Fluoroquinolones acts by interacting with type II topoisomerases (DNA gyrase and topoisomerases IV). Related to this mechanism of action, bacteria have developed resistance mechanisms consisting in some target mutations (GyrA/GyrB for DNA gyrase and ParC/ParE for topoisomerase IV) or in a reduced access to the target itself, by either decreased permeability or augmented expression of efflux pumps, such as AcrAB and MexAB. Along with these classical mechanisms of chromosomal resistance, the presence of fluoroquinolones resistant proteins (Qnr) has been recently evidenced, codified by transmissible genes by means of plasmids, especially in Enterobacter spp., Escherichia coli and Klebsiella pneumoniae, whereas Proteus mirabilis and non fermenter Gram-negative, like Acinetobacter spp. and Pseudomonas aeruginosa, are not involved in such a kind of resistance. Qnr proteins determine a slight increase in MIC values, which often remains below the susceptibility breakpoint. More relevant is their impact on MPC values. Additionally, new specific resistance mechanisms have been described. AAC(6’)-Ib-cr represents the first enzyme able to inactivate, by acetylation, antimicrobials of two different classes, aminoglycosides and fluoroquinolones. However, ciprofloxacin and norfloxacin, but not levofloxacin, are susceptible to this enzyme action. Finally, the presence of another resistance mechanism has been reported, an efflux-pump plasmid-mediated, codified by the gepA gene, which acts by a selective mechanism. Only idrophilic fluoroquinolones, i.e. norfloxacin and ciprofloxacin, but not all the other ones, i.e. levofloxacin, moxifloxacin, etc…, are affected by this mechanism. In the light of these new information, it is clear that, in terms of bacterial resistance, it is not any more possible to assimilate one fluoroquinolones to another, since different molecules can be diversely active, due to the specific resistance mechanism.

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Fluoroquinolones therapeutic efficacy is closely related to the achievement of the highest concentration (concentration-dependent drugs). However, following exposure to antibiotics, along with a decrease in the overall bacterial population, a selection of resistant bacterial population can also occur. In such a scenario, the Mutant Prevention Concentration (MPC) has to be considered, the antibiotic concentration that approximatively allows to obtain inhibition of fully susceptible as well as low resistant strains. In the range between MPC and MIC values, the Mutant Selection Window (MSW) is delineated, a range of antibiotic concentrations within a selection of mutant strains could possibly take place. The clinical impact of these microbiological observations can be found in the importance that the drug concentration a patient will be exposed to, consequently assumes: a concentration that doesn’t reach MIC, although doesn’t alter the resistance pattern, will not guarantee the recovery; increasing concentration up to values comprised within the MSW, leads to killing of susceptible bacteria and to a successful clinical response; on the other hand, the possibility does exist that less susceptible microorganisms are selected. Finally, a third higher concentration profile subsists, corresponding to the MPC, above the MSW, which permits to obtain both the results. Such an approach has been extensively studied with fluoroquinolones. A number of studies suggests that different fluoroquinolones are contradistinguished by a diverse MPC value. Multiple factors can influence the risk of selecting bacterial resistance: mutagenicity of the fluoroquinolone utilized, size of microbial population to treat, antibiotic concentration attainable at the site infection, pathophysiologic features of the patient, and lastly the prescribing behaviour, not always appropriate.

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Among Gram negative bacteria, Pseudomonas aeruginosa, the extended spectrum β-lactamases (ESBL)-producing strains, Acinetobacter spp, in particular the multiresistant Acinetobacter baumannii, and Stenotrophomonas maltophilia are the most implicated micrororganisms in the ever more increasing problem of bacterial resistance. Possible solutions have to be searched, on one hand, in the use of new drugs but, on the other hand, in the re-evaluation of those already available drugs, possibly considering a new role for old drugs such as colistine and fosfomycin. Concerning ESBL-producing strains, the most recent data provided by EARSS report, in Italy, an incidence rate of 10-25%. The insurgence of an infection sustained by an ESBL+ve strain is strictly related to some well known risk factors, like the hospital stay itself, the disease severity, the length of stay in ICU, intubation and mechanical ventilation, catetherization, urinary or artery, and the past exposure to antibiotics. The raise in ESBL producing strains is closely related to the increasing use of cephalosporins. In the setting of a Gram negative infection, the combination therapy guarantees a higher coverage by reducing insurgence of possible resistance mechanisms, possibly resulting synergistic, and allowing a de-escalation therapy, although to this latter other problems, such as tolerability, costs and compliance, can be related. Another basic aspect to take into account of, in order to achieve the maximal efficacy of the antibiotic treatment, is the right dosage. In the idea to look for the best approach for the antibiotic treatment of a severe infection in a hospital setting, when a Gram negative aetiology is implicated, it can be possibly presumed that the right way consists in avoiding inappropriate antibiotic therapies, making therapeutic choices based on guidelines resulted from local epidemiological data, initiating the therapy promptly, avoiding excessive use of antibiotics, possibly modifying therapy at the light of clinical data and microbiological results (de-escalation).

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In response to the overuse and misuse of antibiotics, leading to increasing bacterial resistance and the decreasing development of new antibiotics, the Council for Appropriate and Rational Antibiotic Therapy (an independent, interdisciplinary panel of healthcare professionals established to advocate the appropriate use of antibiotics) has developed criteria to guide proper antibiotic selection. These criteria include: establishment of a need to justify use of antibiotics (e.g., colonization versus disease); evidence-based results; therapeutic benefits; safety; use of pharmacodynamic indices for optimal drug and optimal duration; cost-effectiveness. Promoting the appropriate use of antibiotics should provide for optimal outcomes for our patients.

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