Abstract
More than 5 million Americans are bitten by animals, usually dogs, annually. Bite patients comprise ∼1% of all patients who visit emergency departments (300,000/year), and approximately 10,000 require hospitalization and intravenous antibiotics. Ceftaroline is the bioactive component of the prodrug ceftaroline fosamil, which is FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs), including those containing methicillin-resistant Staphylococcus aureus (MRSA). There are no in vitro data about the activity of ceftaroline against Pasteurella multocida subsp. multocida and Pasteurella multocida subsp. septica, other Pasteurella spp., or other bite wound isolates. We therefore studied the in vitro activity of ceftaroline against 243 animal bite isolates. MICs were determined using the broth microdilution method according to CLSI guidelines. Comparator drugs included cefazolin, ceftriaxone, ertapenem, ampicillin-sulbactam, azithromycin, doxycycline, and sulfamethoxazole-trimethoprim (SMX-TMP). Ceftaroline was the most active agent against all 5 Pasteurella species, including P. multocida subsp. multocida and P. multocida subsp. septica, with a maximum MIC of ≤0.008 μg/ml; more active than ceftriaxone and ertapenem (MIC90s, ≤0.015 μg/ml); and more active than cefazolin (MIC90, 0.5 μg/ml) doxycycline (MIC90, 0.125 μg/ml), azithromycin (MIC90, 0.5 μg/ml), ampicillin-sulbactam (MIC90, 0.125 μg/ml), and SMX-TMP (MIC90, 0.125 μg/ml). Ceftaroline was also very active against all S. aureus isolates (MIC90, 0.125 μg/ml) and other Staphylococcus and Streptococcus species, with a maximum MIC of 0.125 μg/ml against all bite isolates tested. Ceftaroline has potential clinical utility against infections involving P. multocida, other Pasteurella species, and aerobic Gram-positive isolates, including S. aureus.
INTRODUCTION
In 2011, the Humane Society of the United States estimated that 78.2 million dogs and 86.4 million cats were kept as pets in 62% of American households (19). Bites occur in 4.7 million Americans yearly, which extrapolates to one of every two Americans being bitten in their lifetime, usually by a dog (14–16). Animal bite wounds account for 800,000 medical visits annually and comprise the reason for approximately 1% of all emergency department visits (29). It has been estimated that 3 to 18% of dog bites and 28 to 80% of cat bites will become infected (29). Of the 300,000 bite patients who visit an emergency department, approximately 10,000 will require hospitalization and intravenous antibiotics (24, 27). Bite wounds that require attention are often those to the extremities, especially the person's dominant hand, and those caused by larger dogs, which can exert more than 450 pounds/inch2 of pressure with their jaws, leading to extensive crush injury (14, 15, 18, 27).
While there are a plethora of bacteria isolated from animal bite wounds (2, 27), Pasteurella species are present in 75% of infected cat bite wounds (Pasteurella multocida subsp. multocida in 54%, P. multocida subsp. septica in 28%) and in 50% of infected dog bite wounds (P. canis in 50%, P. multocida subsp. multocida in 12%, P. multocida subsp. septica in 10%) (27). However, the emergence of methicillin-resistant Staphylococcus aureus (MRSA; USA300 clone) in infections shared between pets and human handlers (22) raises the issue of whether treatment of severe animal bite wounds requires MRSA coverage. Currently recommended regimens include amoxicillin-clavulanate orally and ampicillin-sulbactam, carbapenems, and cefoxitin intravenously (26), but all of these lack activity against MRSA.
Ceftaroline fosamil is FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs), including those containing MRSA. There are scant data about the activity of ceftaroline against Pasteurella multocida subsp. multocida and P. multocida subsp. septica, other Pasteurella spp., or other bite isolates. Ge et al. (13) reported the in vitro activity of ceftaroline against 22 P. multocida isolates whose subspecies were not determined and found it to have good activity. As there are no data about the activity of ceftaroline against the specific Pasteurella species, including Pasteurella multocida subsp. multocida, P. multocida subsp. septica, P. dagmatis, P. canis, P. stomatis, or other Pasteurella spp., or its activity against other bite isolates, including Staphylococcus spp. and Streptococcus spp., we therefore studied the in vitro activity of ceftaroline against 243 animal bite isolates, including 156 Pasteurella strains.
MATERIALS AND METHODS
Bacterial strains.
The organisms were recovered from human clinical samples, identified by standard methods (21), and stored in 20% skim milk at −70°C. They were taken from the freezer and transferred at least twice on blood agar to ensure purity and good growth.
Broth dilution tests.
Broth microdilution trays were prepared in-house using a Quick-Spense apparatus (100 μl/well; Sandy Spring Instrument Co. Inc., Germantown, MD) and frozen at −70°C until use. Cell paste from 48-h cultures was suspended in brucella broth, further diluted in 8.5% saline, and added to the trays with an inoculator device for a final concentration of 1 × 105 to 5 × 105 CFU/ml. Trays for Pasteurella and streptococci were supplemented with 3% lysed horse blood. Colony counts were determined on every 10th panel.
All testing was conducted according to procedures in the CLSI M7-A9 and M45-A2 documents (7, 8). Control organisms included P. multocida subsp. multocida ATCC 12947, P. multocida subsp. septica ATCC 51688, Escherichia coli ATCC 25922, and S. aureus ATCC 29213.
Drugs included ceftaroline, cefazolin, ceftriaxone, ertapenem, ampicillin-sulbactam, azithromycin, doxycycline, and sulfamethoxazole-trimethoprim (SMX-TMP), which are commonly used in the treatment of ABSSSIs. Ceftaroline was obtained from Cerexa Pharmaceuticals, and other drugs were obtained from Sigma (St. Louis MO) or USP (Rockville, MD) and reconstituted according to the manufacturers' instructions.
The MIC was defined as the lowest concentration that yielded no visible growth.
RESULTS
Results of the comparative in vitro activity of ceftaroline against the study isolates are shown in Table 1. Ceftaroline was the most active agent against all 5 Pasteurella species, including P. multocida subsp. multocida and P. multocida subsp. septica, with a maximum MIC of ≤0.008 μg/ml. It was more active than ceftriaxone and ertapenem (MIC90s, ≤0.015 μg/ml) and more active than cefazolin (MIC90, 0.5 μg/ml), doxycycline (MIC90, 0.125 μg/ml), azithromycin (MIC90, 0.5 μg/ml), ampicillin-sulbactam (MIC90, 0.125 μg/ml), and SMX-TMP (MIC90, 0.125 μg/ml). Ceftaroline was also very active against all S. aureus isolates (MIC90, 0.125 μg/ml) and other Staphylococcus and Streptococcus species, with a maximum MIC of 0.125 μg/ml against all bite isolates tested.
Table 1.
Comparative in vitro activity of ceftaroline and 7 other agents against 243 animal bite wound isolates, including 156 Pasteurella speciesa
| Organism (no. of isolates) | Agent | MIC (μg/ml) |
||
|---|---|---|---|---|
| Range | 50% | 90% | ||
| P. canis (23) | Ceftaroline | ≤0.008 | ≤0.008 | ≤0.008 |
| Cefazolin | 0.06–0.5 | 0.25 | 0.5 | |
| Ceftriaxone | ≤0.015 | ≤0.015 | ≤0.015 | |
| Ampicillin-sulbactam | ≤0.015–0.125 | 0.03 | 0.06 | |
| Ertapenem | ≤0.015 | ≤0.015 | ≤0.015 | |
| Azithromycin | 0.06–0.125 | 0.125 | 0.125 | |
| Doxycycline | 0.06–0.125 | 0.125 | 0.125 | |
| SMX-TMP | 0.03–0.125 | 0.03 | 0.06 | |
| P. dagmatis (13) | Ceftaroline | ≤0.008 | ≤0.008 | ≤0.008 |
| Cefazolin | 0.125–0.5 | 0.25 | 0.5 | |
| Ceftriaxone | ≤0.015 | ≤0.015 | ≤0.015 | |
| Ampicillin-sulbactam | 0.03–0.06 | 0.06 | 0.06 | |
| Ertapenem | ≤0.015 | ≤0.015 | ≤0.015 | |
| Azithromycin | 0.03–0.125 | 0.06 | 0.06 | |
| Doxycycline | 0.125 | 0.125 | 0.125 | |
| SMX-TMP | 0.03–0.125 | 0.06 | 0.06 | |
| P. stomatis (20) | Ceftaroline | ≤0.008 | ≤0.008 | ≤0.008 |
| Cefazolin | 0.125–0.5 | 0.25 | 0.5 | |
| Ceftriaxone | ≤0.015 | ≤0.015 | ≤0.015 | |
| Ampicillin-sulbactam | 0.03–0.06 | 0.06 | 0.06 | |
| Ertapenem | ≤0.015 | ≤0.015 | ≤0.015 | |
| Azithromycin | 0.03–0.125 | 0.06 | 0.06 | |
| Doxycycline | 0.125 | 0.125 | 0.125 | |
| SMX-TMP | 0.03–0.125 | 0.06 | 0.06 | |
| P. multocida subsp. multocida (50) | Ceftaroline | ≤0.008 | ≤0.008 | ≤0.008 |
| Cefazolin | 0.06–1 | 0.5 | 0.5 | |
| Ceftriaxone | ≤0.015 | ≤0.015 | ≤0.015 | |
| Ampicillin-sulbactam | ≤0.015–0.125 | 0.06 | 0.125 | |
| Ertapenem | ≤0.015–0.03 | ≤0.015 | ≤0.015 | |
| Azithromycin | 0.03–1 | 0.25 | 1 | |
| Doxycycline | 0.06–0.5 | 0.125 | 0.125 | |
| SMX-TMP | 0.015–0.125 | 0.06 | 0.125 | |
| P. multocida subsp. septica (50) | Ceftaroline | ≤0.008 | ≤0.008 | ≤0.008 |
| Cefazolin | 0.125–1 | 0.5 | 0.5 | |
| Ceftriaxone | ≤0.015–0.6 | ≤0.015 | ≤0.015 | |
| Ampicillin-sulbactam | 0.03–0.125 | 0.125 | 0.125 | |
| Ertapenem | ≤0.015 | ≤0.015 | ≤0.015 | |
| Azithromycin | 0.03–1 | 0.125 | 1 | |
| Doxycycline | 0.06–0.25 | 0.125 | 0.125 | |
| SMX-TMP | 0.015–0.25 | 0.06 | 0.125 | |
| S. aureus (30) | Ceftaroline | 0.06–0.25 | 0.125 | 0.125 |
| Cefazolin | 0.06–2 | 0.5 | 0.5 | |
| Ceftriaxone | 1–16 | 2 | 2 | |
| Ampicillin-sulbactam | ≤0.015–1 | 0.5 | 1 | |
| Ertapenem | 0.06–0.5 | 0.06 | 0.125 | |
| Azithromycin | 1–2 | 2 | 2 | |
| Doxycycline | 0.03–2 | 0.06 | 0.125 | |
| SMX-TMP | 0.06–0.125 | 0.06 | 0.125 | |
| S. epidermidis (12) | Ceftaroline | 0.03–0.125 | 0.03 | 0.125 |
| Cefazolin | 0.125–4 | 0.25 | 4 | |
| Ceftriaxone | 1–>16 | 1 | 16 | |
| Ampicillin-sulbactam | 0.015–2 | 0.125 | 1 | |
| Ertapenem | 0.06–8 | 0.125 | 2 | |
| Azithromycin | 2 | 2 | 2 | |
| Doxycycline | 0.06–8 | 0.125 | 1 | |
| SMX-TMP | 0.06–8 | 0.125 | 0.25 | |
| Staphylococcus speciesb (15) | Ceftaroline | 0.015–0.125 | 0.06 | 0.06 |
| Cefazolin | 0.06–16 | 0.25 | 1 | |
| Ceftriaxone | 1–16 | 2 | 4 | |
| Ampicillin-sulbactam | 0.03–1 | 0.06 | 0.5 | |
| Ertapenem | 0.06–1 | 0.125 | 0.125 | |
| Azithromycin | 1–4 | 2 | 2 | |
| Doxycycline | 0.03–2 | 0.06 | 0.125 | |
| SMX-TMP | 0.06–0.25 | 0.125 | 0.25 | |
| Streptococcus sanguis (10) | Ceftaroline | ≤0.008–0.015 | ≤0.008 | 0.015 |
| Cefazolin | 0.06–0.5 | 0.25 | 0.5 | |
| Ceftriaxone | 0.03–0.5 | 0.125 | 0.25 | |
| Ampicillin-sulbactam | 0.015–0.06 | 0.03 | 0.06 | |
| Ertapenem | 0.03–0.125 | 0.03 | 0.06 | |
| Azithromycin | 0.015–1 | 0.06 | 1 | |
| Doxycycline | 0.06–8 | 0.125 | 4 | |
| SMX-TMP | ≤0.008–0.06 | 0.03 | 0.06 | |
| Streptococcus intermedius (10) | Ceftaroline | ≤0.008–0.015 | ≤0.008 | 0.015 |
| Cefazolin | 0.125–1 | 0.25 | 1 | |
| Ceftriaxone | 0.06–0.25 | 0.125 | 0.25 | |
| Ampicillin-sulbactam | 0.015–0.25 | 0.03 | 0.06 | |
| Ertapenem | ≤0.015–0.25 | 0.03 | 0.06 | |
| Azithromycin | ≤0.008–1 | 0.06 | 0.5 | |
| Doxycycline | 0.03–8 | 0.06 | 0.125 | |
| SMX-TMP | 0.015–2 | 0.06 | 1 | |
| Streptococcus mitis (10) | Ceftaroline | ≤0.008–0.03 | 0.015 | 0.015 |
| Cefazolin | 0.03–2 | 0.5 | 2 | |
| Ceftriaxone | 0.125–1 | 0.25 | 0.5 | |
| Ampicillin-sulbactam | ≤0.008–1 | 0.125 | 0.25 | |
| Ertapenem | ≤0.015–0.25 | 0.125 | 0.125 | |
| Azithromycin | 0.03–1 | 0.06 | 1 | |
| Doxycycline | 0.06–2 | 0.125 | 1 | |
| SMX-TMP | 0.25–>8 | 1 | 8 | |
The quality control strains for ceftaroline were P. multocida subsp. multocida ATCC 12947 and P. multocida subsp. septica ATCC 51688.
Staphylococcus species included S. cohnii (n = 2), S. pseudintermedius (n = 5), S. felis (n = 1), and S. warneri (n = 7).
The quality control strains P. multocida subsp. multocida ATCC 12947 and P. multocida subsp. septica ATCC 51688 were each run three times, and the ceftaroline MIC was ≤0.008 μg/ml on each occasion.
DISCUSSION
The antimicrobials selected for therapy of infected animal bite wounds must have activity against the components of the biting animals' oral flora, including P. multocida and its subspecies. The susceptibility of P. multocida can be problematic to the clinician, as the in vitro susceptibility of oral cephalosporins cannot be inferred from their susceptibility to intravenous cefazolin (17). In addition, dogs and cats can harbor MRSA in their nasal passages and orally (1, 20). The transmission of epidemic, potentially invasive MRSA clones between companion animals such as dogs and cats and their owners, household members, and veterinarians has been increasingly reported (4, 10). Consequently, the potential for MRSA to be a component of infected animal bite wounds is cause for concern (22). Currently recommended regimens (26) do not include agents with coverage against MRSA, and clinical regimens for bite wounds with coverage against MRSA have not, to our knowledge, been reported. With up to 20% of the population being colonized with MRSA, the potential for MRSA to be introduced via the victims' own skin flora also needs to be considered.
Ceftaroline fosamil was FDA approved in October 2010 for the treatment of ABSSSIs, including those containing MRSA, but scant data about its activity against P. multocida, other Pasteurella species, and animal bite isolates in general exist. Ge et al. (13) reported ceftaroline to be active in vitro against 22 Pasteurella multocida isolates form Luxembourg but gave few clinical data about their source. Our in vitro study suggests that ceftaroline has excellent activity against all Pasteurella strains (all isolates were susceptible to ≤0.06 μg/ml), including P. multocida subsp. multocida, P. multocida subsp. septica, P. canis, P. dagmatis, and P. stomatis. Ceftaroline was also very active against all the S. aureus strains (all isolates were susceptible to ≤0.25 μg/ml), Staphylococcus epidermidis, Staphylococcus intermedius, and Staphylococcus warneri strains (all isolates were susceptible to ≤0.125 μg/ml), and streptococci (all isolates were susceptible to ≤0.03 μg/ml). These MIC values compared favorably to those of all the other study agents. Ceftaroline has variable activity against anaerobic bacteria (6), with good activity against anaerobic Gram-positive cocci and beta-lactamase-negative Gram-negative bacilli but poor activity against the Bacteroides fragilis group, which are rare animal bite pathogens (27).
S. intermedius is a coagulase-positive Staphylococcus species that is part of the canine oral flora and has been isolated from infected dog bite wounds (28). It was isolated from 39% of 135 gingival cultures from indoor canine breeds, which frequently weighed <40 lb, while S. aureus was isolated from larger (weight, >40 lb) outdoor working breeds (28). S. intermedius can yield a false-positive rapid penicillin binding protein 2a latex agglutination test and can be misidentified as MRSA (23). Adding to the confusion among canine isolates is the description of methicillin-resistant S. pseudintermedius (3, 5, 12), which has emerged as a worldwide veterinary canine pathogen. Our in vitro data show ceftaroline to have good activity against S. pseudintermedius.
Our results with the more typical Gram-positive cocci studied are similar to those previously reported (11, 13, 25). Azithromycin, which has an FDA indication for the treatment of uncomplicated skin and soft tissue infections and has a breakpoint of ≤1 μg/ml for P. multocida (8), had an MIC90 of 1 μg/ml against P. multocida subsp. multocida and one of 0.5 μg/ml against P. multocida subsp. septica. The MIC breakpoint for azithromycin against staphylococci is ≤1 μg/ml by EUCAST standards (9) and ≤2 μg/ml by CLSI standards, and the MIC90 for all our staphylococcal strains tested was 2 μg/ml, suggesting some caution in its use for the treatment of infected animal bite wounds.
Ceftaroline has potential clinical utility against infections involving P. multocida, other Pasteurella species, and aerobic Gram-positive isolates, including S. aureus.
ACKNOWLEDGMENTS
This study was supported by a grant from Forest Laboratories.
We thank Eliza Leoncio for excellent technical assistance and Alice E. Goldstein for various forms of assistance.
Footnotes
Published ahead of print 1 October 2012
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