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Antibiotic resistance was recognized soon after the discovery of antibiotics. During the past 50 years the rise in the frequency of resistance, particularly to multiple drugs, has thwarted treatment of patients in the hospital and the community. 1 Bacteria have continued to respond to human attempts to keep them in check. Methicillin was developed and introduced in the 1960s to circumvent inactivation by the common beta-lactamases that caused penicillin resistance. But methicillin-resistant Staphylococcus aureus (MRSA) emerged soon after to combat the beta-lactamase-resistant penicillin analog. More recently vancomycin, the antibiotic of choice for treating multidrug-resistant MRSA, has confronted resistant strains in Japan, the United States and Europe. 2 In England MRSA with heterogeneous resistance to vancomycin has been implicated in the treatment failure of 12 out of 14 patients who underwent orthopedic procedures. 3 Heterogeneous resistance to vancomycin implies that only one in a million progeny of the isolates taken from the patients showed intermediate resistance to vancomycin. Some hospital-acquired vancomycin-resistant enterococcal infections are resistant to all current antibiotics. 4 Other problem strains in the hospital include Klebsiella and Enterobacter and the opportunistic pathogens Pseudomonas aeruginosa and Acinetobacter baumanii.In the community a number of different bacteria that cause relatively common diseases have acquired multidrug resistance. These include strains of Streptococcus pneumoniae, which cause otitis media, pneumonia and meningitis. This finding is at least partially linked to misuse and overuse of antibiotics for viral-caused ear infections and upper respiratory symptoms. Although two-thirds of all ear infections are bacterial, 5 85% will resolve with no antibiotic treatment, yet antibiotics are prescribed for almost every child in the United States. 5 Because of widespread resistance, penicillin can no longer be relied on for treating meningitis caused by S. pneumoniae. A combination of drugs, i.e. vancomycin plus a cephalosporin, is recommended for the treatment of this community-acquired infection. 6Neisseria gonorrhoeae, previously easily treated with a single penicillin injection, has become so frequently resistant to this antibiotic that alternative drugs have been required. Today resistance to tetracyclines and fluoroquinolones has developed in N. gonorrhoeae as well, making a third generation cephalosporin the preferred antibiotic therapy. There are no other single dose drug therapy options remaining to treat this community-acquired disease when cephalosporin resistance emerges. The history of Neisseria treatment illustrates an important phenomenon of drug resistance. With time there is often an accumulation of resistance to many drugs in the same organism. 1Another example is Streptococcus pyogenes, the “flesh-eating bacteria” and the cause of strep throat. Historically this organism remained susceptible to all drugs. Its present day resistance to erythromycin and tetracycline reveals that with continued antibiotic use over time, resistance, even multidrug resistance, will emerge. 7 Likewise Escherichia coli and other enteric organisms such as Salmonella have also acquired multidrug resistance. Some Salmonella strains, like Salmonella typhimurium DT104, are resistant to five different antibiotics; therefore fluoroquinolones have become the only remaining effective treatment. When quinolones were first introduced, it was thought that bacteria resistant to quinolones would not become a problem because of the high susceptibility of the bacterium and the seemingly low frequency of resistance. This hope has been dispelled. Resistance to fluoroquinolones has appeared and patients are failing treatment. 8 This resistance requires at least two chromosomal mutations to be clinically relevant. Today in certain parts of Asia, 50 to 60% of E. coli may be fluoroquinolone-resistant.Simplistically antibiotic resistance is a natural expression of evolution and bacterial genetics.