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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.
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.
This study was supported by Forest Laboratories, Inc. Scientific Therapeutics Information, Inc., provided editorial assistance that was funded by Forest Laboratories, Inc.
Published ahead of print on 25 January 2010.