An antibiotic is a substance derived from living organisms, usually \Tbacteria\t or molds, that kills microorganisms or inhibits their growth. Some antibiotics also interfere with life processes in higher organisms, but the term commonly applies to substances that act against microorganisms. Many synthetic drugs are also used to treat bacterial, fungal, or other parasitic infections, and may be called antibiotics, but strictly speaking the term is reserved for substances derived from living agents. The more general term might be antibacterials or antimicrobials. The use of moldy and fermented substances from dung and soybean curd to treat wounds and superficial swellings is described in the earliest medical records from China, Egypt, and Mesopotamia and dates back to at least 1500 BC. For more than 3,000 years, moderately effective methods for treating superficial infections were known, but ignorance of the causes of \Tinfectious disease\t precluded understanding of antibiosis. In 1874, William Roberts (1830-99) of Manchester, England, noted that the growth of fungi was often antagonistic to that of bacteria, and vice versa. He specifically observed that a mold, Penicillium glaucum, was immune to bacterial infection. Shortly thereafter, Louis \TPasteur\t and Jules Francois Joubert (1834-1910) noted that anthrax bacilli failed to grow if cultures became contaminated with airborne molds, and they suggested that this observation might have significant therapeutic implications. Important advances were delayed nearly half a century while the focus of research on infectious diseases shifted to immune serums, vaccines, and the use of chemical agents. DISCOVERY OF PENICILLIN In 1928, Alexander \TFleming\t noticed that growth of the pus-producing bacterium, Staphylococcus aureus, had stopped around an area in which an airborne mold contaminant, Penicillium notatum, had begun to grow. Fleming determined that a chemical substance had diffused from the mold and named it \Tpenicillin\t. The small, impure amounts he initially extracted lacked potency, yielding disappointing results in early attempts to treat human infections with penicillin. In 1939, Ernst Boris \Tchain\t, Howard Walter \TFlorey\t, and Edward Penley Abraham at Oxford University began to study the possibility that purer, more stable penicillin preparations might be effective. In 1941 the partially purified material was administered to a policeman suffering from osteomyelitis. Dramatic improvement ensued, but the supply was exhausted before a cure could be effected and the patient died. Nonetheless, the matter obviously deserved further exploration, and the outbreak of World War II added an element of urgency. The war, however, interfered with attempts to make penicillin in England on a large scale. Chain therefore hand-carried a vial of the mold to the United States, where the necessary industrial capacity was available for mass production. Application of beer-brewing technology yielded large amounts of mold liquor, from which partially purified penicillin could be laboriously recovered for clinical use. The first batches became available for military use in 1943. The material was so scarce that patients' urine was collected and the excreted penicillin recrystallized to be used again. Meanwhile, Rene \TDubos\t at the Rockefeller Institute had been pursuing Pasteur's original train of thought. Observing that microbial populations in soil held one another in check, he isolated and purified an antibiotic from a soil bacterium in 1939. It and similar substances subsequently isolated were effective when applied to superficial wounds but proved too toxic for systemic administration. By 1944, Selman Abraham \TWaksman\t and his colleagues had isolated streptomycin from a soil microbe and proved its effectiveness against the tubercle bacillus. Between 1945 and 1960, a systematic search was carried on for antibiotics derived from bacteria and molds found all over the world. Many hundreds of antibiotics were discovered, and dozens were screened for antibiotic activity and toxicity. Many were eventually marketed, and prescription use accounted for hundreds of tons annually. In 1957, penicillin was synthesized in the laboratory. Efforts followed to synthesize penicillins effective against bacteria that had become resistant to the original penicillin, but complete synthesis of penicillins proved prohibitively expensive. However, harvesting the basic molecules of penicillin from Penicillium molds and then tacking on diverse molecules proved feasible and led to a large number of tailor-made penicillin variants. The 1960s witnessed a veritable explosion of so-called semisynthetic (part mold-made, part synthetic) penicillins, each designed to deal with the increasing problem of penicillin-resistant bacteria, to achieve better absorption and higher concentrations in the body, or to broaden the penicillins' effective antimicrobial spectrum. The history of streptomycin and other major antibiotics is similar. The period from 1960 to the present has witnessed an enormous proliferation of laboratory-designed variations of the basic bacteria and molds isolated from nature, and a search through soil molds has yielded such recent classes of antibiotics as the broad-spectrum carbapenems and, in the 1980s, the monobactams, which may prove particularly useful in dealing with hospital-derived infections. Synthetic antibacterials such as the quinolones are finding a similar application (see also \Tbiopharmaceuticals\t). CLASSIFICATION OF ANTIBIOTICS The most common classification is based on mechanism of action. Antibiotics that inhibit the growth of the bacterial cell wall include the commonly used penicillin and cephalothin groups and such less-often used antibiotics as vancomycin and bacitracin. Antibiotics that act like detergents on the cell membrane--and therefore disrupt the passage of nutrients into the bacterial cell--include the antibacterials polymyxin and colistin, and the antifungals mycostatin and amphotericin. Antibiotics that interfere with protein synthesis in the bacterial cell include the tetracyclines, the aminoglycosides (streptomycin, kanamycin, neomycin, gentamicin, and amikacin), and the macrolide group comprising erythromycin, lincomycin, and clindamycin. Antibacterials that disrupt bacterial-gene replication include the antifungal griseofulvin and the synthetic quinolone drugs. Bactericidal and Bacteriostatic Effects Another classification system is based on whether an antibiotic kills microorganisms (bactericidal effect) or merely inhibits growth (bacteriostatic effect). Penicillins, aminoglycosides, vancomycin, bacitracin, the polymyxins, and colistin are bactericidal. Tetracycline, on the other hand, is bacteriostatic. When susceptible bacteria are exposed to tetracycline, growth will cease temporarily and then resume. Chloramphenicol and the macrolides are also bacteriostatic. These distinctions are clinically significant, since lethal infectious diseases will respond only to bactericidal agents. Spectrum of Activity A further classification system rests on the effective target range (activity spectrum) of an antibiotic, as defined by two criteria: (1) the species of susceptible microorganisms (for example, Staphylococcus, Streptococcus, E. Coli, and so on), and (2) whether the species are gram-positive or gram-negative. Bacteria retaining a blue stain despite treatment with iodine and acid alcohol are called gram-positive, and those losing it are gram-negative. The penicillins are effective against most gram-positive bacteria, whereas aminoglycosides are chiefly effective against gram-negative bacteria. These two groups of antibiotics are therefore termed narrow-spectrum agents. Tetracyclines and chloramphenicol are effective against a broad range of gram-positive and gram-negative bacteria, rickettsia, and other microorganisms and are therefore called broad-spectrum antibiotics. BACTERIAL SENSITIVITY The susceptibility of a given bacterial species to an antibiotic is usually determined either from laboratory tests or from the result of treating an established infection. In laboratory tests, bacteria isolated from an infected patient are inoculated into tubes containing a liquid culture medium enriched with graded concentrations of an antibiotic agent. The lowest concentration of antibiotic that inhibits microbial growth is termed the minimal inhibitory concentration (MIC). When this is compared with concentrations attainable in the body, one can judge whether the bacteria are sensitive, partly sensitive, or resistant to the antibiotic. Alternatively, the surface of a semisolid growth medium can be inoculated with bacteria, and antibiotic-impregnated filter-paper disks placed on that surface. The antibiotics leave clear zones around disks where growth of susceptible bacteria has been inhibited. The diameter of the inhibitory zones can be measured accurately and the results precisely interpreted to indicate sensitivity, partial resistance, or resistance to the antibiotics being tested. These relatively simple laboratory procedures usually permit accurate predictions of therapeutic responses. Occasionally, however, such tests do not correlate with clinical results, particularly when a person has a malignant disease, immune-system impairment, severe injury, or is receiving drugs that reduce resistance to infection. Outcome may also be unpredictable because of failure to absorb the antibiotic, deterioration of the antibiotic during storage, or its inactivation by simultaneously administered drugs. RESISTANCE TO ANTIBIOTICS Innate properties and acquired mechanisms account for microbial resistance to antibiotics. Innate resistance depends on the mechanism of action of an antibiotic. Thus, penicillin may not be able to reach the cell wall of resistant gram-negative bacteria because the cells are protected by a relatively thick, slimy coating. Such resistance can be overcome if the penicillin molecule can be modified to penetrate the coating. Resistance may be acquired by mutation or by the transfer of resistance genes from other bacteria. A mutation in the genetic apparatus of a bacterial cell may enable that cell to bypass the metabolic step blocked by an antibiotic or eliminate a receptor within a microorganism required for the antibiotic to exert its effects. Mutants are usually disadvantaged for survival in nature, but if a mutation occurs while the bacterial population is under pressure from an antibiotic, then the resistant mutant survivors may propagate. Thus, for example, resistant bacteria readily accumulate in hospitals where antibiotics are used freely. When an antibiotic is later banned from use in the hospital, the natural, antibiotic sensitive (wild) strains will gradually displace the resistant variants. Sensitive bacteria can also acquire genes from resistant bacteria that code for the production of antibiotic-destroying enzymes. These genes, called resistance transfer factors, are frequently acquired in groups, and previously sensitive bacteria may suddenly become resistant to a broad variety of antibiotics. The extrachromosomal genes are contained in packages (plasmids) that replicate in synchrony with bacterial-cell replication but independently of the chromosomal genes. Plasmids are used in recombinant \TDNA\t technology to alter the genetic makeup of bacterial cells (see \Tgenetic engineering\t). SELECTION OF AN ANTIBIOTIC An exact diagnosis of an infection can be established only by the demonstration of causative agents in a person's body fluids or tissues, or through the specific traces left by an infection in the antibody composition of the blood. If the diagnosis of an infectious disease has been proved by laboratory tests or is strongly suspected, the physician must still decide whether available antibiotics can be used effectively to treat the infection and whether the potential benefits of treatment outweigh the risks and costs involved. If a patient is so ill that the 24 to 48 hours required for diagnostic tests would probably result in further deterioration or even death, the physician immediately prescribes an antibiotic based on estimates of the most likely source of the infection. The physician first obtains specimens of blood, other body fluids, and any collections of infected material and sends them to the laboratory together with the available clinical information. The laboratory is thus guided to isolate and cultivate the most probable infectious agents possibly contained in specimens and to perform antibiotic sensitivity tests. When the laboratory reports arrive, the physician can make necessary adjustments in the antibiotic regimen. If the risk entailed by delaying antibiotic therapy appears small, the physician can obtain all necessary specimens and suspend therapy until the infectious agent is identified. The delay may protect the patient from unnecessary exposure to toxic or allergy-causing antibiotics, overgrowth by resistant microorganisms, and unnecessary expense. PREVENTIVE USES Antibiotics have long been used in attempts to protect healthy persons against infection by specific bacteria to which they may be exposed, to reduce the risk of infection in people with chronic illnesses, and to limit or prevent infection in patients with traumatic or surgical wounds. In the first case, prophylaxis, or prevention, usually succeeds when a single antibiotic will block infection by a specific microorganism or eradicate it shortly after it becomes established. Failure is common in other circumstances, since the objective is to prevent infection by any and all microorganisms, with neither targets nor weapons sharply defined. However, some success is reported for prophylaxis before surgery for implanting an artificial heart valve or hip joint, and before surgery involving the intestinal tract. Misguided attempts at prophylaxis frequently result in an increased incidence of infections, with antibiotic resistant microorganisms. The risks of toxic and allergic reactions--and unwarranted costs--are incurred with no potential benefit. Specialists estimate that at least 90 percent of antibiotic prescriptions are unnecessary or inappropriate. Antibiotics are also added to commercial animal feed in minute quantities, both for prophylaxis and because growth in animals is markedly increased. To minimize the problem of resistant strains, many countries restrict such use to antibiotics that are not prescribed to humans. COMMONLY USED ANTIBIOTICS Penicillin G, the first modern antibiotic to come into widespread use, is still the safest, most effective, and cheapest antibiotic. The ratio between toxic and clinically effective doses is several hundred to a thousandfold except in newborn infants and persons with poor kidney function, or when the antibiotic is applied directly to brain tissue. Penicillin G can be administered by mouth, but absorption is limited, and it may be destroyed by the acid in the stomach. It is injectable into muscle or vein; and absorption, distribution, and excretion follow predictable patterns. Allergic sensitization frequently follows application to the skin and mucus membranes; therefore it is not recommended for topical use. Penicillin G is a bactericidal, narrow-spectrum antibiotic that is highly effective against gram-positive bacteria, especially staphylococci, which cause boils, osteomyelitis, wound infections, and infections of the heart and blood vessels; streptococci, which cause "strep" throat, predispose to rheumatic fever and acute glomerulonephritis, infect abrasions and wounds, and cause blood poisoning and childbed fever; pneumococci, which cause the most common form of bacterial pneumonia; and against the bacteria that cause syphilis, gonorrhea, and common forms of bacterial meningitis. Nevertheless, penicillin G has several shortcomings. It is destroyed by stomach acid and by enzymes (penicillinases) produced by several microorganisms, its spectrum of activity is limited, and it frequently causes allergic reactions. The phenoxy-penicillins (such as penicillin V) resist degradation by stomach acid and can therefore be taken by mouth. Antibacterial spectrum is roughly similar to that of penicillin G, and penicillin V is also destroyed by penicillinases. Ampicillin is effective against a wider bacterial spectrum that includes some gram-negative bacteria, especially the typhoid bacillus and a Hemophilus influenzae, which causes the most common form of bacterial meningitis in infants between 6 months and 3 years of age, and many of the bacteria commonly causing urinary tract infections. Probably no more toxic than penicillin G, it does appear to be twice as likely to cause allergic skin rashes, and it often causes diarrhea. It is also destroyed by penicillinases. Amoxicillin is a very similar agent that is better absorbed and less likely to cause diarrhea. Methicillin (Staphcillin) resists penicillinase destruction and must be given by injection. It was the first penicillin effective against resistant "hospital staphylococcus," its only clinical indication. Much less effective than penicillin G against penicillin-G-sensitive bacteria, methicillin also first demonstrated that penicillins could be toxic to the kidneys. Oxacillin, cloxacillin, dicloxacillin, and nafcillin are similar to methicillin in that they resist destruction by penicillinase and can be given by mouth. Carbenicillin extends the antibacterial spectrum of the penicillins to cover Pseudomonas strains, its only clinical indication. These gram-negative bacteria cause serious infections in hospitalized and debilitated patients. Mezlocillin, piperacillin, and ticarcillin are other extended-spectrum pencillins. Their main use is treating Pseudomonas infection and as prophylaxis in immunocompromised patients, such as cancer patients, who are at serious risk of developing a gram-negative infection. Cephalosporins Cephalosporins are semisynthetic derivatives of cephalosporin C, which is produced by Cephalosporium acremonium, a fungus. They are very similar to penicillins in structure and activity and, in general, are active against many gram-positive, gram-negative, and some anaerobic bacteria. First-generation cephalosporins were first available in the 1970s and, like penicillin G, are used against gram-positive organisms. Second-generation cephalosporins are generally active against organisms susceptible to first-generation agents, but their activity is expanded to include some gram-negative organisms. Third-generation agents have little activity against gram-positive organisms but are more active than second-generation agents against gram-negative organisms. Available only in the injectable form, they are used in hospitalized patients such as those with Pseudomonas infections. Macrolides Erythromycin is one of the safest antibiotics and rarely causes toxic reactions other than gastrointestinal irritation. The rare allergic reactions are usually limited to mild skin rashes, fever, and some changes in the cellular components of the blood. If the dosage is increased more than twofold beyond standard amounts, or if the chemical structure is altered to improve absorption, severe liver damage may occur. The principal use for erythromycin is in the treatment of mild to moderately severe gram-positive bacterial infections in patients allergic to penicillin, for the prevention of streptococcal infections in penicillin-allergic patients with a history of acute rheumatic fever, and for the treatment of pneumonia due to Mycoplasma. All macrolides are bacteriostatic and tend to penetrate poorly into the cerebrospinal fluid. They are therefore not used for treating meningitis. Clindamycin, clinically similar to macrolides but chemically different, is effective against \Lanaerobe\ls that often cause wound infections following abdominal trauma or surgery. It has been known to cause massive diarrhea and colitis, in as many as 15 to 20 percent of treated patients, and is therefore reserved for treating severe, anaerobic infections. Aminoglycosides The aminoglycosides--streptomycin, neomycin, gentamicin, tobramycin, amikacin, netilmicin, and kanamycin--are second only to the penicillins in importance. The oldest member of the group, streptomycin, was the second antibiotic to come into widespread clinical usage and the first to demonstrate significant effectiveness against the tubercle bacillus. Bactericidal, narrow-spectrum antibiotics, aminoglycosides are highly effective against most gram-negative bacteria. They are largely ineffective against gram-positive bacteria, with the exception of staphylococci, and they are ineffective against other forms of microbial life. All aminoglycosides are toxic to the auditory apparatus (the organs responsible for maintaining equilibrium) and the kidneys. All can cause allergic reactions, including fever, skin rashes, changes in the cellular composition of the blood, and--rarely--sudden death. The rapidity with which bacteria acquire resistance to these antibiotics has necessitated a continuing search for new aminoglycosides. Tetracyclines First discovered in the late 1940s, the tetracyclines are highly effective, broad-spectrum, bacteriostatic antibiotics. They are effective against a wide variety of gram-positive and gram-negative bacteria, rickettsia, and the large viruslike agents that cause trachoma and related diseases, and are partly effective against some biologically more complex protozoan parasites. The broad-spectrum activity of these agents results in eliminating much of the patient's normal microbial population, with consequent overgrowth of resistant remnants that are normally harmless. This has caused black, hairy tongue and fungal infections of the perineal area, the underarm area, and the gastrointestinal tract. A sore, red mouth may occur, probably due to vitamin deficiencies induced by elimination of the normal, vitamin-producing members of the host's microbial population. Tetracyclines are administered orally, usually for acne or urinary tract infections. Chloramphenicol Chloramphenicol is a highly effective, broad-spectrum bacteriostatic antibiotic with principal activity against gram-positive and gram-negative bacteria and rickettsia. One of the safest antibiotics, it has acquired a bad reputation because a few treated patients developed severe depression of bone marrow function (impaired red blood cell, white blood cell, and platelet production). Since substitutes exist for almost every indication where chloramphenicol might be considered, treatment with chloramphenicol can only be justified on the basis of demonstrated and documented need. Such can be found in the treatment of typhoid fever where the infecting bacteria have been shown resistant to ampicillin and sensitive to chloramphenicol. Another indication is in the treatment of bacterial meningitis; penetration of chloramphenicol into the cerebrospinal fluid space is better than with any other antibiotic, and it displays the necessary spectrum of activity to deal with most bacterial causes of meningitis. Harold J. Simon, M.D. Bibliography: Conte, J. E., Jr., and Barriere, S. L., Manual of Antibiotics and Infectious Diseases, 6th ed. (1988); Egorov, N.S., Antibiotics (1985); Grayson, Martin, ed., Antibiotics, Chemotherapeutics, and Antibacterial Agents (1983); Holt, K.L., Antibiotics and Adverse Effects (1987); Hughes, W. H., and Stewart, H. C., Alexander Fleming and Penicillin (1977); Parascondola, John, ed., The History of Antibiotics (1980); Zoler, M. L., "Antibiotic Options," Medical World News, Mar. 23, 1987.