A and B formation in stationary-phase cultures of toxigenic C. difficile. Cadazolid also inhibited C. difficile spore formation substantially at growth-inhibitory concentrations. In the hamster and mouse models for CDAD, cadazolid was active, conferring full protection from diarrhea and death with a potency similar to that of vancomycin. These findings support further investigations of cadazolid for the treatment of CDAD. 相似文献
10.
CT Mascio LI Mortin KT Howland AD Van Praagh S Zhang A Arya CL Chuong C Kang T Li JA Silverman 《Antimicrobial agents and chemotherapy》2012,56(10):5023-5030
CB-183,315 is a novel lipopeptide antibiotic structurally related to daptomycin currently in phase 3 clinical development for Clostridium difficile-associated diarrhea (CDAD). We report here the in vitro mechanism of action, spontaneous resistance incidence, resistance by serial passage, time-kill kinetics, postantibiotic effect, and efficacy of CB-183,315 in a hamster model of lethal infection. In vitro data showed that CB-183,315 dissipated the membrane potential of Staphylococcus aureus without inducing changes in membrane permeability to small molecules. The rate of spontaneous resistance to CB-183,315 at 8× the MIC was below the limit of detection in C. difficile. Under selective pressure by serial passage with CB-183,315 against C. difficile, the susceptibility of the bacteria changed no more than 2-fold during 15 days of serial passages. At 16× the MIC, CB-183,315 produced a ≥3-log reduction of C. difficile in the time-kill assay. The postantibiotic effect of CB-183,315 at 8× the MIC was 0.9 h. At 80× the MIC the postantibiotic effect was more than 6 h. In the hamster model of CDAD, CB-183,315 and vancomycin both demonstrated potent efficacy in resolving initial disease onset, even at very low doses. After the conclusion of dosing, CB-183,315 and vancomycin showed a similar dose- and time-dependent pattern with respect to rates of CDAD recurrence. 相似文献
11.
Ellie J. C. Goldstein Diane M. Citron Kerin L. Tyrrell 《Antimicrobial agents and chemotherapy》2014,58(2):1187-1191
We determined the comparative activity of SMT19969 (SMT) against 162 strains representing 35 well-characterized Clostridium species in clusters I to XIX and 13 Clostridium species that had no 16S rRNA match. SMT MICs ranged from 0.06 to >512 μg/ml and were not species related. SMT might have less impact on normal gut microbiota than other Clostridium difficile infection (CDI) antimicrobials. 相似文献
12.
Patrizia Spigaglia Fabrizio Barbanti Thomas Louie Frédéric Barbut Paola Mastrantonio 《Antimicrobial agents and chemotherapy》2009,53(6):2463-2468
Recent studies have suggested that exposure to fluoroquinolones represents a risk factor for the development of Clostridium difficile infections and that the acquisition of resistance to the newer fluoroquinolones is the major reason facilitating wide dissemination. In particular, moxifloxacin (MX) and levofloxacin (LE) have been recently associated with outbreaks caused by the C. difficile toxinotype III/PCR ribotype 027/pulsed-field gel electrophoresis type NAP1 strain. In this study, we evaluated the potential of MX and LE in the in vitro development of fluoroquinolone resistance mediated by GyrA and GyrB alterations. Resistant mutants were obtained from five C. difficile parent strains, susceptible to MX, LE, and gatifloxacin (GA) and belonging to different toxinotypes, by selection in the presence of increasing concentrations of MX and LE. Stable mutants showing substitutions in GyrA and/or GyrB were obtained from the parent strains after selection by both antibiotics. Mutants had MICs ranging from 8 to 128 μg/ml for MX, from 8 to 256 μg/ml for LE, and from 1.5 to ≥32 μg/ml for GA. The frequency of mutation ranged from 3.8 × 10−6 to 6.6 × 10−5 for MX and from 1.0 × 10−6 to 2.4 × 10−5 for LE. In total, six different substitutions in GyrA and five in GyrB were observed in this study. The majority of these substitutions has already been described for clinical isolates or has occurred at positions known to be involved in fluoroquinolone resistance. In particular, the substitution Thr82 to Ile in GyrA, the most common found in resistant C. difficile clinical isolates, was observed after selection with LE, whereas the substitution Asp426 to Val in GyrB, recently described in toxin A-negative/toxin B-positive epidemic strains, was observed after selection with MX. Interestingly, a reduced susceptibility to fluoroquinolones was observed in colonies isolated after the first and second steps of selection by both MX and LE, with no substitution in GyrA or GyrB. The results suggest a relevant role of fluoroquinolones in the emergence and selection of fluoroquinolone-resistant C. difficile strains also in vivo.Recent outbreaks of Clostridium difficile infections (CDI), with increased severity, high relapse rates, and significant mortality, have been related to the emergence of the hypervirulent C. difficile clone toxinotype III/PCR ribotype 027/pulsed-field gel electrophoresis type NAP1 (5, 23, 25-29, 31). Several studies have suggested that exposure to fluoroquinolones represents a risk factor for the development of CDI caused by C. difficile III/027/NAP1 and that the acquisition of resistance to the newer fluoroquinolones could have promoted its wide dissemination (6, 17, 30, 32-34).Fluoroquinolones are a family of broad-spectrum antibiotics extensively used in the treatment of a great variety of human infections. The in vitro activity of the older fluoroquinolones, such as ciprofloxacin, has been reported to be moderate or poor against anaerobes, including C. difficile (3, 8), whereas the third and the fourth generations of fluoroquinolones are characterized by improved activity against gram-positive cocci and anaerobic bacteria (19, 36). Fluoroquinolones act by inhibiting the action of DNA gyrase and topoisomerase IV, which are related but distinct enzymes involved in DNA synthesis (18). The mechanisms of resistance to fluoroquinolones in bacteria are basically two: (i) alterations in the targets of fluoroquinolones and (ii) decreased accumulation inside the bacteria due to impermeability of the membrane and/or an overexpression of efflux pump systems (19, 20, 36). The first mechanism of resistance is widespread in many bacteria, and it is due to amino acid substitutions in the quinolone-resistance determining region (QRDR) of the target enzymes (35). This is the principal mechanism of resistance also in C. difficile, and since, as already observed in other species, this bacterium does not have genes for topoisomerase IV, resistance is determined by alterations in the QRDR of either DNA gyrase subunit GyrA or GyrB (10, 38).Different amino acid substitutions have been identified in GyrA and GyrB in fluoroquinolone-resistant C. difficile strains. The most frequent is the amino acid change Thr82 to Ile in GyrA, which also characterizes the epidemic clone III/027/NAP1 (11, 38). Two other GyrA substitutions, Asp71 to Val and Ala118 to Thr, have been more rarely observed (1, 2, 10, 12, 38). Four different amino acid substitutions have been identified in GyrB: Arg447 to Lys, Arg447 to Leu, Asp426 to Asn, and Asp426 to Val (10, 11, 38). In particular, Asp426 to Val has been described in toxin A-negative/toxin B-positive C. difficile epidemic strains of recent isolation (11).In this study, we evaluated the potential of moxifloxacin (MX) and levofloxacin (LE), recently associated with outbreaks caused by C. difficile III/027/NAP1 (25, 31, 33), for the in vitro development of fluoroquinolone resistance mediated by GyrA and GyrB alterations in five different susceptible C. difficile strains. The sequence changes occurring in the QRDR of the derived fluoroquinolone-resistant mutants were analyzed and correlated with the in vitro resistance to MX, LE, and gatifloxacin (GA), another fluoroquinolone recently involved in C. difficile outbreaks (17, 33). 相似文献
13.
Effects of Subinhibitory Concentrations of Antibiotics on Colonization Factor Expression by Moxifloxacin-Susceptible and Moxifloxacin-Resistant Clostridium difficile Strains 下载免费PDF全文
Cécile Denève Sylvie Bouttier Bruno Dupuy Frédéric Barbut Anne Collignon Claire Janoir 《Antimicrobial agents and chemotherapy》2009,53(12):5155-5162
14.
We have used the hamster model of antibiotic-induced Clostridium difficile intestinal disease to evaluate nitazoxanide (NTZ), a nitrothiazole benzamide antimicrobial agent. The following in vitro and in vivo activities of NTZ in the adult hamster were examined and compared to those of metronidazole and vancomycin: (i) MICs and minimum bactericidal concentrations (MBCs) against C. difficile, (ii) toxicity, (iii) ability to prevent C. difficile-associated ileocecitis, and (iv) propensity to induce C. difficile-associated ileocecitis. The MICs and MBCs of NTZ against 15 toxigenic strains of C. difficile were comparable to those of vancomycin or metronidazole. C. difficile-associated ileocecitis was induced with oral clindamycin and toxigenic C. difficile in a group of 60 hamsters. Subgroups of 10 hamsters were given six daily intragastric treatments of NTZ (15, 7.5, and 3.0 mg/100 g of body weight [gbw]), metronidazole (15 mg/100 gbw), vancomycin (5 mg/100 gbw), or saline (1 ml/100 gbw). Animals receiving saline died 3 days post-C. difficile challenge. During the treatment period, NTZ (>/=7.5 mg/100 gbw), like metronidazole and vancomycin, prevented outward manifestations of clindamycin-induced C. difficile intestinal disease. Six of ten hamsters on a scheduled dose of 3.0 mg of NTZ/100 gbw survived for the complete treatment period. Of these surviving animals, all but three died of C. difficile disease by between 3 and 12 days following discontinuation of antibiotic therapy. Another group of hamsters received six similar daily doses of the three antibiotics, followed by an inoculation with toxigenic C. difficile. All of the NTZ-treated animals survived the 15-day postinfection period. Upon necropsy, all hamsters appeared normal: there were no gross signs of toxicity or C. difficile intestinal disease, nor was C. difficile detected in the cultures of the ceca of these animals. By contrast, vancomycin and metronidazole treatment induced fatal C. difficile intestinal disease in 20 and 70% of recipients, respectively. 相似文献
15.
Carmela T. M. Mascio Laurent Chesnel Grace Thorne Jared A. Silverman 《Antimicrobial agents and chemotherapy》2014,58(7):3976-3982
Surotomycin (CB-183,315) is an orally administered, minimally absorbed, selective bactericidal cyclic lipopeptide in phase 3 development for the treatment of Clostridium difficile-associated diarrhea. The aim of this study was to evaluate the emergence of resistance in C. difficile (ATCC 700057 and three recent clinical isolates from the restriction endonuclease analysis groups BI, BK, and K), vancomycin-susceptible (VS) Enterococcus faecalis (ATCC 49452), vancomycin-resistant (VR) E. faecalis (ATCC 700802), VS Enterococcus faecium (ATCC 6569), and VR E. faecium (ATCC 51559) under anaerobic conditions. The rate of spontaneous resistance was below the limit of detection (<10−8 to <10−9) for surotomycin at 16 and 32× the MIC for all isolates tested. Under selective pressure by serial passage, C. difficile grew in a maximum of 4 μg/ml surotomycin (final MICs of 2 to 8 μg/ml [4- to 16-fold higher than those of the naive control]) at day 15, with the exception of the C. difficile BK strain, which grew in 16 to 32 μg/ml (final MICs of 8 to 32 μg/ml [16- to 64-fold higher than those of the naive control]). Enterococci remained relatively unchanged over 15 days, growing in a maximum of 8 μg/ml surotomycin (final MICs of 2 to 16 μg/ml [8- to 64-fold higher than those of the naive control]). Of the isolates tested, no cross-resistance to vancomycin, rifampin, ampicillin, metronidazole, or moxifloxacin was observed. Surotomycin at 20× MIC demonstrated equally rapid bactericidal activity (≥3-log-unit reduction in CFU/ml in ≤8 h) against naive and reduced-susceptibility isolates of C. difficile, VS Enterococcus (VSE), and VR Enterococcus (VRE), except for C. difficile BK (2.6-log-unit reductions for both). These results suggest that emergence of resistance to surotomycin against C. difficile, E. faecalis, and E. faecium is likely to be rare. 相似文献
16.
P N Levett 《The Journal of antimicrobial chemotherapy》1991,27(1):55-62
Killing of Clostridium difficile by metronidazole and vancomycin was studied with a batch culture method. Pre-reduced 50 ml volumes of brain heart infusion broth containing one of a range of concentrations of either vancomycin or metronidazole were inoculated with approximately 10(6) cfu/ml of C. difficile. The cultures were incubated anaerobically at 35 degrees C for 24 h. Total viable counts and spore counts were performed with a modified Miles and Misra technique. Concentrations of metronidazole and vancomycin below the respective MICs had no effect on the growth of C. difficile. A significant reduction in numbers of vegetative cells and spores occurred in the presence of concentrations of both agents close to their respective MICs. A bacteriostatic effect was observed when vancomycin concentrations similar to those occurring in faeces following oral administration of the drug were used. In contrast, rapid killing of vegetative cells occurred over a wide range of metronidazole concentrations greater than the MIC. 相似文献
17.
Raul C. Rudoy John D. Nelson Kenneth C. Haltalin 《Antimicrobial agents and chemotherapy》1974,5(5):439-443
Trimethoprim and sulfamethoxazole were tested alone and in combination against 227 recently isolated Shigella strains. Variations in medium constituents and inoculum size were used to determine the optimal testing conditions. The plate dilution method with addition of 5% lysed horse blood to the susceptibility test medium and an inoculum size of 10(2) organisms was found to provide satisfactory results. All 227 strains were inhibited by low concentrations of trimethoprim, and all were susceptible to the combination of 0.06 mug of trimethoprim per ml and 1.25 mug of sulfamethoxazole per ml. Sixteen percent of these strains were resistant to ampicillin, 33% to tetracycline, 15% to chloramphenicol, and 27% to cephalothin. Based on these in vitro observations, trimethoprim and sulfamethoxazole appear worth evaluating for treatment of shigellosis due to multiply antibiotic-resistant strains. 相似文献
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Frdric Barbut Dominique Decr Batrice Burghoffer Danile Lesage Franoise Delisle Valrie Lalande Michel Delme Vronique Avesani Nassita Sano Cyril Coudert Jean-Claude Petit 《Antimicrobial agents and chemotherapy》1999,43(11):2607-2611
Glycopeptides (vancomycin and teicoplanin) and metronidazole are the drugs of choice for the treatment of Clostridium difficile infections, but trends in susceptibility patterns have not been assessed in the past few years. The objective was to study the MICs of glycopeptides and metronidazole for unrelated C. difficile strains isolated in 1991 (n = 100) and in 1997 (n = 98) by the agar macrodilution, the E-test, and the disk diffusion methods. Strain susceptibilities to erythromycin, clindamycin, tetracycline, rifampin, and chloramphenicol were also determined by the ATB ANA gallery (bioMérieux, La Balme-les-Grottes, France). The MICs at which 50% of isolates are inhibited (MIC(50)s) and MIC(90)s of glycopeptides and metronidazole remained stable between 1991 and 1997. All the strains were inhibited by concentrations that did not exceed 2 microgram/ml for vancomycin and 1 microg/ml for teicoplanin. Comparison of MICs determined by the agar dilution method recommended by the National Committee for Clinical Laboratory Standards and the E test showed correlations (+/-2 dilutions) of 86. 6, 95.9, and 99% for metronidazole, vancomycin, and teicoplanin, respectively. The E test always underestimated the MICs. Strains with decreased susceptibility to metronidazole (MICs, >/=8 microgram/ml) were isolated from six patients (n = 4 in 1991 and n = 2 in 1997). These strains were also detected by the disk diffusion method (zone inhibition diameter, =21 mm); they belonged to nontoxigenic serogroup D (n = 5) and toxigenic serogroup H (n = 1). Decreased susceptibility to erythromycin (MICs, >/=1 microgram/ml), clindamycin (MICs, >/=2 microgram/ml), tetracycline (MICs, >/=8 microgram/ml), rifampin (MICs, >/=4 microgram/ml), and chloramphenicol (MICs, >/=16 microgram/ml) was observed in 64.2, 80.3, 23.7, 22.7, and 14.6% of strains, respectively. Strains isolated in 1997 were more susceptible than those isolated in 1991, and this trend was correlated to a major change in serogroup distribution. Periodic studies are needed in order to detect changes in serogroups and the emergence of strains with decreased susceptibility to therapeutic drugs. 相似文献
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In vitro susceptibility of Clostridium difficile to new beta-lactam and quinolone antibiotics. 下载免费PDF全文
The in vitro susceptibilities of 34 to 73 clinical isolates of Clostridium difficile to 24 antimicrobial agents, including 18 beta-lactams, 4 fluoroquinolones, clindamycin, and metronidazole were examined. Metronidazole was the most active (MIC for 90% of the isolates [MIC90], 0.5 microgram/ml), followed by the carbapenems (Sch 34343, 4 micrograms/ml; imipenem, 8 micrograms/ml) and the antipseudomonas penicillins (piperacillin, 8 micrograms/ml; ticarcillin, 32 micrograms/ml; carbenicillin, 32 micrograms/ml). A monobactam (aztreonam) and most cephalosporins were either highly inactive (cefoxitin, cefuroxime, cefotiam, cefsulodin, ceftizoxime, cefbuperazone, and cefotaxime), with an MIC90 of greater than or equal to 128 micrograms/ml, or moderately inactive (ceftriaxone, cefmenoxime, cefoperazone, ceftazidime, and moxalactam), with an MIC90 of greater than or equal to 32 micrograms/ml. Clindamycin (MIC90, 32 micrograms/ml) and the fluoroquinolones (ciprofloxacin, 8 micrograms/ml; A-56619, 8 micrograms/ml; A-56620, 8 micrograms/ml; norfloxacin, 32 micrograms/ml) were only variably active. These in vitro data per se may not necessarily predict the relative risks for C. difficile-associated diarrhea or colitis during therapy with these agents. However, these data, in concert with knowledge of drug bioavailability in feces and the broad-spectrum antimicrobial activity on the resident bowel flora, may provide additional insight into the mechanisms and predictability of this complication with these agents. Careful monitoring for the emergence of C. difficile and fecal cytotoxin and for diarrhea during therapy with these agents is clearly indicated. 相似文献