Trovafloxacin compared with levofloxacin, ofloxacin, ciprofloxacin, azithromycin and clarithromycin against unusual aerobic and anaerobic human and animal bite-wound pathogens

BMS-284756, a new des-fluoro(6) quinolone, was very active against 240 aerobic and 180 anaerobic isolates from bite victims. It inhibited 403 of 420 (96%) isolates, including those of Moraxella spp., CDC group EF-4, and Eikenella corrodens at <2 g/ml and those of all Pasteurella spp. and Bergeyella zoohelcum at <0.015 g/ml. Fusobacterium russii and 6 of 11 Fusobacterium nucleatum isolates of animal bite origin were resistant, but isolates of human bite origin were susceptible, which suggests that they were of a different subspecies.Many of the 4.5 million Americans bitten by animals or humans each year require either therapeutic or prophylactic antimicrobial therapy; approximately 30,000 of these patients visit an emergency department for medical treatment, and an additional 10,000 are hospitalized with serious wound infections involving complex polymicrobial floras (4, 18). While many patients receive a beta-lactam agent such as amoxicillinclavulanate, approximately 20% report a history of an adverse reaction to penicillin or other beta-lactam antibiotics (2) and require an appropriate alternative agent.Older fluoroquinolones, such as ciprofloxacin, have limited activities against certain gram-positive aerobes and many anaerobic species typically encountered in human and animal bite wounds (5, 7). BMS-284756 {T-3811ME; 1-cyclopropyl-8--4-oxo-1,4-dihydro-3-quinolinecarboxylic acid methanesulfonate monohydrate)} is a new des-fluoro(6) quinolone that lacks the six-position fluorine characterizing the previous generation of fluoroquinolones. Preliminary data indicate that this drug has a broad spectrum of activity against most gram-positive and gram-negative aerobes and anaerobes, including certain strains that are resistant to other fluoroquinolones (3,8).Studies have focused on more typical isolates, especially respiratory and intra-abdominal pathogens (8, 17), but have not evaluated the drug against the specific range of bacteria, such as Pasteurella species, Eikenella corrodens, Prevotella heparinolytica, and Porphyromonas macacae, commonly found in human and animal bite wound infections. In this study, we determined the activity of BMS-284756 against 420 aerobic and anaerobic strains recently isolated from such infections in humans. The specific sources of the strains were 117 dog bite, 156 cat bite, 132 human bite, and 15 other animal bite wounds. All isolates were identified by standard criteria (1, 9-13, 16); the numbers and species tested are given in ; and doxycycline and penicillin G by Sigma Chemical Co., St. Louis, Mo. Antimicrobial agents were reconstituted according to the manufacturers' instructions. Serial twofold dilutions were added to the media on the day of testing.To ensure purity and good growth, frozen cultures were transferred twice on Trypticase soy blood or chocolate agar (Hardy Diagnostics, Santa Maria, Calif.) for the aerobes and on brucella agar supplemented with hemin, vitamin K 1 , and 5% sheep blood (Anaerobe Systems, Morgan Hill, Calif.) for the anaerobes. Susceptibility testing wa...

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confidence: 99%

“…Prior studies (6,7) have noted that some strains of F. nu- a Corynebacterium accolens (n ϭ 1), C. amycolatum (n ϭ 1), "C. aquaticum" (n ϭ 10), C. argentoratense (n ϭ 1), C. jeikeium (n ϭ 1), C. minutissimum (n ϭ 3), C. propinquum (n ϭ 1), and C. ulcerans (n ϭ 1).…”

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confidence: 99%

In Vitro Activities of the Des-Fluoro(6) Quinolone BMS-284756 against Aerobic and Anaerobic Pathogens Isolated from Skin and Soft Tissue Animal and Human Bite Wound Infections

Goldstein

Citron

Merriam

et al. 2002

“…corrodens has a unique antibiotic susceptibility profile (3,(8)(9)(10) as it is usually susceptible to beta-lactam antibiotics, such as penicillin and ampicillin, but is resistant to penicillinaseresistant penicillins, such as dicloxacillin. Penicillin-resistant strains of E. corrodens have been increasingly isolated from human clinical specimens (23,24).…”

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confidence: 99%

In Vitro Activities of a New Des-Fluoroquinolone, BMS 284756, and Seven Other Antimicrobial Agents against 151 Isolates of Eikenella corrodens

Goldstein

Citron

Merriam

et al. 2002

The des-fluoroquinolone BMS 284756 was active in vitro against all 151 clinical strains of Eikenella corrodens at a MIC of <0.25 g/ml and was comparable in activity to moxifloxacin and levofloxacin. The MIC at which 90% of the isolates were inhibited by penicillin G was 2 g/ml; MICs for 8.6% of the strains (13 of 151) were >4 g/ml, including for two beta-lactamase-producing isolates. Amoxicillin-clavulanate and ampicillin-sulbactam inhibited all strains at a MIC of <1 g/ml.Eikenella corrodens, a capnophilic, fastidious, slow-growing, gram-negative rod, has been increasingly implicated in a variety of infections associated with the human oral flora (1-2, 4-6). It is part of the normal oral microbiota recovered in approximately 60% of plaque samples (1, 7) and has been associated with human periodontitis (21). E. corrodens may also be found on the surface of the tongue, tonsils, and buccal mucosa and in saliva. Humans may harbor more than one clonal type of E. corrodens in the oral cavity; the significance of this is presently unknown.While little is known about the role of the virulence factors of E. corrodens in pathogenicity (1,19), common E. corrodensassociated infections include oral alveolar abscesses, parotitis, sinusitis, osteomyelitis of the mandible, bacteremia, and endocarditis following dental manipulation (4,12,17,22). A strong association between subgingival E. corrodens and Actinobacillus actinomycetemcomitans in juvenile periodontitis has also been suggested (16). A knowledgeable basis for therapeutic selection of appropriate antimicrobial agents is essential.Eikenella corrodens has a somewhat peculiar antimicrobial susceptibility pattern, being susceptible to penicillin but resistant to penicillinase-resistant penicillins such as dicloxacillin, erythromycin, other macrolides, clindamycin, metronidazole, and aminoglycosides (8, 9). The fluoroquinolones have been previously shown to be active against E. corrodens (10), but most have limited activity against anaerobic bacteria which are frequent copathogens in oral flora-based infections. The new des-fluoroquinolone BMS 284756 has been reported to have improved anaerobic activity (3,25). To see if BMS 284756 is of clinical utility in multibacterial oral infections, we studied its comparative in vitro activity against 151 clinical isolates of E. corrodens.The strains tested were previously isolated from human infections (respiratory and/or oral isolates, 54; human and animal bites, 29; soft-tissue wounds, 15; other sources, 49) and identified by standard criteria (11, 18). Isolates were gramnegative, capnophilic rods that were positive for oxidase, nitrate reductase, and ornithine decarboxlyase. Negative reactions were observed for catalase, urease, lysine decarboxylase, arginine dihydrolase, esculin hydrolysis, indole production, and acidification of carbohydrates. Susceptibility testing was performed as previously reported (8, 9). Brucella agar supplemented with hemin, vitamin K1, and laked sheep blood was the basal medium. There is no NCCLS referen...

“…In particular, liposomes made up of dimyristoylphosphatidylcholine-cholesterol-dipalmitoylphosphatidylserine and dimyristoylphosphatidylcholine-cholesterol-dihexadecylphosphate (4:3:4 molar ratio) provided the best improvement in antimicrobial activity against the various bacterial strains investigated. The liposome formulation produced higher intracellular fluoroquinolone concentrations than those achieved simultaneously with the free drug in both E. coli and P. aeruginosa.Since the discovery of the original DNA gyrase inhibitor nalidixic acid, numerous structural modifications have been carried out to the quinolone nucleus to increase antimicrobial activity and improve pharmacokinetic performance (12,22,29,46).The efficacy of fluoroquinolone antibiotics has led to their proposed use for the treatment and prophylaxis of different bacterial diseases: therapy for the respiratory tract, skin structure, and bone and gastrointestinal infections, as well as urinary tract infections (20,21,23,36,41). However, many studies were developed to improve the potency and spectrum, to achieve sustained blood levels, and to reduce as much as possible drug interactions with various metabolic pathways and physiological processes.…”

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confidence: 99%

“…The efficacy of fluoroquinolone antibiotics has led to their proposed use for the treatment and prophylaxis of different bacterial diseases: therapy for the respiratory tract, skin structure, and bone and gastrointestinal infections, as well as urinary tract infections (20,21,23,36,41). However, many studies were developed to improve the potency and spectrum, to achieve sustained blood levels, and to reduce as much as possible drug interactions with various metabolic pathways and physiological processes.…”

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confidence: 99%

Ofloxacin-Loaded Liposomes: In Vitro Activity and Drug Accumulation in Bacteria

Furneri¹,

Fresta

Puglisi

et al. 2000

Different ofloxacin-loaded unilamellar vesicles were prepared by the extrusion technique, and their antimicrobial activities were determined in comparison to those of the free drug by means of MIC determinations with both American Type Culture Collection standards and wild-type bacterial strains (six strains of Enterococcus faecalis, seven strains of Escherichia coli, six strains of Staphylococcus aureus, and six strains of Pseudomonas aeruginosa). The accumulation of ofloxacin and liposome-ofloxacin was measured by determining the amount of the drug inside the bacteria as a function of time. Encapsulated fluoroquinolone yielded MICs which were at least twofold lower than those obtained with the free drug. In particular, liposomes made up of dimyristoylphosphatidylcholine-cholesterol-dipalmitoylphosphatidylserine and dimyristoylphosphatidylcholine-cholesterol-dihexadecylphosphate (4:3:4 molar ratio) provided the best improvement in antimicrobial activity against the various bacterial strains investigated. The liposome formulation produced higher intracellular fluoroquinolone concentrations than those achieved simultaneously with the free drug in both E. coli and P. aeruginosa.Since the discovery of the original DNA gyrase inhibitor nalidixic acid, numerous structural modifications have been carried out to the quinolone nucleus to increase antimicrobial activity and improve pharmacokinetic performance (12,22,29,46).The efficacy of fluoroquinolone antibiotics has led to their proposed use for the treatment and prophylaxis of different bacterial diseases: therapy for the respiratory tract, skin structure, and bone and gastrointestinal infections, as well as urinary tract infections (20,21,23,36,41). However, many studies were developed to improve the potency and spectrum, to achieve sustained blood levels, and to reduce as much as possible drug interactions with various metabolic pathways and physiological processes. Particularly, the use of antibiotic "carrier/delivery systems" would result in enhanced concentrations of the antimicrobial agent at the site of infection. In fact, delivery systems can contribute to (i) targeting of the drug to the infected tissues, (ii) increasing intracellular antibiotic concentrations, and (iii) reducing toxicity of potentially toxic drugs resulting from the targeting to the infectious organisms.Liposomes are possible carriers for controlled drug delivery and targeting by the intravenous route. As with most drug carriers, liposomes have been extensively used in an attempt to improve the selective delivery and the therapeutic index of antimicrobial agents (3, 47). Liposomes, artificial phospholipid membranes, are usually produced from naturally occurring, biodegradable, and nontoxic lipids, such as lecithin, cholesterol, and phosphatidylserine.The aim of the study described here was to investigate the antimicrobial activity against and accumulation in bacteria of ofloxacin-loaded liposomes (of different lipid compositions) in comparison to those of free drugs. Our preliminary experi...