The increasing spread of multi-resistant strains of bacteria, particularly in the hospital setting, is currently one of the major challenges that antibiotic therapy must face. Initial, inappropriate antibiotic treatment that does not provide sufficient activity against multi-resistant pathogens is often responsible for increased mortality. The micro-organisms causing infections that are particularly problematic to treat include the Gram-negative bacilli, in particular Pseudomonas aeruginosa, and the Gram-positive cocci, such as methicillin-resistant Staphylococcus aureus (MRSA) or enterococci. The most appropriate empirical therapy should include broad-spectrum antibiotics with the ability to reach therapeutic concentrations in the site of the infection in order to limit the emergence of resistant strains. The use of combinations of antibiotics that have synergistic effects on certain bacterial species can contribute substantially to achieving this goal. A large body of published data shows that the efficacy and induction of resistance vary markedly when different antibiotics are used, alone or in combination, and when different concentrations of the antibiotics are reached in the various sites of infection. In vitro studies have shown that, compared to monotherapy with a single antibiotic, synergistic combinations of antibiotics lead to significantly less selection of resistant strains of both P. aeruginosa and MRSA.

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S. pneumoniae and methicillin-resistant S. aureus are the main Gram-positive pathogens responsible for severe infections. In the context of community infections S. pneumoniae is the leading Gram-positive pathogen causing severe infections such as purulent meningitis and pneumonia. The typical pattern of antibiotic sensitivity of this bacterium, frequently resistant to macrolides and with significantly reduced sensitivity to penicillin, is only a relative therapeutic problem in that the preserved sensitivity to third-generation cephalosporins and respiratory fluoroquinolones is sufficient to make these antibiotics valid therapeutic solutions without having to use the latest generation of drugs. On the other hand, methicillin-resistant S. aureus, one of the main bacteria responsible for nosocomial infections such as bacteraemia and respiratory tract infections in severely ill patients, is a more challenging therapeutic problem since, historically, the therapeutic options available in clinical practice have been fewer and essentially limited to glycopeptides. The recent availability of oxazolidinones and the pharmacologically more rational and appropriate use of the glycopeptides have undoubtedly brought substantial benefits; the imminent introduction of new molecules active against Gram-positive pathogens will certainly make an important contribution, although their use in clinical practice will need to be monitored.

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Pseudomonas aeruginosa is often involved in the aetiology of numerous infections, particularly those occurring in hospital. The infections in which P. aeruginosa most frequently has a pathogenic role include respiratory tract infections, particularly those occurring in patients with chronic obstructive pulmonary disease (COPD), nosocomial pneumonia, ventilator-associated pneumonia, and cystic fibrosis, as well as those developing in patients with AIDS, bacteraemia, sepsis, urinary tract infections, especially those related to catheterisation or kidney transplants, infections in neutropenic patients, and skin infections, particular those developing in surgical wounds or in burns. Thus, in practice, P. aeruginosa is ubiquitously present in all body districts. Particular attention should also be given to the presence of P. aeruginosa in the community setting, for example when it causes community-acquired pneumonia in the elderly or pneumonia in patients with advanced stage COPD. The mortality rate of patients with severe P. aeruginosa infections is very high. Treatment should be initiated very promptly with the most suitable drug, perhaps making use of combination therapy with a beta-lactam and a fluoroquinolone when indicated, and continued for a sufficiently long period. As far as concerns future therapeutic options for the treatment of P. aeruginosa infections, the only two new molecules that will probably become available are doripenem and ceftobiprole. Given this prospective, trust must be placed in the already known drugs, exploiting them more appropriately.

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