The fluoroquinolones, a new class of potent orally absorbed antimicrobial agents, are reviewed, considering structure, mechanisms of action and resistance, spectrum, variables affecting activity in vitro, pharmacokinetic properties, clinical efficacy, emergence of resistance, and tolerability. The primary bacterial target is the enzyme deoxyribonucleic acid gyrase. Bacterial resistance occurs by chromosomal mutations altering deoxyribonucleic acid gyrase and decreasing drug permeation. The drugs are bactericidal and potent in vitro against members of the family Enterobacteriaceae, Haemophilus spp., and Neisseria spp., have good activity against Pseudomonas aeruginosa and staphylococci, and (with several exceptions) are less potent against streptococci and have fair to poor activity against anaerobic species. Potency in vitro decreases in the presence of low pH, magnesium ions, or urine but is little affected by different media, increased inoculum, or serum. The effects of the drugs in combination with a beta-lactam or aminoglycoside are often additive, occasionally synergistic, and rarely antagonistic. The agents are orally absorbed, require at most twice-daily dosing, and achieve high concentrations in urine, feces, and kidney and good concentrations in lung, bone, prostate, and other tissues. The drugs are efficacious in treatment of a variety of bacterial infections, including uncomplicated and complicated urinary tract infections, bacterial gastroenteritis, and gonorrhea, and show promise for therapy of prostatitis, respiratory tract infections, osteomyelitis, and cutaneous infections, particularly when caused by aerobic gram-negative bacilli. Fluoroquinolones have also proved to be efficacious for prophylaxis against travelers9 diarrhea and infection with gram-negative bacilli in neutropenic patients. The drugs are effective in eliminating carriage of Neisseria meningitidis. Patient tolerability appears acceptable, with gastrointestinal or central nervous system toxicities occurring most commonly, but only rarely necessitating discontinuance of therapy. In 17 of 18 prospective, randomized, double-blind comparisons with another agent or placebo, fluoroquinolones were tolerated as well as or better than the comparison regimen. Bacterial resistance has been uncommonly documented but occurs, most notably with P. aeruginosa and Staphylococcus aureus and occasionally other species for which the therapeutic ratio is less favorable. Fluoroquinolones offer an efficacious, well-tolerated, and cost-effective alternative to parenteral therapies of selected infections.

Fluoroquinolone antimicrobial agents.

Recent taxonomic advances have now implicated several different Vibrio species as human pathogens. While the most common clinical presentation of Vibrio infection continues to be gastroenteritis, an increasing number of extraintestinal infections are being reported, particularly in immunocompromised individuals. Detection of Vibrio infections requires a good clinical history and the use of appropriate isolation and identification procedures by the laboratory to confirm illnesses attributed to Vibrio species. Except for Vibrio cholerae O1 and Vibrio parahaemolyticus, there is little direct evidence linking the production of a myriad of cell-associated or extracellular factors produced by each species with human disease and pathogenesis. Many questions regarding pathogenic Vibrio species remain unanswered, including their frequency and distribution in environmental specimens (water, shellfish), infective doses, virulence potential of individual isolates, and markers associated with such strains.

Current perspectives on the epidemiology and pathogenesis of clinically significant Vibrio spp.

The importance of the genus Aeromonas in human disease has recently become better appreciated through the use of improved methodologies for the recovery and identification of aeromonads from biologic specimens and as a result of medical studies aimed at determining the clinical significance of these bacteria when isolated from localized and invasive infections of humans. Taxonomic schemes currently allow for the identification of six Aeromonas species (five mesophilic and one psychrophilic), four of the five mesophilic species having been recovered from infectious processes or isolated from clinical material of human origin. Two major categories of human illness attributed to Aeromonas species have been observed: acute gastroenteritis in both pediatric and adult populations and disseminated disease (e.g., bacteremia) in persons with underlying hematologic malignancies or hepatic dysfunctions. Although the role of mesophilic aeromonads as important agents of bacterial gastroenteritis remains unconfirmed because of the inability to fulfill Koch's postulates (no animal model), several lines of compelling clinical and laboratory evidence indicate that these microorganisms are significant enteric pathogens. Members of the genus Aeromonas have been recognized for almost 100 years. Their initial observation is credited to Sanarelli, who reported in 1891 the isolation from a frog of a bacterium (Bacillus hydrophilus) that, upon reinoculation into cold- and warmblooded animals, produced septicemia and disease

Mesophilic Aeromonads in Human Disease: Current Taxonomy, Laboratory Identification, and Infectious Disease Spectrum

Although the first Aeromonas strain was described by Zimmermann as early as in 1890, it took 60 years until Caselitz established human pathogenicity of strains then called "Vibrio jamaicensis". Since then, and especially in the last 10 years, there have been increasing numbers of reports on different infections caused by members of the genus Aeromonas. These include sepsis; meningitis; cellulitis; necrotizing fasciitis; ecthyma gangrenosum; pneumonia; peritonitis; conjunctivitis; corneal ulcer; endophthalmitis; osteomyelitis; suppurative arthritis; myositis; subphrenic abscess; liver abscess; cholecystitis and/or ascending cholangitis; urinary tract infection; endocarditis; ear, nose, and throat infections; balanitis; etc. The role of Aeromonas in gastrointestinal disease is very controversial. Increasing epidemiological data suggest that these organisms play a major role in enteric infections, but so far enteropathogenicity has not been demonstrable in experiments where volunteers were given high numbers of Aeromonas possessing different virulence factors. Virulence factors include hemolysin(s), enterotoxin(s), hemagglutinins, invasivity, and others; but these are not found more frequently in strains isolated from patients with diarrhea than from healthy controls. Whether there is a correlation between species and disease remains to be elucidated and requires more information about the taxonomy of this genus.

Aeromonas as a human pathogen.

Burkholderia cepacia has recently been recognized as an important pathogen in chronic lung disease in patients with cystic fibrosis (CF). Because of the social, psychological, and medical implications of the isolation of B. cepacia from CF patients, accurate identification of this organism is essential. We compared the accuracies of four commercial systems developed for the identification of nonfermenting, gram-negative bacilli with that of conventional biochemical testing for 150 nonfermenters including 58 isolates of B. cepacia recovered from respiratory secretions from CF patients. The accuracies of the four systems for identifying all nonfermenters ranged from 57 to 80%, with the RapID NF Plus system being most accurate. The accuracies of these systems for identifying B. cepacia ranged from 43 to 86%, with the Remel system being most accurate. Depending on the commercial system, from two to seven isolates were misidentified as B. cepacia. The relatively poor performance of the commercial systems requires that identification of certain nonfermenters be confirmed by conventional biochemical testing. These organisms include B. cepacia, Burkholderia sp. other than B. cepacia, and infrequently encountered environmental species (Pseudomonas and Flavobacterium species). In addition, conventional biochemical testing should be done if a commercial system fails to assign an identification to an organism. Confirmatory testing should preferably be performed by a reference laboratory with experience in working organisms isolated from CF patients.

Accuracy of four commercial systems for identification of Burkholderia cepacia and other gram-negative nonfermenting bacilli recovered from patients with cystic fibrosis.

Twenty-eight strains of Aeromonas spp. were analyzed for their ability to grow on two different kinds of cefsulodin-Irgasan (triclosan; Ciba-Geigy AG, Basel, Switzerland)-novobiocin (CIN) agar containing 15 or 4 mg of cefsulodin per ml and on inositol-bile salts-brilliant green (IBB) agar. Relative to blood agar, 68% of the strains were inhibited by more than 2 logs (i.e., less than 1% growth) at 37 degrees C (39% at 25 degrees C) on CIN I (high cefsulodin concentration), 7% were inhibited at either temperature on CIN II (low cefsulodin concentration), 4% were inhibited on IBB agar at 37 degrees C, and none were inhibited on IBB agar at 25 degrees C. These results reflect the MICs of cefsulodin on CIN Base: the MIC for 50% of the strains was 8 mg/liter at 37 and 25 degrees C, and the MICs for 90% of the strains were 16 mg/liter at 37 degrees C and 64 mg/liter at 25 degrees C. The MICs of Irgasan and novobiocin were far beyond the concentrations used in CIN media. We argue that CIN agar containing 4 mg of cefsulodin per ml (CIN II) can be used for the simultaneous detection of Aeromonas spp. and Yersinia spp.

Growth of Aeromonas spp. on cefsulodin-Irgasan-novobiocin agar selective for Yersinia enterocolitica.

Summary From the faeces of a diarrhoeic patient, we isolated a strain of Kluyvera ascorbata on cefsulodin-irgasan-novobiocin (CIN) agar, a highly selective medium used for Yersinia enterocolitica . Since no selective media have been described for Kluyvera spp., we tested 5 strains each of K. ascorbata and K. cryocrescens for their ability to grow on CIN agar. K. ascorbata exhibited an inhibition on CIN of less than 10% CFU compared to blood agar, whereas K. cryocrescens did not grow at all even with inocula as high as 10 5 CFU per plate. This phenomenon correlated very well with MIC values to irgasan, which were >128 mg/l for K. ascorbata and ≤0.25 mg/l for K. cryocrescens . No significant differences between the two species were observed for the other two antibiotics contained in CIN. This phenotypic character has been used to differentiate 18 strains belonging to either species on the basis of a simple disk test: with disks containing 5, 25, or 125 μg irgasan, K. ascorbata never showed zones of inhibition, whereas K. cryocrescens produced zones of ≥15, ≥21.5 and ≥25.0 mm in diameter, respectively.

Differentiation of Kluyvera cryocrescens from Kluyvera ascorbata by irgasan susceptibility testing.

The API 20 NE (Rapid NFT) system for identification of non-enteric aerobic gram-negative rods was evaluated using 431 strains of species covered by the analytical profile index and previously identified by conventional methods. In an analysis of several parameters, 343 (80 %) of the strains were identified correctly with good to excellent probabilities of positive reactions (80.0–99.9%), 190(55%) of these within 24 h; 74(17%) yielded primary identifications with lower probabilities. Only 3 % of the strains could not be correctly identified. The system is very satisfactory for routine use, but could be improved by modified pre-testing of the strains and by including more species in the profile index.

Evaluation of pertinent parameters of a new identification system for non-enteric gram-negative rods.

The antibacterial activity of fleroxacin (Ro 23-6240, AM-833), a new 6-fluoroquinolone, was determined against 149 strains of enteropathogenic bacteria (17 species) and 191 strains (28 species) of glucose non-fermentative Gram-negative rods (excluding Pseudomonas aeruginosa), and against 15 strains of Legionella pneumophila. The cumulative susceptibility of these groups of bacteria to Ro 23-6240 at the 2 mg/l level were 99.2%, 80.1 and 100% of tested strains, respectively.

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Fleroxacin (Ro 23-6240): activity in virtro against 355 enteropathogenic and non-fermentative Gram-negative bacilli and Legionella pneumophila

Thein vitro activity of the free acid of cefetamet pivoxil (Ro 15-8075) was tested against 355 clinical isolates, namely enteropathogenic bacteria, glucose non-fermentative gram-negative rods (excludingPseudomonas aeruginosa) andLegionella pneumophila. Ceftriaxone was included in the study as reference compound. Although the free acid of the orally active cephalosporin was generally weaker than ceftriaxone, it inhibited 88.2% and 94.5% of Enterobacteriaceae and Vibrionaceae at a concentration of 4 mg/l and 8 mg/l or less, respectively.Campylobacter jejuni proved resistant to both compounds. The activity of the new compound against glucose non-fermentative gram-negative rods was generally insufficient to be of promise for broad clinical use. Although the compound was at least twofold more active than ceftriaxone againstPseudomonas acidovorans, Pseudomonas alcaligenes andPseudomonas cepacia, the former was at least two dilution steps less active than the latter against 14 species of the other less common glucose non-fermentative organisms.

J. Zollinger-Iten

Papers

Growth of Aeromonas spp. on cefsulodin-Irgasan-novobiocin agar selective for Yersinia enterocolitica.

Differentiation of Kluyvera cryocrescens from Kluyvera ascorbata by irgasan susceptibility testing.

Evaluation of pertinent parameters of a new identification system for non-enteric gram-negative rods.

Fleroxacin (Ro 23-6240): activity in virtro against 355 enteropathogenic and non-fermentative Gram-negative bacilli and Legionella pneumophila

Cefetamet pivoxil: bacteriostatic and bactericidal activity of the free acid against 355 gram-negative rods.