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“Collateral damage” is a term used to refer to ecological adverse effects of antibiotic therapy; namely, the selection of drug-resistant organisms and the unwanted development of colonization or infection with multidrug-resistant organisms. The risk of such damage can be assessed for different antibiotic classes by a variety of epidemiologic studies. Cephalosporin use has been linked to subsequent infection with vancomycin-resistant enterococci, extended-spectrum β-lactamase—producing Klebsiella pneumoniae, β-lactam—resistant Acinetobacter species, and Clostridium difficile. Quinolone use has been linked to infection with methicillin-resistant Staphylococcus aureus and with increasing quinolone resistance in gram-negative bacilli, such as Pseudomonas aeruginosa. Neither third-generation cephalosporins nor quinolones appear suitable for sustained use in hospitals as “workhorse” antibiotic therapy.