O Aminoglycosides

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The discovery of streptomycin, the first aminoglycoside antibiotic to be used in chemotherapy, was the result of a planned and deliberate search begun in 1939 and brought to fruition in 1944 by Schatz and associates.104 This success stimulated worldwide searches for antibiotics from the actinomycetes and, particularly, from the genus Streptomyces. Among the many antibiotics isolated from that genus, several are compounds closely related in structure to streptomycin. Six of them—kanamycin, neomycin, paromomycin, gentamicin, tobramycin, and netilmicin— currently are marketed in the United States. Amikacin, a semisynthetic derivative of kanamycin A, has been added, and it is possible that additional aminoglycosides will be introduced in the future.

All aminoglycoside antibiotics are absorbed very poorly (less than 1% under normal circumstances) following oral administration, and some of them (kanamycin, neomycin, and paromomycin) are administered by that route for the treatment of GI infections. Because of their potent broad-spectrum antimicrobial activity, they are also used for the treatment of systemic infections. Their undesirable side effects, particularly ototoxicity and nephrotoxicity, have restricted their systemic use to serious infections or infections caused by bacterial strains resistant to other agents. When administered for systemic infections, aminoglycosides must be given parenterally, usually by intramuscular injection. An additional antibiotic obtained from Streptomyces, spectinomycin, is also an aminoglycoside but differs chemically and microbiologically from other members of the group. It is used exclusively for the treatment of uncomplicated gonorrhea.


Aminoglycosides are so named because their structures consist of amino sugars linked glycosidically. All have at least one aminohexose, and some have a pentose lacking an amino group (e.g., streptomycin, neomycin, and paromomycin). Additionally, each of the clinically useful aminoglycosides contains a highly substituted 1,3-diaminocyclohexane central ring; in kanamycin, neomycin, gentamicin, and tobramycin, it is deoxystreptamine, and in streptomycin, it is streptadine. The aminoglycosides are thus strongly basic compounds that exist as polycations at physiological pH. Their inorganic acid salts are very soluble in water. All are available as sulfates. Solutions of the aminoglycoside salts are stable to autoclav-ing. The high water solubility of the aminoglycosides no doubt contributes to their pharmacokinetic properties. They distribute well into most body fluids but not into the central nervous system, bone, or fatty or connective tissues. They tend to concentrate in the kidneys and are excreted by glomerular filtration. Aminoglycosides are apparently not metabolized in vivo.

Spectrum of Activity

Although the aminoglycosides are classified as broad-spectrum antibiotics, their greatest usefulness lies in the treatment of serious systemic infections caused by aerobic Gram-negative bacilli. The choice of agent is generally between kanamycin, gentamicin, tobramycin, netilmicin, and amikacin. Aerobic Gram-negative and Gram-positive cocci (with the exception of staphylococci) tend to be less sensitive; thus, the ¡-lactams and other antibiotics tend to be preferred for the treatment of infections caused by these organisms. Anaerobic bacteria are invariably resistant to the aminoglycosides. Streptomycin is the most effective of the group for the chemotherapy of TB, brucellosis, tularemia, and Yersinia infections. Paromomycin is used primarily in the chemotherapy of amebic dysentery. Under certain circumstances, aminoglycoside and ¡-lactam antibiotics exert a synergistic action in vivo against some bacterial strains when the two are administered jointly. For example, carbeni-cillin and gentamicin are synergistic against gentamicin-sen-sitive strains of P. aeruginosa and several other species of Gram-negative bacilli, and penicillin G and streptomycin (or gentamicin or kanamycin) tend to be more effective than either agent alone in the treatment of enterococcal endocarditis. The two antibiotic types should not be combined in the same solution because they are chemically incompatible. Damage to the cell wall caused by the ¡-lactam antibiotic is believed to increase penetration of the aminoglycoside into the bacterial cell.

Mechanism of Action

Most studies concerning the mechanism of antibacterial action of the aminoglycosides were carried out with streptomycin. However, the specific actions of other amino-glycosides are thought to be qualitatively similar. The amino-glycosides act directly on the bacterial ribosome to inhibit the initiation of protein synthesis and to interfere with the fidelity of translation of the genetic message. They bind to the 30S ri-bosomal subunit to form a complex that cannot initiate proper amino acid polymerization.105 The binding of streptomycin and other aminoglycosides to ribosomes also causes misreading mutations of the genetic code, apparently resulting from failure of specific aminoacyl RNAs to recognize the proper codons on messenger RNA (mRNA) and hence incorporation of improper amino acids into the peptide chain.106 Evidence suggests that the deoxystreptamine-containing aminoglyco-sides differ quantitatively from streptomycin in causing misreading at lower concentrations than those required to prevent initiation of protein synthesis, whereas streptomycin is equally effective in inhibiting initiation and causing misreading.107 Spectinomycin prevents the initiation of protein synthesis but apparently does not cause misreading. All of the commercially available aminoglycoside antibiotics are bactericidal, except spectinomycin. The mechanism for the bactericidal action of the aminoglycosides is not known.

Microbial Resistance

The development of strains of Enterobacteriaceae resistant to antibiotics is a well-recognized, serious medical problem. Nosocomial (hospital acquired) infections caused by these organisms are often resistant to antibiotic therapy. Research has established clearly that multidrug resistance among Gram-negative bacilli to various antibiotics occurs and can be transmitted to previously nonresistant strains of the same species and, indeed, to different species of bacteria. Resistance is transferred from one bacterium to another by extrachromosomal R factors (DNA) that self-replicate and are transferred by conjugation (direct contact). The amino-glycoside antibiotics, because of their potent bactericidal action against Gram-negative bacilli, are now preferred for the treatment of many serious infections caused by coliform bacteria. A pattern of bacterial resistance to each of the amino-glycoside antibiotics, however, has developed as their clinical use has become more widespread. Consequently, there are bacterial strains resistant to streptomycin, kanamycin, and gentamicin. Strains carrying R factors for resistance to these antibiotics synthesize enzymes that are capable of acetylating, phosphorylating, or adenylylating key amino or hydroxyl groups of the aminoglycosides. Much of the recent effort in aminoglycoside research is directed toward identifying new, or modifying existing, antibiotics that are resistant to inactivation by bacterial enzymes.

Resistance of individual aminoglycosides to specific inactivating enzymes can be understood, in large measure, by using chemical principles. First, one can assume that if the target functional group is absent in a position of the structure normally attacked by an inactivating enzyme, then the antibiotic will be resistant to the enzyme. Second, steric factors may confer resistance to attack at functionalities otherwise susceptible to enzymatic attack. For example, conversion of a primary amino group to a secondary amine inhibits N-acetylation by certain aminoglycoside acetyl transferases. At least nine different types of aminoglyco-side-inactivating enzymes have been identified and partially characterized.108 The sites of attack of these enzymes and the biochemistry of the inactivation reactions is described briefly, using the kanamycin B structure (which holds the dubious distinction of being a substrate for all of the enzymes described) for illustrative purposes (Fig. 8.7).

Aminoglycoside-inactivating enzymes include (a) aminoacetyltransferases (designated AAC), which acety-late the 6'-NH2 of ring I, the 3-NH2 of ring II, or the 2'-NH2 of ring I; (b) phosphotransferases (designated APH), which phosphorylate the 3'-OH of ring I or the 2"-OH of ring III; and (c) nucleotidyltransferases (ANT), which adenylate the 2"-OH of ring III, the 4'-OH of ring I, or the 4"-OH of ring III.

The gentamicins and tobramycin lack a 3'-hydroxyl group in ring I (see the section on the individual products for structures) and, consequently, are not inactivated by the phosphotransferase enzymes that phosphorylate that group in the kanamycins. Gentamicin C1 (but not gentamicins Cla

Figure 8.7 • Inactivation of kanamycin B by bacterial enzymes.

or C2 or tobramycin) is resistant to the acetyltransferase that acetylates the 6'-amino group in ring I of kanamycin B. All gentamicins are resistant to the nucleotidyltransferase enzyme that adenylylates the secondary equatorial 4"-hydroxyl group of kanamycin B because the 4"-hydroxyl group in the gentamicins is tertiary and is oriented axially. Removal of functional groups susceptible to attacking an aminoglyco-side occasionally can lead to derivatives that resist enzymatic inactivation and retain activity. For example, the 3'-deoxy-, 4'-deoxy-, and 3',4'-dideoxykanamycins are more similar to the gentamicins and tobramycin in their patterns of activity against clinical isolates that resist one or more of the aminoglycoside-inactivating enzymes.

The most significant breakthrough yet achieved in the search for aminoglycosides resistant to bacterial enzymes has been the development of amikacin, the 1-n-l-(-)-amino-a-hydroxybutyric acid (l-AHBA) derivative of kanamycin A. This remarkable compound retains most of the intrinsic potency of kanamycin A and is resistant to virtually all aminoglycoside-inactivating enzymes known, except the aminoacetyltransferase that acetylates the 6'-amino group and the nucleotidyltransferase that adenylylates the 4'-hydroxyl group of ring I.108,109 The cause of amikacin's resistance to enzymatic inactivation is unknown, but it has been suggested that introduction of the l-AHBA group into kanamycin A markedly decreases its affinity for the inactivating enzymes. The importance of amikacin's resistance to enzymatic inactivation is reflected in the results of an investigation on the comparative effectiveness of amikacin and other aminoglycosides against clinical isolates of bacterial strains known to be resistant to one or more of the aminoglycosides.110 In this study, amikacin was effective against 91% of the isolates (with a range of 87%-100%, depending on the species). Of the strains susceptible to other systemi-cally useful aminoglycosides, 18% were susceptible to kanamycin, 36% to gentamicin, and 41% to tobramycin.

Low-level resistance associated with diminished amino-glycoside uptake has been observed in certain strains of P. aeruginosa isolated from nosocomial infections.111 Bacterial susceptibility to aminoglycosides requires uptake of the drug by an energy-dependent active process.112 Uptake is initiated by the binding of the cationic aminoglycoside to anionic phospholipids of the cell membrane. Electron transport-linked transfer of the aminoglycoside through the cell membrane then occurs. Divalent cations such as Ca2+ and

Mg2+ antagonize the transport of aminoglycosides into bacterial cells by interfering with their binding to cell membrane phospholipids. The resistance of anaerobic bacteria to the lethal action of the aminoglycosides is apparently because of the absence of the respiration-driven active-transport process for transporting the antibiotics.

Structure-Activity Relationships

Despite the complexity inherent in various aminoglycoside structures, some conclusions on SARs in this antibiotic class have been made.113 Such conclusions have been formulated on the basis of comparisons of naturally occurring aminoglycoside structures, the results of selective semisynthetic modifications, and the elucidation of sites of inactivation by bacterial enzymes. It is convenient to discuss sequentially aminoglycoside SARs in terms of substituents in rings I, II, and III.

Ring I is crucially important for characteristic broad-spectrum antibacterial activity, and it is the primary target for bacterial inactivating enzymes. Amino functions at 6' and 2' are particularly important as kanamycin B (6'-amino, 2'-amino) is more active than kanamycin A (6'-amino, 2'-hydroxyl), which in turn is more active than kanamycin C (6'-hydroxyl, 2'-amino). Methylation at either the 6'-carbon or the 6'-amino positions does not lower appreciably antibacterial activity and confers resistance to enzymatic acety-lation of the 6'-amino group. Removal of the 3'-hydroxyl or the 4'-hydroxyl group or both in the kanamycins (e.g., 3',4'-dideoxykanamycin B or dibekacin) does not reduce antibacterial potency. The gentamicins also lack oxygen functions at these positions, as do sisomicin and netilmicin, which also have a 4',5'-double bond. None of these derivatives is inactivated by phosphotransferase enzymes that phosphory-late the 3'-hydroxyl group. Evidently, the 3'-phosphorylated derivatives have very low affinity for aminoglycoside-bind-ing sites in bacterial ribosomes.

Few modifications of ring II (deoxystreptamine) functional groups are possible without appreciable loss of activity in most of the aminoglycosides. The 1-amino group of kanamycin A can be acylated (e.g., amikacin), however, with activity largely retained. Netilmicin (1-n-ethylsi-somicin) retains the antibacterial potency of sisomicin and is resistant to several additional bacteria-inactivating enzymes. 2"-Hydroxysisomicin is claimed to be resistant to bacterial strains that adenylate the 2"-hydroxyl group of ring III, whereas 3-deaminosisomicin exhibits good activity against bacterial strains that elaborate 3-acetylating enzymes.

Ring III functional groups appear to be somewhat less sensitive to structural changes than those of either ring I or ring II. Although the 2"-deoxygentamicins are significantly less active than their 2"-hydroxyl counterparts, the 2"-amino derivatives (seldomycins) are highly active. The 3 "-amino group of gentamicins may be primary or secondary with high antibacterial potency. Furthermore, the 4"-hydroxyl group may be axial or equatorial with little change in potency.

Despite improvements in antibacterial potency and spectrum among newer naturally occurring and semisynthetic aminoglycoside antibiotics, efforts to find agents with improved margins of safety have been disappointing. The potential for toxicity of these important chemotherapeutic agents continues to restrict their use largely to the hospital environment.

The discovery of agents with higher potency/toxicity ratios remains an important goal of aminoglycoside research. In a now somewhat dated review, however, Price114 expressed doubt that many significant clinical breakthroughs in aminoglycoside research would occur in the future.


Streptomycin Sulfate, Sterile

Streptomycin sulfate is a white, odorless powder that is hygroscopic but stable toward light and air. It is freely soluble in water, forming solutions that are slightly acidic or nearly neutral. It is very slightly soluble in alcohol and is insoluble in most other organic solvents. Acid hydrolysis yields strep-tidine and streptobiosamine, the compound that is a combination of l-streptose and n-methyl-l-glucosamine.

Triacidic Base

Streptomycin acts as a triacidic base through the effect of its two strongly basic guanidino groups and the more weakly basic methylamino group. Aqueous solutions may be stored at room temperature for 1 week without any loss of potency, but they are most stable if the pH is between 4.5 and 7.0. The solutions decompose if sterilized by heating, so sterile solutions are prepared by adding sterile distilled water to the sterile powder. The early salts of streptomycin contained impurities that were difficult to remove and caused a histamine-like reaction. By forming a complex with calcium chloride, it was possible to free the streptomycin from these impurities and to obtain a product that was generally well tolerated.

The organism that produces streptomycin, S. griseus, also produces several other antibiotic compounds: hydroxystrep-tomycin, mannisidostreptomycin, and cycloheximide (q.v.).

Of these, only cycloheximide has achieved importance as a medicinally useful substance. The term streptomycin A has been used to refer to what is commonly called streptomycin, and mannisidostreptomycin has been called streptomycin B. Hydroxystreptomycin differs from streptomycin in having a hydroxyl group in place of one of the hydrogen atoms of the streptose methyl group. Mannisidostreptomycin has a man-nose residue attached in glycosidic linkage through the hy-droxyl group at C-4 of the n-methyl-l-glucosamine moiety. The work of Dyer et al.115,116 to establish the stereochemical structure of streptomycin has been completed, and confirmed with the total synthesis of streptomycin and dihydrostrepto-mycin by Japanese scientists.117

Clinically, a problem that sometimes occurs with the use of streptomycin is the early development of resistant strains of bacteria, necessitating a change in therapy. Other factors that limit the therapeutic use of streptomycin are chronic toxicities. Neurotoxic reactions have been observed after the use of streptomycin. These are characterized by vertigo, disturbance of equilibrium, and diminished auditory perception. Additionally, nephrotoxicity occurs with some frequency. Patients undergoing therapy with streptomycin should have frequent checks of renal monitoring parameters. Chronic toxicity reactions may or may not be reversible. Minor toxic effects include rashes, mild malaise, muscular pains, and drug fever.

As a chemotherapeutic agent, streptomycin is active against numerous Gram-negative and Gram-positive bacteria. One of the greatest virtues of streptomycin is its effectiveness against the tubercle bacillus, M. tuberculosis. By itself, the antibiotic is not a cure, but it is a valuable adjunct to other treatment modalities for TB. The greatest drawback to the use of streptomycin is the rather rapid development of resistant strains of microorganisms. In infections that may be because of bacteria sensitive to both streptomycin and penicillin, the combined administration of the two antibiotics has been advocated. The possible development of damage to the otic nerve by the continued use of streptomycin-containing preparations has discouraged the use of such products. There has been an increasing tendency to reserve streptomycin products for the treatment of TB. It remains one of the agents of choice, however, for the treatment of certain "occupational" bacterial infections, such as brucellosis, tularemia, bubonic plague, and glanders. Because streptomycin is not absorbed when given orally or destroyed significantly in the GI tract, at one time it was used rather widely in the treatment of infections of the intestinal tract. For systemic action, streptomycin usually is given by intramuscular injection.

Neomycin Sulfate

In a search for antibiotics less toxic than streptomycin, Waksman and Lechevalier118 isolated neomycin (Mycifradin, Neobiotic) in 1949 from Streptomyces fradiae. Since then, the importance of neomycin has increased steadily, and today, it is considered one of the most useful antibiotics for the treatment of GI infections, dermatological infections, and acute bacterial peritonitis. Also, it is used in abdominal surgery to reduce or avoid complications caused by infections from bacterial flora of the bowel. It has broad-spectrum activity against various organisms and shows a low incidence of toxic and hypersensitivity reactions. It is absorbed very slightly from the digestive tract, so its oral use ordinarily does not

Neomycin Resistance

produce any systemic effect. The development of neomycin-resistant strains of pathogens is rarely reported in those organisms against which neomycin is effective.

Neomycin as the sulfate salt is a white to slightly yellow, crystalline powder that is very soluble in water. It is hygroscopic and photosensitive (but stable over a wide pH range and to autoclaving). Neomycin sulfate contains the equivalent of 60% of the free base.

Neomycin, as produced by S. fradiae, is a mixture of closely related substances. Included in the "neomycin complex" is neamine (originally designated neomycin A) and neomycins B and C. S. fradiae also elaborates another antibiotic, the fradicin, which has some antifungal properties but no antibacterial activity. This substance is not present in "pure" neomycin.

The structures of neamine and neomycins B and C are known, and the absolute configurational structures of neamine and neomycin were reported by Hichens and Rinehart.119 Neamine may be obtained by methanolysis of neomycins B and C, during which the glycosidic link between deoxystreptamine and d-ribose is broken. Therefore, neamine is a combination of deoxystreptamine and neosamine C, linked glycosidically (a) at the 4-position of deoxystrepta mine. According to Hichens and Rinehart, neomycin B differs from neomycin C by the nature of the sugar attached terminally to d-ribose. That sugar, called neosamine B, differs from neosamine C in its stereochemistry. Rinehart et al.120 have suggested that in neosamine the configuration is 2,6-di-amino-2,6-dideoxy-l-idose, in which the orientation of the 6-aminomethyl group is inverted to the 6-amino-6-deoxy-d-glucosamine in neosamine C. In both instances, the glycosidic links were assumed to be a. Huettenrauch121 later suggested, however, that both of the diamino sugars in neomycin C have the d-glucose configuration and that the glycosidic link is fi in the one attached to d-ribose. The latter stereochemistry has been confirmed by the total synthesis of neomycin C.122

Paromomycin Sulfate

The isolation of paromomycin (Humatin) was reported in 1956 from a fermentation with a Streptomyces sp. (PD 04998), a strain said to resemble S. rimosus very closely. The parent organism had been obtained from soil samples collected in Colombia. Paromomycin, however, more closely resembles neomycin and streptomycin in antibiotic activity than it does oxytetracycline, the antibiotic obtained from S. rimosus.

Structure Neosamine

The general structure of paromomycin was reported by Haskell et al.123 as one compound. Subsequently, chromatographic determinations have shown paromomycin to consist of two fractions, paromomycin I and paromomycin II. The absolute configurational structures for the paromomycins, as shown in the structural formula, were suggested by Hichens and Rinehart119 and confirmed by DeJongh et al.124 by mass spectrometric studies. The structure of paromomycin is the same as that of neomycin B, except that paromomycin contains d-glucosamine instead of the 6-amino-6-deoxy-d-glucosamine found in neomycin B. The same structural relationship is found between paromomycin II and neomycin C. The combination of d-glucosamine and deoxystreptamine is obtained by partial hydrolysis of both paromomycins and is called paromamine [4-(2-amino-2-deoxy-a-4-glucosyl)deoxystreptamine].

Paromomycin has broad-spectrum antibacterial activity and has been used for the treatment of GI infections caused by Salmonella and Shigella spp., and enteropathogenic E. coli. Currently, however, its use is restricted largely to the treatment of intestinal amebiasis. Paromomycin is soluble in water and stable to heat over a wide pH range.

Kanamycin Sulfate

Kanamycin (Kantrex) was isolated in 1957 by Umezawa and coworkers125 from Streptomyces kanamyceticus. Its activity against mycobacteria and many intestinal bacteria, as well as several pathogens that show resistance to other antibiotics, brought a great deal of attention to this antibiotic. As a result, kanamycin was tested and released for medical use in a very short time.

Research activity has been focused intensively on determining the structures of the kanamycins. Chromatography showed that S. kanamyceticus elaborates three closely related structures: kanamycins A, B, and C. Commercially available kanamycin is almost pure kanamycin A, the least toxic of the three forms. The kanamycins differ only in the sugar moieties attached to the glycosidic oxygen on the 4-position of the central deoxystreptamine. The absolute configuration of the deoxystreptamine in kanamycins reported by Tatsuoka et al.126 is shown above. The chemical relationships among the kanamycins, the neomycins, and the paromomycins were reported by Hichens and Rinehart.119 The kanamycins do not have the d-ribose molecule that is present in neomycins and paromomycins. Perhaps this structural difference is related to the lower toxicity observed with kanamycins. The kanosamine fragment linked glycosidically to the 6-position of deoxystreptamine is 3-amino-3-deoxy-d-glucose (3-d-glucosamine) in all three kanamycins. The structures of the kanamycins have been proved by total synthesis.127,128 They differ in the substituted d-glucoses attached glycosidically to the 4-position of the deoxystreptamine ring. Kanamycin A contains 6-amino-6-deoxy-d-glucose; kanamycin B contains 2,6-di-amino-2,6-dideoxy-d-glucose; and kanamycin C contains 2-amino-2-deoxy-d-glucose (see preceding diagram).

Kanamycin is basic and forms salts of acids through its amino groups. It is water soluble as the free base, but it is used in therapy as the sulfate salt, which is very soluble. It is stable to both heat and chemicals. Solutions resist both acids and alkali within the pH range of 2.0 to 11.0. Because of possible inactivation of either agent, kanamycin and penicillin salts should not be combined in the same solution.

The use of kanamycin in the United States usually is restricted to infections of the intestinal tract (e.g., bacillary dysentery) and to systemic infections arising from Gramnegative bacilli (e.g., Klebsiella, Proteus, Enterobacter, and Serratia spp.) that have developed resistance to other antibiotics. It has also been recommended for preoperative antisepsis of the bowel. It is absorbed poorly from the intestinal tract; consequently, systemic infections must be treated by intramuscular or (for serious infections) intravenous injections. These injections are rather painful, and the concomitant use of a local anesthetic is indicated. The use of kanamycin in the treatment of TB has not been widely advocated since the discovery that mycobacteria develop resistance very rapidly. In fact, both clinical experience and experimental work129 indicate that kanamycin develops cross-resistance in the tubercle bacilli with dihydrostrepto-mycin, viomycin, and other antitubercular drugs. Like streptomycin, kanamycin may cause decreased or complete loss of hearing. On development of such symptoms, its use should be stopped immediately.


Amikacin, 1-N-amino-a-hydroxybutyrylkanamycin A (Amikin), is a semisynthetic aminoglycoside first prepared in Japan. The synthesis formally involves simple acylation of the 1-amino group of the deoxystreptamine ring of kanamycin A with l-AHBA. This particular acyl derivative retains about 50% of the original activity of kanamycin A against sensitive strains of Gram-negative bacilli. The l-AHBA derivative is much more active than the d-isomer.130 The remarkable feature of amikacin is that it resists attack by most bacteria-inactivating enzymes and, therefore, is effective against strains of bacteria that are resistant to other aminoglycosides,110 including gentamicin and tobramycin. In fact, it is resistant to all known aminoglycoside-inactivat-ing enzymes, except the aminotransferase that acetylates the 6'amino group109 and the 4'-nucleotidyl transferase that adenylylates the 4'-hydroxyl group of aminoglycosides.108

Amikacin Chemical Structure

Preliminary studies indicate that amikacin may be less ototoxic than either kanamycin or gentamicin.131 Higher dosages of amikacin are generally required, however, for the treatment of most Gram-negative bacillary infections. For this reason, and to discourage the proliferation of bacterial strains resistant to it, amikacin currently is recommended for the treatment of serious infections caused by bacterial strains resistant to other aminoglycosides.

Gentamicin Sulfate

Gentamicin (Garamycin) was isolated in 1958 and reported in 1963 by Weinstein et al.132 to belong to the streptomycinoid (aminocyclitol) group of antibiotics. It is obtained commercially from Micromonospora purpurea. Like the other members of its group, it has a broad spectrum of activity against many common pathogens, both Gram-positive and Gramnegative. Of particular interest is its strong activity against P. aeruginosa and other Gram-negative enteric bacilli.

Gentamicin is effective in the treatment of various skin infections for which a topical cream or ointment may be used. Because it offers no real advantage over topical neomycin in the treatment of all but pseudomonal infections, however, it is recommended that topical gentamicin be reserved for use in such infections and in the treatment of burns complicated by pseudomonemia. An injectable solution containing 40 mg of gentamicin sulfate per milliliter may be used for serious systemic and genitourinary tract infections caused by Gramnegative bacteria, particularly Pseudomonas, Enterobacter, and Serratia spp. Because of the development of strains of these bacterial species resistant to previously effective broad-spectrum antibiotics, gentamicin has been used for the treatment of hospital-acquired infections caused by such organisms. Resistant bacterial strains that inactivate gentamicin by adenylylation and acetylation, however, appear to be emerging with increasing frequency.

Gentamicin sulfate is a mixture of the salts of compounds identified as gentamicins C1, C2, and Cla. These gentamicins were reported by Cooper et al.133 to have the structures shown in the diagram. The absolute stereochemistries of the sugar components and the geometries of the glycosidic linkages have also been established.134

Coproduced, but not a part of the commercial product, are gentamicins A and B. Their structures were reported by Maehr and Schaffner135 and are closely related to those of the gentamicins C. Although gentamicin molecules are similar in many ways to other aminocyclitols such as streptomycins, they are sufficiently different that their medical effectiveness is significantly greater. Gentamicin sulfate is a white to buff substance that is soluble in water and insoluble in alcohol, acetone, and benzene. Its solutions are stable over a wide pH range and may be autoclaved. It is chemically incompatible with carbenicillin, and the two should not be combined in the same intravenous solution.

Tobramycin Sulfate

Introduced in 1976, tobramycin sulfate (Nebcin) is the most active of the chemically related aminoglycosides called ne-bramycins obtained from a strain of Streptomyces tenebrar-

ius. Five members of the nebramycin complex have been identified chemically.136

Images Disodium Inosinate

Factors 4 and 4' are 6"-O-carbamoylkanamycin B and kanamycin B, respectively; factors 5' and 6 are 6"-O-car-bamoyltobramycin and tobramycin; and factor 2 is apramycin, a tetracyclic aminoglycoside with an unusual bi-cyclic central ring structure. Kanamycin B and tobramycin probably do not occur in fermentation broths per se but are formed by hydrolysis of the 6-O"-carbamoyl derivatives in the isolation procedure.

The most important property of tobramycin is its activity against most strains of P. aeruginosa, exceeding that of gen-tamicin by twofold to fourfold. Some gentamicin-resistant strains of this troublesome organism are sensitive to tobramycin, but others are resistant to both antibiotics.137 Other Gram-negative bacilli and staphylococci are generally more sensitive to gentamicin. Tobramycin more closely resembles kanamycin B in structure (it is 3'-deoxykanamycin B).

Netilmicin Sulfate

Netilmicin sulfate, 1-N-ethylsisomicin (Netromycin), is a semisynthetic derivative prepared by reductive ethylation138 of sisomicin, an aminoglycoside antibiotic obtained from Micromonospora inyoensis.139 Structurally, sisomicin and netilmicin resemble gentamicin Cla, a component of the gentamicin complex.

Against most strains of Enterobacteriaceae, P. aeruginosa, and S. aureus, sisomicin and netilmicin are comparable to gentamicin in potency.140 Netilmicin is active, however, against many gentamicin-resistant strains, in particular among E. coli, Enterobacter, Klebsiella, and Citrobacter spp. A few strains of gentamicin-resistant P. aeruginosa, S. marcescens, and indole-positive Proteus spp. are also sensitive to netilmicin. Very few gentamicin-resistant bacterial strains are sensitive to sisomicin, however. The potency of netilmicin against certain gentamicin-resistant bacteria is attributed to its resistance to inactivation by bacterial enzymes that adenylylate or phosphorylate gentamicin and sisomicin. Evidently, the introduction of a 1-ethyl group in sisomicin markedly decreases the affinity of these enzymes for the molecule in a manner similar to that observed in the 1-N-s-amino-a-hydroxybutyryl amide of kanamycin A (amikacin). Netilmicin, however, is inactivated by most of the bacterial enzymes that acetylate aminoglycosides, whereas amikacin is resistant to most of these enzymes.

The pharmacokinetic and toxicological properties of netilmicin and gentamicin appear to be similar clinically, though animal studies have indicated greater nephrotoxicity for gentamicin.

Sisomicin Sulfate

Although sisomicin has been approved for human use in the United States, it has not been marketed in this country. Its antibacterial potency and effectiveness against aminoglyco-side-inactivating enzymes resemble those of gentamicin. Sisomicin also exhibits pharmacokinetics and pharmacological properties similar to those of gentamicin.

Spectinomycin Hydrochloride, Sterile

The aminocyclitol antibiotic spectinomycin hydrochloride (Trobicin), isolated from Streptomyces spectabilis and once called actinospectocin, was first described by Lewis and Clapp.141 Its structure and absolute stereochemistry have been confirmed by x-ray crystallography.142 It occurs as the white, crystalline dihydrochloride pentahydrate, which is stable in the dry form and very soluble in water. Solutions of spectinomycin, a hemiacetal, slowly hy-drolyze on standing and should be prepared freshly and used within 24 hours. It is administered by deep intramuscular injection.

Spectinomycin is a broad-spectrum antibiotic with moderate activity against many Gram-positive and Gramnegative bacteria. It differs from streptomycin and the streptamine-containing aminoglycosides in chemical and antibacterial properties. Like streptomycin, spectinomycin interferes with the binding of transfer RNA (tRNA) to the ri-bosomes and thus with the initiation of protein synthesis. Unlike streptomycin or the streptamine-containing antibiotics, however, it does not cause misreading of the messenger. Spectinomycin exerts a bacteriostatic action and is inferior to other aminoglycosides for most systemic infections. Currently, it is recommended as an alternative to penicillin G salts for the treatment of uncomplicated gonorrhea. A cure rate of more than 90% has been observed in clinical studies for this indication. Many physicians prefer to use a tetracycline or erythromycin for prevention or treatment of suspected gonorrhea in penicillin-sensitive patients because, unlike these agents, spectinomycin is ineffective against syphilis. Furthermore, it is considerably more expensive than erythromycin and most of the tetracyclines.


Among the most important broad-spectrum antibiotics are members of the tetracycline family. Nine such compounds—tetracycline, rolitetracycline, oxytetracycline, chlortetracycline, demeclocycline, meclocycline, methacy-cline, doxycycline, and minocycline—have been introduced into medical use. Several others possess antibiotic activity. The tetracyclines are obtained by fermentation procedures from Streptomyces spp. or by chemical transformations of the natural products. Their chemical identities have been established by degradation studies and confirmed by the synthesis of three members of the group, oxy-tetracycline,143,144 6-demethyl-6-deoxytetracycline,145 and anhydrochlortetracycline,146 in their (a) forms. The important members of the group are derivatives of an octahydron-aphthacene, a hydrocarbon system that comprises four annulated six-membered rings. The group name is derived from this tetracyclic system. The antibiotic spectra and chemical properties of these compounds are very similar but not identical.

The stereochemistry of the tetracyclines is very complex. Carbon atoms 4, 4a, 5, 5a, 6, and 12a are potentially chiral, depending on substitution. Oxytetracycline and doxycycline, each with a 5a-hydroxyl substituent, have six asymmetric centers; the others, lacking chirality at C-5, have only five. Determination of the complete, absolute stereochemistry of the tetracyclines was a difficult problem. Detailed x-ray diffraction analysis147-149 established the stereochemical formula shown in Table 8.6 as the orientations found in the natural and semisynthetic tetracyclines. These studies also confirmed that conjugated systems exist in the structure from C-10 through C-12 and from C-1 through C-3 and that the formula represents only one of several canonical forms existing in those portions of the molecule.

Structure of the Tetracyclines

The tetracyclines are amphoteric compounds, forming salts with either acids or bases. In neutral solutions, these substances exist mainly as zwitterions. The acid salts, which are formed through protonation of the enol group on C-2, exist as crystalline compounds that are very soluble in water. These amphoteric antibiotics will crystallize out of aqueous solutions of their salts, however, unless stabilized by an excess of acid. The hydrochloride salts are used most commonly for oral administration and usually are encapsulated because they are bitter. Water-soluble salts may be obtained also from bases, such as sodium or potassium hydroxides, but they are not stable in aqueous solutions. Water-insoluble salts are formed with divalent and polyvalent metals.

The unusual structural groupings in the tetracyclines produce three acidity constants in aqueous solutions of the acid salts (Table 8.7). The particular functional groups responsible for each of the thermodynamic pKa values were determined by Leeson et al.150 as shown in the diagram that follows. These groupings had been identified previously by Stephens et al.151 as the sites for protonation, but their earlier assignments, which produced the values responsible for

TABLE 8.6 Structures of Tetracyclines

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  • Quintino
    Why paromomycin is administered orall and its an aminoglycoside?
    3 years ago
  • archie
    Are aminoglycosides chemically stable in acid Base?
    2 years ago
  • frans
    Are aminoglycosides basic or acidic drugs?
    2 years ago
  • deborah
    Why neomycin is given orally and other aminoglycosides are given parenterally?
    2 years ago
  • marroc
    Why are all amino glycoside more active at alkaline pH than acid pH?
    2 years ago

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