Aminoglycosides

Aminoglycosides belong to a group of natural and semisynthetic antibiotics. Streptomycin was the first member. It was discovered by Waksrnan and colleagues and used for the treatment of tuberculosis. 

Toxic effects, which depends on dose and duration of treatment, mainly manifest as ototoxicity. Aminoglycosides also may cause nephrotoxicity and are reversible if they are withdrawn. They are known to cause neuromuscular blockade hence, care is necessary when used along with neuromuscular-blocking agents. Other reactions include allergy and cross-reactivity infections, as well as 

Aminoglycosides are fast acting, but they can also cause ear and kidney problems if the dose levels are not carefully controlled. 

The aminoglycoside antibiotics used to be the only compounds effective against the particularly resistant Pseudomonas aeruginosa (see earlier) and it is only recently that alternative treatments have been unveiled (see above). 

HPI After 2 days of treatment for her UTI, LD now returns to the clinic complaining of chills, fever, nausea, flank pain, and increased lower tract symptoms (frequency, dysuria, and urgency). 

What are the most likely organisms to be causing LD s pyelonephritis  

What are appropriate antibiotics that can be used for the treatment of pyelonephritis  

The infecting organisms causing pyelonephritis are typically similar to the infecting pathogens responsible for lower UTIs. In uncomplicated cases, antibiotics used for treatment of lower tract Infections also can be used for the treatment of upper tract infections. These agents typically include fluoroquinolones and TMP-SMX. In more serious cases, pyelonephritis may be accompanied by bacteremia, warranting hospitalization and parenteral therapy. 

Aminoglycosides are parenteral antibiotics most widely used in the treatment of infections due to enteric gramnegative bacteria. However, aminoglycosides are often used in combination with cell wall-active agents such as beta-lactams or vancomycin for treatment of endocarditis. Aminoglycosides initially diffuse passively across the baae-rial outer membrane and are then actively transported into the cytoplasm. This active transport is inhibited in low pH or anaerobic conditions. Once inside the cytoplasm, aminoglycosides inhibit protein synthesis by binding to the bacterial 

The term aminogl)icosi(k is commonly used to refer to members of the class of antibacterial antibiotics, the stmctures of which ate derived from D-streptamine [488-52-8] (1, R = OH), D-2-deoxystreptamine [2037-48-1] (1, R = H), or closely related compounds. The terms 

Historically, the first example of an amiaoglycoside antibiotic is generally considered to be streptomycia [57-92-1] C2H2C)Ny0 2 CHO), or 

0-2-deoxy-2-(methylamiQo)-a-L-glucopyraQOsyl-(l— 2)-0-5-deoxy-3-C-formyl-a-L-lyxofuraQOsyl-(l— 4)-Ai,AT-bis(aminoiminometbyl)-T.-streptamine) isolated ia 1944 from a strain of Streptomjcesgriseus (1 4). This discovery, a milestone ia the history of antibacterial chemotherapy (5), was the starting poiat for research and development activities that continue to be important ia the management of bacterial iafectious disease. 

In 1991 the foUowiag amiaoglycosides were most important ia medical practice. Clinical experience is most extensive for the first four. 

0-3-deoxy-4-C-methyl-3-(methylamiQo)-P-L-arabiQopyranosyl-(l— 6)-0-[2,6-diamiQO-2,3,4,6-tetradeoxy-a-D- f2v (9-hexopyranosyl-(l— 4)]-2-deoxy-D-streptamiae. 

Brand Name/ Company Amikin (AmikacinJ/Apothecon Nebcin (Tobramycin)/Eli Lilly and Company Garamycin (Gentamicin)/Schering Corporation  

Class Semisynthetic aminoglycoside antibiotics with activity against Pseudomonas species, Escherichia coii. Proteus species, Providencia species, Klebsiella species, Enterobacter speaes, Serratia species, Acinetobacter species, Citrobacter freundii, Staphylococcus species Aminoglycosides generally have a low level of activity against grampositive organisms Lo o u c  

Mechanism of Action Inhibit normal protein synthesis in susceptible organisms  

Indications Treatment of the following serious infections due to susceptible gramnegative bacteria Septicemia Respiratory tract Bone and joint Central nervous system Skin and soft tissue Intra-abdominal Burns and postoperative infection Complicated, recurrent UTIs (aminoglycosides are not indicated for uncomplicated, initial episodes of UTIs)  

Contraindication History of hypersensitivity or serious toxic reaction to aminoglycosides  

The discovery of streptomycin, the First aminoglyatsidcann-biotic to be used in chemotherapy, was the result of a planned and deliberate search begun in 1939 and brought to frailicci in 1944 by Schatz and associates. This success stimutual 

spite the complexity inherent in various aminnglyaisidc structures, some conclusions on SARs in this antibiotic clat- 

Streptomycin Sulfate, Sterile, USP. Streptomycin sulfate is a white, odorless powder that is hygroscopic but stable 

Clinically, a problem that sometimes (Kcurs 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 arc 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 (K curs with some frequency. 

Patients undei oing therapy with streptomycin should have frequent cheeks 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. 

Describe the mechanisms of action of aminoglycoside antibiotics and the mechanisms by which bacterial resistance to this class of drugs occurs. 

List the major clinical applications of aminoglycosides and describe their main toxic effects. Describe the pharmacokinetics of this drug class, with special reference to the importance of renal clearance and its relationship to toxicity. 

Understand the concepts of time-dependent and concentration-dependent killing actions of antibiotics and know what is meant by the postantibiotic effect. 

Streptomycin Streptomycin is used in the treatment of tuberculosis, plague, and tularemia. Because of the risk of ototoxicity, streptomycin should not be used when other drugs will serve. 

Neomycin Owing to its toxic potential, neomycin is only used topically or locally, eg, in the gastrointestinal tract. 

Streptomycin, the first aminogylcoside, was isolated from a strain of Streptomyces griseus and became available 

Bacterial resistance to aminoglycosides is mediated through bacterial enzymes (phosphotransferases, acetyl-transferases, adenyltransferases), which inactivate aminoglycosides and prevent their binding to the ribosome. Genes encoding these enzymes are frequently located on plasmids, facilitating rapid transfer of resistance to other bacteria. 

Aminoglycosides are not well absorbed from the gastrointestinal tract but are well absorbed after intramuscular or subcutaneous injection. Effective concentrations are achieved in synovial, pleural, peritoneal, and pericardial fluids. Intrauterine and intramammary administration is also effective, but significant tissue residues result. Aminoglycosides do not bind significantly to plasma proteins, and as they are large polar molecules, they are poorly lipid-soluble and do not readily enter cells or penetrate cellular barriers. This means that therapeutic concentrations are not easily achieved in cerebrospinal or ocular fluids. Tlieir volumes of distribution are small, and the half-lives in plasma are relatively short (1-2 h). Elimination is entirely via the kidney. 

The limited information available suggests that aminoglycoside residues persist at trace levels in the environment (see also discussion in Chapter 3). 

The Joint EAOAVHO Expert Committee on Food Additives (JECEA) has evaluated toxicological and residue depletion data for dihydrostreptomycin and streptomycin, gentamicin, kanamycin, neomycin, and spectinomycin (see list in Table 1.2). On the basis of the risk assessments carried out by the JECEA, ADIs were allocated for all of these substances except kanamycin. In addition, on the basis of JECEA recommendations, CAC MRLs were established for dihydrostreptomycin and streptomycin in muscle, liver, kidney, and fat of cattle, sheep, pigs, and chickens, and in cow s milk and sheep s milk for 

Gentamycin is a widely used antibiotic but presents a number of undesirable side-effects when administered in high doses. Thus, it is vital to be able to monitor serum levels accurately. In the past this has been achieved using a number of assay methods other than HPLC. However, recently an HPLC method which compares favourably with microbiological assay methods has been described (Marples and Oates, 1982). This system utilises pre-column derivatisation with o-phthal-aldehyde to facilitate fluorimetric detection with subsequent resolution on a Spherisorb 5-ODS reversed phase support using isocratic conditions with methanol-water-EDTA (Fig. 11.9.4). Baseline resolution of tobramycin and four gentamycin components was achieved by this method. 

A further alternative utilises initial sample derivatisation with o-phthalaldehyde and subsequent separation on a cation-exchange support coupled to a reversed phase support. The mobile phase was a methanol-aqueous sodium acetate mixture the composition of which was altered for the specific compound being separated (Essers, 1984). 

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