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Protein binding of antibacterials in plasma and tissues has long been considered a component of their pharmacokinetic parameters, playing a potential role in distribution, excretion and therapeutic effectiveness. Since the beginning of the 'antibacterial era', this factor has been extensively analysed for all antibacterial classes, showing that wide variations of the degree of protein binding occur even in the same antibacterial class, as with beta-lactams. As the understanding of protein binding grew, the complexity of the binding system was increasingly perceived and its dynamic character described. Studies of protein binding of the fluoroquinolones have shown that the great majority of these drugs exhibit low protein binding, ranging from approximately 20 to 40% in plasma, and that they are bound predominantly to albumin. The potential role in pharmacokinetics-pharmacodynamics of binding of fluoroquinolones to plasma, tissue and intracellular proteins has been analysed, but it has not been established that protein binding has any significant direct or indirect impact on therapeutic effectiveness. Regarding the factors influencing the tissue distribution of antibacterials, physicochemical characteristics and the small molecular size of fluoroquinolones permit a rapid penetration into extravascular sites and intracellularly, with a rapid equilibrium being established between intravascular and extravascular compartments. The high concentrations of these drugs achieved in tissues, body fluids and intracellularly, in addition to their wide antibacterial spectrum, mean that fluoroquinolones have therapeutic effectiveness in a large variety of infections. The tolerability of quinolones has generally been reported as good, based upon long experience in using pefloxacin, ciprofloxacin and ofloxacin in clinical practice. Among more recently developed molecules, good tolerability has been reported for levofloxacin, moxifloxacin and gatifloxacin, but certain other new compounds have been removed from the market because of renal, hepatic and cardiac toxicity. To what extent the protein binding of fluoroquinolones can play a role in their tolerability is unclear. In terms of drug-drug interactions, the role of protein binding is questionable: several drug combinations can be responsible for toxicity, such as with beta-lactams, metronidazole, theophylline, nonsteroidal anti-inflammatory agents or a series of drugs used for cardiac diseases, but protein binding does not seem to be involved in these interactions. In conclusion, protein binding of fluoroquinolones appears to be a complex phenomenon, but has no clear role in therapeutic effectiveness or toxicity.

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The epidemiology of extended-spectrum beta-lactamase (ESBL)-producing strains of Klebsiella pneumoniae was studied over a 16-month period in a medical intensive care unit (ICU). A control program involving enhanced isolation procedures, surveillance cultures at admission and then at 1-week intervals, and selective digestive decontamination (SDD) was instituted. Phenotypic and genotypic markers (plasmid content and DNA macrorestriction polymorphism determined by pulsed-field gel electrophoresis) were used to compare 138 strains of ESBL-producing K. pneumoniae. The incidence of colonization and/or infection with ESBL producers was 11.9%. ESBL-producing K. pneumoniae strains were isolated from 64 of 65 patients. Fifty-five cases were considered acquired in the ICU, while nine cases were imported. Forty-five infections occurred in 32 patients; 20 infections involved the urinary tract. SDD failed to reduce the incidence of acquisition of ESBL-producing K. pneumoniae. Combined use of markers was necessary to achieve accurate differentiation of strains. A single epidemic clone (SHV-4 beta-lactamase-producing K. pneumoniae) was the cause of 85% of the ICU-acquired cases. Sporadic occurrence of SHV-5, TEM-3, SHV-2, and SHV-3 producers accounted only for a few cases.

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The in vitro susceptibilities of 75 clinical isolates of Xanthomonas maltophilia to nalidixic acid, five fluoroquinolones, latamoxef, and doxycycline were determined. Spontaneous mutants were selected, at a frequency of about 10'-to 10-from four strains by culturing the strains in the presence of each quinolone.Selection in the presence of nalidixic acid provided mutants that were either resistant only to that compound or that exhibited cross-resistance to all the fluoroquinolones tested. Cross-resistance was always observed for mutants selected on any of the five fluoroquinolones. It was always associated with chloramphenicol resistance and, frequently, with doxycycline resistance. The electrophoretic alterations of the outer membrane proteins of the mutants suggest that different mechanisms may be involved in quinolone resistance in X. maltophilia.Xanthomonas maltophilia has recently been isolated with increasing frequency and is mainly responsible for nosocomial infections in compromised hosts (17). Its natural resistance restricts the choice of antibiotics for use in the treatment of infected patients (1, 2, 11, 16), and quinolones have been considered as a possible option for therapy (17). The agar diffusion method has revealed a particular phenotype of quinolone susceptibility for this species (12). In the current study, we determined the MICs of nalidixic acid, pefloxacin, ciprofloxacin, ofloxacin, temafloxacin, sparfloxacin, latamoxef, and doxycycline for 75 clinical isolates ofX. maltophilia. Since the emergence of mutants resistant to quinolones and unrelated drugs has been described in several species of gram-negative bacilli (5-7, 14, 18, 20), especially Pseudomonas aeruginosa (8,15), from 4 of the 75 strains of X. maltophilia, we selected mutants that were resistant to six quinolones. The resistance patterns of the mutants were studied, and the electrophoretic profiles of the outer membrane proteins (OMPs) were analyzed for each type of mutant.MICs were determined by a twofold serial agar dilution method on Mueller-Hinton agar by using a replicating spot device, with an inoculum of about 104 CFU per spot.Spontaneous mutants were selected from four susceptible strains by spreading approximately 2 x 108 CFU onto plates of Mueller-Hinton agar containing each of the six quinolones at concentrations of 4, 8, and 16 times the respective MICs for the strains. After 48 h at 37°C, the frequencies of mutation were evaluated and the MICs of the six quinolones, doxycycline, latamoxef, and chloramphenicol were determined. The mutants were classified according to their patterns of resistance to these nine antibiotics. From each type of mutant, OMP fractions were prepared as described previously (6) and were submitted to sodium dodecyl sulfatepolyacrylamide gel electrophoresis for separation (13.5% acrylamide, 0.36% bisacrylamide).