Abstract
The activity of gatifloxacin against 308 aerobes and 112 anaerobes isolated from bite wound infections was studied. Gatifloxacin was active at ≤0.016 μg/ml against all 148 Pasteurella isolates (eight species and three subspecies) tested and all other aerobes tested, including Actinobacillus-Haemophilus spp., Eikenella corrodens, Neisseria weaveri, Weeksella zoohelcum, staphylococci, and streptococci. Fusobacteria were sometimes resistant. Gatifloxacin MICs at which 90% of the isolates were inhibited were 0.125 μg/ml against Bacteroides tectum and Prevotella spp., 0.25 μg/ml against Porphyromonas spp., and 0.5 μg/ml against peptostreptococci.
Approximately 5 million Americans are bitten annually by animals (2, 7, 21, 25), and many bites become infected with a wide variety of fastidious aerobic bacteria and anaerobic veterinary bacteria (1, 3, 4, 8, 15, 20, 25). These unusual isolates are not included in published susceptibility testing surveys of newer antimicrobial compounds (9, 10). A clinician must rely on published studies to guide both empirical and subsequent specific antimicrobial therapeutic choices.
Gatifloxacin (BMS-206584; AM-1155) is a new 8-methoxy fluoroquinolone [1-cyclopropyl-6-fluoro-1,4-dihydro-8-meth-oxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid) with R and S enantiomers that have identical pharmacokinetics after oral and intravenous administration and a broad spectrum of activity (5, 13, 14, 26). In order to determine its activity against various pathogenic species, we compared the susceptibilities of 420 recent clinical bite wound isolates to gatifloxacin and five other fluoroquinolones.
The strains were previously isolated from bite wounds and identified by standard criteria (11, 12, 16, 17, 24). The specific bite sources (n) were dogs (146), cats (208), humans (23), and other (24). Twelve bovine respiratory strains, especially Pasteurella haemolytica, were included for comparative purposes; 7 American Type Culture Collection (ATCC) strains and 6 control strains were also tested. The numbers and species of isolates tested are shown in Table 1.
TABLE 1.
Comparative in vitro activities of gatifloxacin, levofloxacin, trovafloxacin, sparfloxacin, ciprofloxacin, grepafloxacin, and amoxicillin-clavulanate against 420 aerobic and anaerobic skin and soft tissue animal and human bite wound pathogens
| Organism (no. of isolates) | Agent | MIC (μg/ml)
|
||
|---|---|---|---|---|
| Range | 50% | 90% | ||
| Pasteurella multocida subsp. multocida (30) | Gatifloxacin | 0.008–0.03 | 0.016 | 0.016 |
| Levofloxacin | 0.008–0.03 | 0.016 | 0.03 | |
| Trovafloxacin | 0.008–0.03 | 0.016 | 0.016 | |
| Sparfloxacin | 0.004–0.008 | 0.008 | 0.008 | |
| Ciprofloxacin | 0.004–0.03 | 0.016 | 0.016 | |
| Grepafloxacin | 0.004–0.008 | 0.004 | 0.008 | |
| Amoxicillin-clavulanate | 0.06–0.25 | 0.25 | 0.25 | |
| Pasteurella multocida subsp. septica (43) | Gatifloxacin | 0.008–0.03 | 0.016 | 0.016 |
| Levofloxacin | 0.008–0.03 | 0.016 | 0.03 | |
| Trovafloxacin | 0.004–0.016 | 0.008 | 0.016 | |
| Sparfloxacin | 0.002–0.016 | 0.008 | 0.016 | |
| Ciprofloxacin | 0.004–0.03 | 0.016 | 0.016 | |
| Grepafloxacin | 0.004–0.016 | 0.008 | 0.016 | |
| Amoxicillin-clavulanate | 0.06–0.5 | 0.25 | 0.5 | |
| Pasteurella canis (21) | Gatifloxacin | 0.004–0.016 | 0.008 | 0.016 |
| Levofloxacin | 0.002–0.016 | 0.008 | 0.016 | |
| Trovafloxacin | 0.002–0.016 | 0.008 | 0.016 | |
| Sparfloxacin | ≤0.001–0.016 | 0.008 | 0.016 | |
| Ciprofloxacin | 0.002–0.016 | 0.004 | 0.008 | |
| Grepafloxacin | ≤0.001–0.016 | 0.004 | 0.016 | |
| Amoxicillin-clavulanate | 0.03–0.25 | 0.125 | 0.25 | |
| Pasteurella stomatis (19) | Gatifloxacin | 0.002–0.016 | 0.008 | 0.016 |
| Levofloxacin | 0.008–0.016 | 0.016 | 0.016 | |
| Trovafloxacin | 0.008–0.03 | 0.008 | 0.016 | |
| Sparfloxacin | 0.002–0.008 | 0.004 | 0.008 | |
| Ciprofloxacin | 0.004–0.016 | 0.008 | 0.016 | |
| Grepafloxacin | 0.002–0.016 | 0.004 | 0.008 | |
| Amoxicillin-clavulanate | 0.06–0.25 | 0.125 | 0.25 | |
| Pasteurella haemolytica (7) | Gatifloxacin | 0.008–0.03 | 0.016 | |
| Levofloxacin | 0.03–0.06 | 0.03 | ||
| Trovafloxacin | 0.016–0.125 | 0.06 | ||
| Sparfloxacin | 0.016–0.03 | 0.016 | ||
| Ciprofloxacin | 0.016–0.03 | 0.016 | ||
| Grepafloxacin | 0.016–0.06 | 0.03 | ||
| Amoxicillin-clavulanate | 0.06–0.25 | 0.06 | ||
| Pasteurella speciesa (17) | Gatifloxacin | 0.008–0.03 | 0.016 | 0.03 |
| Levofloxacin | 0.008–0.06 | 0.016 | 0.06 | |
| Trovafloxacin | 0.008–0.125 | 0.016 | 0.125 | |
| Sparfloxacin | 0.002–0.06 | 0.008 | 0.06 | |
| Ciprofloxacin | 0.004–0.03 | 0.016 | 0.03 | |
| Grepafloxacin | 0.002–0.06 | 0.008 | 0.06 | |
| Amoxicillin-clavulanate | 0.06–0.25 | 0.25 | 0.25 | |
| Actinobacillus-Haemophilus speciesb (9) | Gatifloxacin | ≤0.001–0.03 | 0.008 | |
| Levofloxacin | ≤0.001–0.06 | 0.008 | ||
| Trovafloxacin | ≤0.001–0.03 | 0.008 | ||
| Sparfloxacin | 0.002–0.016 | 0.008 | ||
| Ciprofloxacin | ≤0.001–0.06 | 0.008 | ||
| Grepafloxacin | ≤0.001–0.06 | 0.008 | ||
| Amoxicillin-clavulanate | ≤0.016–0.5 | 0.03 | ||
| EF-4b (13) | Gatifloxacin | 0.004–0.06 | 0.016 | 0.03 |
| Levofloxacin | 0.008–0.06 | 0.03 | 0.06 | |
| Trovafloxacin | 0.008–0.06 | 0.016 | 0.06 | |
| Sparfloxacin | 0.004–0.06 | 0.016 | 0.03 | |
| Ciprofloxacin | 0.004–0.06 | 0.03 | 0.06 | |
| Grepafloxacin | 0.008–0.125 | 0.03 | 0.06 | |
| Amoxicillin-clavulanate | 0.06–0.5 | 0.25 | 0.5 | |
| Eikenella corrodens (20) | Gatifloxacin | 0.008–0.125 | 0.016 | 0.016 |
| Levofloxacin | 0.008–0.06 | 0.016 | 0.016 | |
| Trovafloxacin | 0.016–0.06 | 0.016 | 0.016 | |
| Sparfloxacin | 0.016–0.06 | 0.03 | 0.06 | |
| Ciprofloxacin | 0.004–0.03 | 0.008 | 0.016 | |
| Grepafloxacin | 0.016–0.06 | 0.03 | 0.06 | |
| Amoxicillin-clavulanate | 0.06–0.5 | 0.5 | 0.5 | |
| Moraxella catarrhalis (11) | Gatifloxacin | ≤0.001–0.03 | 0.008 | 0.016 |
| Levofloxacin | 0.004–0.06 | 0.008 | 0.06 | |
| Trovafloxacin | 0.008–0.125 | 0.016 | 0.06 | |
| Sparfloxacin | 0.002–0.03 | 0.016 | 0.016 | |
| Ciprofloxacin | 0.002–0.06 | 0.008 | 0.06 | |
| Grepafloxacin | ≤0.001–0.03 | 0.016 | 0.03 | |
| Amoxicillin-clavulanate | 0.03–0.5 | 0.06 | 0.5 | |
| Moraxella speciesc (12) | Gatifloxacin | ≤0.001–0.016 | 0.004 | 0.016 |
| Levofloxacin | 0.004–0.06 | 0.008 | 0.06 | |
| Trovafloxacin | 0.008–0.06 | 0.016 | 0.06 | |
| Sparfloxacin | 0.004–0.016 | 0.008 | 0.016 | |
| Ciprofloxacin | 0.004–0.06 | 0.004 | 0.06 | |
| Grepafloxacin | 0.002–0.03 | 0.004 | 0.03 | |
| Amoxicillin-clavulanate | ≤0.016–0.5 | 0.25 | 0.5 | |
| Neisseria weaveri (13) | Gatifloxacin | 0.002–0.016 | 0.004 | 0.004 |
| Levofloxacin | 0.004–0.06 | 0.008 | 0.016 | |
| Trovafloxacin | 0.016–0.06 | 0.03 | 0.06 | |
| Sparfloxacin | 0.004–0.03 | 0.008 | 0.016 | |
| Ciprofloxacin | 0.002–0.06 | 0.004 | 0.008 | |
| Grepafloxacin | 0.002–0.016 | 0.008 | 0.016 | |
| Amoxicillin-clavulanate | 0.125–0.25 | 0.125 | 0.25 | |
| Neisseria speciesd (10) | Gatifloxacin | 0.002–0.125 | 0.008 | 0.06 |
| Levofloxacin | 0.004–0.125 | 0.008 | 0.125 | |
| Trovafloxacin | 0.002–0.06 | 0.008 | 0.06 | |
| Sparfloxacin | 0.004–0.125 | 0.008 | 0.03 | |
| Ciprofloxacin | 0.002–0.125 | 0.008 | 0.125 | |
| Grepafloxacin | 0.004–0.25 | 0.016 | 0.06 | |
| Amoxicillin-clavulanate | 0.125–1 | 0.5 | 1 | |
| Staphylococcus aureus (23) | Gatifloxacin | ≤0.03–0.06 | 0.06 | 0.06 |
| Levofloxacin | 0.06–0.125 | 0.06 | 0.06 | |
| Trovafloxacin | ≤0.016–0.03 | 0.03 | 0.03 | |
| Sparfloxacin | ≤0.03–0.06 | 0.06 | 0.06 | |
| Ciprofloxacin | 0.06–0.125 | 0.06 | 0.125 | |
| Grepafloxacin | ≤0.03–0.06 | 0.06 | 0.06 | |
| Amoxicillin-clavulanate | 0.25–1 | 0.25 | 0.5 | |
| Staphylococcus speciese (23) | Gatifloxacin | ≤0.03–2 | 0.5 | 1 |
| Levofloxacin | ≤0.06–4 | 1 | 2 | |
| Trovafloxacin | ≤0.016–0.5 | 0.25 | 0.5 | |
| Sparfloxacin | ≤0.03–4 | 0.5 | 2 | |
| Ciprofloxacin | ≤0.016–4 | 1 | 4 | |
| Grepafloxacin | ≤0.06–2 | 0.5 | 1 | |
| Amoxicillin-clavulanate | ≤0.016–0.5 | 0.06 | 0.25 | |
| Streptococcus speciesf (27) | Gatifloxacin | ≤0.03–2 | 0.5 | 1 |
| Levofloxacin | ≤0.06–4 | 1 | 2 | |
| Trovafloxacin | ≤0.016–0.5 | 0.25 | 0.5 | |
| Sparfloxacin | ≤0.03–4 | 0.05 | 2 | |
| Ciprofloxacin | ≤0.016–4 | 1 | 4 | |
| Grepafloxacin | ≤00.06–2 | 0.5 | 1 | |
| Amoxicillin-clavulanate | ≤0.016–0.5 | 0.06 | 0.25 | |
| Weeksella zoohelcum (10) | Gatifloxacin | 0.004–0.03 | 0.016 | 0.03 |
| Levofloxacin | 0.016–0.125 | 0.016 | 0.03 | |
| Trovafloxacin | 0.002–0.125 | 0.06 | 0.06 | |
| Sparfloxacin | 0.004–0.03 | 0.008 | 0.016 | |
| Ciprofloxacin | 0.002–0.125 | 0.016 | 0.125 | |
| Grepafloxacin | 0.004–0.03 | 0.016 | 0.016 | |
| Amoxicillin-clavulanate | ≤0.016–0.125 | 0.06 | 0.06 | |
| Bacteroides tectum (21) | Gatifloxacin | 0.06–0.5 | 0.125 | 0.125 |
| Levofloxacin | 0.25–1 | 0.25 | 0.25 | |
| Trovafloxacin | 0.03–0.25 | 0.06 | 0.06 | |
| Sparfloxacin | 0.25–2 | 0.5 | 1 | |
| Ciprofloxacin | 0.5–4 | 0.5 | 1 | |
| Grepafloxacin | 0.5–4 | 1 | 2 | |
| Amoxicillin-clavulanate | 0.03–0.5 | 0.03 | 0.06 | |
| Fusobacterium nucleatum (18) | Gatifloxacin | 0.25–>8 | 0.25 | >8 |
| Levofloxacin | 0.5–>8 | >8 | >8 | |
| Trovafloxacin | 0.25–4 | 1 | 4 | |
| Sparfloxacin | 2–>8 | 4 | >8 | |
| Ciprofloxacin | 1–>8 | 2 | >8 | |
| Grepafloxacin | 1–8 | 4 | 8 | |
| Amoxicillin-clavulanate | ≤0.016–0.12 | 0.03 | 0.125 | |
| Fusobacterium speciesg (10) | Gatifloxacin | ≤0.03–>8 | 8 | >8 |
| Levofloxacin | 2–>8 | >8 | >8 | |
| Trovafloxacin | 0.5–4 | 4 | 4 | |
| Sparfloxacin | ≤0.03–>8 | >8 | >8 | |
| Ciprofloxacin | 1–>8 | >8 | >8 | |
| Grepafloxacin | 0.125–8 | 8 | 8 | |
| Amoxicillin-clavulanate | ≤0.016–0.25 | 0.125 | 0.125 | |
| Porphyromonas speciesh (25) | Gatifloxacin | ≤0.03–0.25 | 0.125 | 0.25 |
| Levofloxacin | 0.06–1 | 0.25 | 1 | |
| Trovafloxacin | 0.03–0.5 | 0.06 | 0.25 | |
| Sparfloxacin | 0.125–2 | 0.5 | 1 | |
| Ciprofloxacin | 0.125–2 | 0.5 | 2 | |
| Grepafloxacin | 0.125–8 | 1 | 4 | |
| Amoxicillin-clavulanate | ≤0.016–0.06 | ≤0.016 | 0.06 | |
| Prevotella heparinolytica (13) | Gatifloxacin | 0.125 | 0.125 | 0.125 |
| Levofloxacin | 0.5–1 | 0.5 | 1 | |
| Trovafloxacin | 0.125–0.25 | 0.125 | 0.25 | |
| Sparfloxacin | 2 | 2 | 2 | |
| Ciprofloxacin | 2 | 2 | 2 | |
| Grepafloxacin | 0.5–2 | 1 | 2 | |
| Amoxicillin-clavulanate | 0.06–0.25 | 0.125 | 0.25 | |
| Prevotella speciesi (15) | Gatifloxacin | 0.06–0.25 | 0.125 | 0.25 |
| Levofloxacin | 0.25–1 | 0.5 | 1 | |
| Trovafloxacin | 0.06–1 | 0.06 | 1 | |
| Sparfloxacin | 1–8 | 2 | 8 | |
| Ciprofloxacin | 0.125–2 | 1 | 2 | |
| Grepafloxacin | 0.125–8 | 1 | 4 | |
| Amoxicillin-clavulanate | ≤0.016–0.5 | 0.125 | 0.5 | |
| Peptostreptococcus speciesj (10) | Gatifloxacin | 0.06–1 | 0.25 | 0.5 |
| Levofloxacin | 0.25–4 | 0.5 | 1 | |
| Trovafloxacin | 0.06–0.5 | 0.125 | 0.125 | |
| Sparfloxacin | 0.125–0.5 | 0.5 | 0.5 | |
| Ciprofloxacin | 0.25–2 | 0.5 | 2 | |
| Grepafloxacin | 0.25–2 | 0.5 | 1 | |
| Amoxicillin-clavulanate | ≤0.016–0.5 | 0.125 | 0.5 | |
Pasteurella species include (n) Pasteurella multocida subsp. gallicida (4), Pasteurella pneumotropica (1), Pasteurella multocida (2), and other Pasteurella species (10).
Actinobacillus-Haemophilus species include (n) Actinobacillus actinomycetemcomitans (1), other Actinobacillus species (2), Haemophilus parainfluenzae (4), and other Haemophilus species (2).
Moraxella species include all isolates not identified to the species level.
Neisseria species include (n) Neisseria subflava (2), Neisseria elongata subsp. nitroreducens (1), Neisseria cinerea-N. flavescens (1), Neisseria canis (1), and other Neisseria species (5).
Staphylococcus species include (n) Staphylococcus epidermidis (7), Staphylococcus warneri (7), Staphylococcus sciuri-S. lentus (2), Staphylococcus hyicus (1), Staphylococcus simulans (1), and Staphylococcus intermedia (5).
Streptococcus species include (n) Streptococcus constellatus (1), Streptococcus intermedius (4), Streptococcus mitis (10), Streptococcus mutans (10), Streptococcus sanguis I (1), and Streptococcus sanguis II (1).
Fusobacterium species include (n) Fusobacterium gonidiaformans (1), Fusobacterium necrophorum (1), Fusobacterium russii (6), and other fusobacteria (2).
Porphyromonas species include (n) Porphyromonas cangingivalis (2), Porphyromonas canoris (5), Porphyromonas gingivalis (8), Porphyromonas circumdentaria (2), and Porphyromonas macacae (8).
Prevotella species include (n) Prevotella bivia (3), Prevotella buccae (2), Prevotella intermedia (4), Prevotella denticola (1), Prevotella loeschii (1), Prevotella melaninogenica (2), and Prevotella zoogleoformans (2).
Peptostreptococcus species include (n) Peptostreptococcus anaerobius (6), Peptostreptococcus asaccharolyticus (1), Peptostreptococcus magnus (1), and other Peptostreptococcus species (2).
Standard laboratory powders were supplied as follows: gatifloxacin, Bristol Myers Squibb, Wallingford, Conn.; trovafloxacin, Pfizer Inc., New York, N.Y.; ciprofloxacin, Bayer Inc., West Haven, Conn.; levofloxacin, R. W. Johnson Pharmaceutical Research Institute, Raritan, N.J.; grepafloxacin, Glaxo-Wellcome Inc., Research Triangle Park, N.C.; sparfloxacin, Rhone-Poulenc Rorer, Collegeville, Pa.; and amoxicillin-clavulanate, SmithKline Beecham Pharmaceuticals, Philadelphia, Pa.
Susceptibility testing was performed by use of National Committee for Clinical Laboratory Standards (NCCLS) methods (18, 19). Brucella agar supplemented with hemin, vitamin K1, and 5% laked sheep blood was the basal medium used for anaerobic species and for Eikenella corrodens and Weeksella zoohelcum. Mueller-Hinton agar was used for staphylococci, and Mueller-Hinton agar supplemented with 5% sheep blood was used for the remainder of the organisms. Serial dilutions of antimicrobial agents were reconstituted according to the manufacturers’ instructions on the day of the test and added to the agar media at various concentrations.
The agar plates were inoculated with a Steers replicator (Craft Machine Inc., Chester, Pa.). An inoculum of 104 CFU per spot was used for aerobes, and 105 CFU per spot was used for E. corrodens and anaerobes. E. corrodens, W. zoohelcum, and streptococci were incubated in 5% CO2, anaerobic bacteria were incubated in an anaerobic chamber for 48 h; and other organisms were incubated in ambient air at 37°C for 24 h prior to examination.
The control strains tested included Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, Bacteroides fragilis ATCC 25285, Bacteroides thetaiotaomicron ATCC 29761, and Eubacterium lentum ATCC 43055. In addition, P. haemolytica ATCC 33396, Pasteurella multocida subsp. gallicida ATCC 51689, P. multocida subsp. septica ATCC 51688, Pasteurella stomatis ATCC 43327, Pasteurella dagmatis ATCC 43325, Pasteurella canis ATCC 43326, and Neisseria canis ATCC 14687 were used.
The activities of gatifloxacin and the other agents tested against the bite wound isolates are shown in Table 1. Gatifloxacin was active at ≤0.125 μg/ml against all aerobic bite wound isolates, with the exception of some streptococci (MIC at which 90% of the isolates were inhibited [MIC90], 1 μg/ml; range, <0.03 to 2 μg/ml). All six fluoroquinolones tested were active at ≤0.125 μg/ml against all 148 Pasteurella isolates (eight species and three P. multocida subspecies).
The other aerobic genera and species tested were also susceptible to ≤0.125 μg of gatifloxacin per ml, with the exception of streptococci, which varied by species: all Streptococcus mitis isolates were susceptible to ≤0.5 μg/ml, 10 isolates of Streptococcus mutans and other species were susceptible to ≤1 μg/ml, but 2 μg/ml was required for inhibition of 1 of 4 isolates of Streptococcus intermedius.
Gatifloxacin was active against Bacteroides tectum (MIC90, 0.125 μg/ml), Prevotella heparinolytica (MIC90, 0.125 μg/ml), other Prevotella and Porphyromonas spp. (MIC90, 0.25 μg/ml), and peptostreptococci (MIC90, 0.5 μg/ml). Gatifloxacin was slightly more active against Prevotella spp. than was trovafloxacin but otherwise was generally equivalent to trovafloxacin. Consistent with our findings, Ednie et al. (5), using an unspecified NCCLS agar dilution method, reported gatifloxacin to have an MIC50 and an MIC90 of 0.5 and 1 μg/ml, respectively, for 55 peptostreptococcal isolates. Schaumann et al. (22) reported an MIC90 of 0.25 μg/ml for peptostreptococci by using a broth microdilution method, which may account for the disparity.
Fusobacterium species (MIC50 and MIC90, ≥8 μg/ml], including Fusobacterium nucleatum (MIC50, 0.25 μg/ml; MIC90, ≥8 μg/ml), were sometimes resistant to gatifloxacin as well as to the other quinolones. Ednie et al. (5) reported gatifloxacin to have an MIC50 and an MIC90 of 0.5 μg/ml for F. nucleatum and Fusobacterium mortiferum, 0.5 and 1 μg/ml, respectively, for Fusobacterium necrophorum, and 4 μg/ml for Fusobacterium varium. Schaumann et al. (22) tested 17 Fusobacterium species by a broth microdilution method and reported an MIC90 of 8 μg/ml.
Erwin et al. (6) studied Fusobacterium species by an unspecified NCCLS agar dilution method and reported an MIC90 of 0.19 μg/ml for gatifloxacin, which they noted to be more active than trovafloxacin. In contrast, we found that trovafloxacin had an MIC90 of ≤4 μg/ml against fusobacteria; this value was generally within one dilution of the gatifloxacin results. Also in contrast to our findings, Wexler et al. (27) and Spangler et al. (23) noted trovafloxacin MIC90s of 0.5 and 0.25 mg/liter, respectively, for F. nucleatum and MIC90s of 0.5 and 1.0 μg/ml, respectively, for other Fusobacterium spp. Since the same methods were used by us and by Wexler et al. (27), the reason for this disparity is unclear, except that we studied veterinary isolates recovered from human infections, while Wexler et al. used human isolates recovered from other sources. The different medium used by Spangler et al. (23), supplemented Wilkins-Chalgren agar, may account for some variation.
Gatifloxacin appears to be more active than older quinolones against a spectrum of pathogens isolated from human and animal bite wounds and merits further clinical evaluation.
Acknowledgments
We thank Judee H. Knight, Alice E. Goldstein, and David Talan for various forms of assistance.
This study was funded in part by an educational grant from Bristol Myers Squibb, Wallingford, Conn.
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