The introduction of antibiotics and other antimicrobial compounds revolutionized medical treatment of infectious diseases, leading some observers to declare victory in the lengthy war against these illnesses. The proclamation proved to be premature, for microbes demonstrated impressive abilities to escape killing or inactivation by these drugs. In populations of bacteria and other microbes, various clones exist that are resistant to the actions of different drugs. After exposure or improper exposure to these drugs, the more susceptible organisms are killed and the more resistant organisms tend to survive and may come to dominate the population under certain circumstances due to their increased fitness (greater ability to survive and reproduce). Many bacterial resistance elements are contained either singly or in groups within mobile genetic elements (discussed later in this chapter) that may enable rapid transmission of multiple drug resistance genes. As microbial populations develop resistance to existing drugs, humans have responded by producing new drugs. The microbes subsequently find means of evading these drugs, forcing humans to search for more novel agents in the continuing evolutionary waltz of life.

Increased incidence of drug resistance is currently a rapidly growing phenomenon in many types of organisms, including viruses, bacteria, protozoa, and insects. Separate chapters deal with this phenomenon in several organisms, including HIV, tuberculosis, and malaria. In bacteria, genes encoding products that allow bacteria to escape drug actions (resistance genes) often exist on plasmids, circular pieces of extrachromosomal DNA. These genes may also be found in transposons and integrons. These three genetic elements are readily passed between bacteria of the same as well as different species, allowing intra- and interspecies spread of resistance elements.

Bacteria may pass resistance genes to other organisms during the processes of conjugation, transformation, or transduction. During conjugation in gram-positive bacteria, DNA is exchanged between a mating pair of microbes. In gram-negative bacteria, plasmids are transferred to nearby bacteria in an act that often involves elongated pili that join the microbes together. Transformation involves the acquisition of DNA from other bacteria that have previously lysed and released their DNA into the external environment. During transduction, bacteriophages (viruses that infect bacteria) transfer genetic material between bacteria. These mechanisms may lead to multidrug resistance, the acquisition of resistance to three or more drugs, an increasing cause for concern, especially in health care settings.

Human actions may aid in the development of drug resistance. Such actions include noncompliance with instructions regarding the completion of a course of medication and the overuse of antimicrobial drugs in both humans and agriculture.

Antibiotics revolutionized the treatment of infectious diseases of bacterial origin. Older antimicrobial compounds included toxic compounds, such as mercury and arsenic derivatives; gramicidin, discovered by the work of René Dubos and Rollin Hotchkiss; and sulfanilamide. The first antibiotic was penicillin, produced by the fungus Penicillium notatum and discovered almost accidentally by Sir Alexander Fleming in 1928. Two Australian scientists, Howard Florey and Ernst Chain, found means of producing penicillin in the large quantities necessary for general use. Widespread use of penicillin began in the 1940s, whereupon morbidity and mortality rates from bacterial diseases fell drastically. Military forces during World War II benefited greatly as the number of deaths due to wounds infected with organisms such as Staphylococcus aureus and Streptococcus pyogenes diminished. Penicillin is itself attacked (hydrolyzed) by the enzyme β-lactamase. This enzyme is carried on a plasmid that resided within most strains of S. aureus by the end of that war. Currently, 95% of the clinical isolates of these bacteria are penicillin-resistant.

Bacteria soon began to develop resistance to other antibiotics—in 1961, methicillin-resistant strains of S. aureus were reported; during the mid-1970s, strains of P. aeruginosa developed resistance to extended-spectrum cephalosporins, carbapenems, aminoglycosides, and fluoroquinolones; in 1983, strains of E. coli became resistant to penicillin; and the 1990s saw the advent of vancomycin-resistant enterococci. Resistance genes are often contained within mobile genetic elements, allowing rapid transmission between bacteria of the same or different species. Some of these genetic elements have accumulated resistance genes to several drugs, resulting in multidrug resistance. The increased use of antibiotics in human health and in agriculture combined with noncompliance in completion of the course of medication has fueled and accelerated this natural trend in bacterial evolution.

Methicillin- and Vancomycin-Resistant Staphylococcus aureus

Staphylococcus species are common bacteria occurring naturally in the environment and in hospital settings. These gram-positive spherical bacteria reside on the skin or in the nasal or pharyngeal passages of 25% to 40% of the general population. They may enter the body’s interior through cuts, sores, catheters, and breathing tubes. S. aureus is pathogenic, resulting in a wide spectrum of diseases ranging from minor infections of skin or soft tissues to severe sepsis with a high rate of mortality.

Penicillin was the first antibiotic to be highly effective against S. aureus infection. As noted earlier, however, penicillin resistance emerged soon after it became widely used. Other antibiotics effective against the β-lactamase-containing bacteria were introduced in the early 1960s and included methicillin and oxacillin. Within a year of their introduction, however, resistant strains of bacteria were reported in the United Kingdom and later in Europe and Australia, occurring in hospitals throughout the world by the 1980s. These strains came to be known as methicillin-resistant Staphylococcus aureus (MRSA) and were soon found to be resistant not just to methicillin but to all β-lactams, including many penicillins and cephalosporins. Many strains are also resistant to aminoglycosides and fluoroquinones.

MRSA was first reported in the United Kingdom in 1961. Between the 1970s and late 1990s, MRSA slowly began to spread and cause infections, mostly in medical centers or in patients using these facilities. By 2004, some 69% of the staphylococcal isolates in U.S. intensive care units were of the resistant phenotype. Five MRSA clones are responsible for approximately 70% of the current infections.

Infection with MRSA is especially problematic for individuals in a weakened state or immunosuppressed, such as those who are hospitalized; patients undergoing long-term health care, dialysis, or surgery; cancer patients; and the elderly. This type of MRSA is referred to as hospital-associated (HA-MRSA). Risk factors for developing HA-MRSA include exposure to a hospital or long-term health care facility, use of antibiotics within the past year, chronic disease, IV drug use, or close contact with a person having one of these risk factors. HA-MRSA infections usually involve ventilator-associated pneumonia or bacterial invasion of indwelling venous devices or wounds. Such infections are related to increased length of hospital stay and cost and higher mortality.