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Antibiotics. Antibiotics are substances produced by microorganisms that at low concentrations kill or inhibit other microorganisms

Antibiotics are substances produced by microorganisms that at low concentrations kill or inhibit other microorganisms. They are produced commonly by soil microorganisms and probably represent a means by which organisms in a complex environment, such as soil, control the growth of competing microorganisms. The microorganisms that produce antibiotics useful in preventing or treating disease include bacteria (Bacillus and Streptomyces) and fungi (Penicillium, Cephalosporium, and Micromonospora). Antibiotics can inhibit microbes by inhibiting the synthesis of the cell wall.

Other antibiotics, such as the aminoglycosides, chloramphenicol, erythromycins, and clindamycin, inhibit protein synthesis in bacteria. The basic process by which bacteria and animal cells synthesize proteins is similar, but the proteins involved are different. Those antibiotics that are useful as antibacterial agents (selectively toxic) utilize these differences to bind to or inhibit the function of the proteins of the bacterium, thereby preventing the synthesis of new proteins and new bacterial cells. Antibiotics such as polymyxin B and colistin bind to phospholipids in the cell membrane of the bacterium and interfere with its function as a selective barrier; this allows essential macromolecules in the cell to leak out, resulting in the death of the cell. Because other cells, including human cells, have similar or identical phospholipids, these antibiotics are somewhat toxic. One antibiotic, rifampin, interferes with RNA synthesis in bacteria by binding to a subunit on the bacterial enzyme responsible for duplication of RNA. Since the affinity of rifampin is much stronger for the bacterial enzyme responsible for duplication of RNA. Since the affinity of rifampin is much stronger for the bacterial enzyme than for the mammalian enzyme, the mammalian cells are inaffected at therapeutic dosages.

Bacteria, unlike animal cells, have a cell wall surrounding a cytoplasmic membrane. Production of the cell wall involves the partial assembly of wall components inside the cell, transport of these structures through the cell membrane to the growing wall, assembly into the wall, and finally cross-linking of the strands of wall material. Antibiotics that inhibit the synthesis of a cell wall have a specific effect on one or another phase. The result is an alteration in the cell wall and in shape of the organism and the eventual destruction of the bacterium.

The penicillins and cephalosporins both have the unique structure, a ß -lactam ring, that is responsible for their antibacterial activity. The ß -lactam ring interacts with proteins in the cell responsible for the final step in the assembly of the cell wall. Thus, the mechanism of action is identical for both antibiotics; however, the basic chemical structure of the penicillins and cephalosporins differs in other respects, resulting in some difference in pharmacokinetics and the spectrum of antimicrobial activity.

The penicillins can be divided into two groups: the naturally occurring penicillins (penicillin G and penicillin V) and the semisynthetic penicillins. The semisynthetic penicillins are produced by growing the mold Penicillium under conditions whereby only the basic molecule (6-aminopenicillanic acid) is produced. By adding certain chemical groups to this molecule, several different semisynthetic penicillins are produced that vary in resistance to degradation by B- lactamase (penicillinase), an enzyme that specifically breaks the B-lactam ring, thereby inactivating the antibiotic. In addition, the antimicrobial spectrum of activity and pharmacological properties of the natural penicillins can be changed and improved by these chemical modifications.

The naturally occurring penicillins are important chemotherapeutic agents. Even after 40 years of use they are still the drugs of choice for treating streptococcal sore throat, tonsillitis, pneumococcal pneumonia, endocarditis caused by some streptococci, syphilis, gonorrhea, meningococcal infections, and infections caused by some anaerobic organisms. Several microorganisms, most notably the staphylococci, developed resistance to the naturally occurring penicillins, which led to the production of the penicillinase-resistant.

To extend the usefulness of the penicillins to the treatment of infections caused by gram-negative rods, the broad-spectrum penicillins (ampicillin, amoxicillin and carbenicillin) were developed. These penicillins are sensitive to penicillinase, but they are useful in treating urinary tract infections caused by gram-negative rods as well as in treating typhoid and enteric fevers.

The extended-spectrum agents (mezlocillin, azlocillin, and piperacillin) are unique in that they have greater activity against gram- negative bacteria, including Pseudomonas aeruginosa. They have decreased activity, however, against penicillinase-resistant Staphylococcus aureus.

The penicillins are the safest of all antibiotics. The major adverse reaction associated with their use is hypersensitivity, with reactions ranging from a rash to bronchospasm and anaphylaxis. The more serious reactions are uncommon.

The cephalosporins are produced by Cephalosporium acremonium. Modification of the basic molecule (7-aminocephalosporanic acid) has resulted in three generations of cephalosporins. The first-generation cephalosporins have a range of antimicrobial activity similar to the broad-spectrum penicillins. The second-generation cephalosporins have greater ß -lactamase stability than the earlier cephalosporins, and their antibacterial spectrum has been extended to include greater activity against additional species of gram-negative rods. They have decreased activity, however, against gram-positive bacteria. Like the penicillins, the cephalosporins are relatively nontoxic. Because the structure of the cephalosporins is similar to that of penicillin, hypersensitivity reactions can occur in penicillin-hypersensitive patients.

Cycloserine, an antibiotic produced by Streptomyces orchidaceus, is a structural analogue of the amino acid D-alanine, and it interferes with enzymes necessary for incorporation of D-alanine into the bacterial cell wall. It is rapidly absorbed from the gastrointestinal tract and penetrates most tissues quite well; high levels are found in urine. It is used in the treatment of tuberculosis and in some urinary tract infections.

Bacitracin is produced by a special strain of Bacillus subtilis. Because of its toxicity its use is limited to the topical treatment of skin infections caused by streptococci and staphylococci and for eye and ear infections. Vancomycin, an antibiotic produced by Streptomyces orientalis, is poorly absorbed from the gastrointestinal tract and is usually given by intravenous injection. It is an excellent antibiotic for the treatment of serious staphylococcal infections caused by strains resistant to the various penicillins.

The aminoglycosides (streptomycin; neomycin; paromomycin; kanamycin and its derivative, amikacin; tobramycin; netilmicin; and spectinomycin) are produced by Streptomyces species. Gentamicin is produced by the molds Micromonospora purpurea and M. echinospora. All of the aminoglycosides inhibit protein synthesis, although spectinomycin, which has a different structure, does so by a mechanism different from the other aminoglycosides. The aminoglycosides are poorly absorbed from the gastrointestinal tract, so, with some exception, they are given by intramuscular injection. Neomycin is toxic and is used topically. Because it is poorly absorbed from the gastrointestinal tract, paromomycin is used in the treatment of protozoal infections of the intestinal tract.

Streptomycin was the first of the aminoglycosides to be discovered and the second antibiotic used in chemotherapy. One of its more important uses had been as part of the combined therapy for tuberculosis. It still has some use in combination with penicillin for treating infections of heart valves (endocarditis) and with tetracyclines in the treatment of plague, tularaemia, and brucellosis.

Kanamycin is used in the treatment of septicemia (blood poisoning), meningitis, and urinary tract infections caused by gram-negative bacteria. Because many organisms are resistant to its effects, however, kanamycin is now being replaced by other drugs. Gentamicin, tobramycin, netilmicin, and amikacin are similar in their range of antimicrobial activity. They are effective against infections caused by staphylococci and gram-negative bacteria, including Pseudomonas aeruginosa.