Amikacin, bacterial resistance

Structures of several important aminoglycoside antibiotics. Ring II is 2-deoxystreptamine. The resemblance between kanamycin and amikacin and between gentamicin, netilmicin, and tobramycin can be seen. The circled numerals on the kanamycin molecule indicate points of attack of plasmid-mediated bacterial transferase enzymes that can inactivate this drug. , , and , acetyltransferase , phosphotransferase , adenylyltransferase. Amikacin is resistant to modification at , , , and . 

Bacterial Resistance Mechanisms. The most common resistance mechanism involves the inactivation of the aminoglycoside by reactions cat alyzed by plasmid borne enzymes. In general, amikacin and isepam icin tend to be least susceptible to inactivation by this mechanism, while netilmicin and dibekacin are intermediate and gentamicin and tobramycin are most susceptible. Less common resistance mechanisms include decreased affinity for the antibiotic by the bacterial ribosome, and decreased rate of transport into the bacterial cytoplasm. 

These depend on the fact that bacterial resistance to aminoglycosides (Chapter 13), such as gentamicin, tobramycin, amikacin, netilmicin, streptomycin, spectinomycin, etc. and chloramphenicol is frequently associated with the presence of specific enzymes (often coded for by transmissible plasmids), which either acetylate, adenylylate or phosphory-late the antibiotics, thereby rendering them inactive (Chapter 13). Aminoglycosides may be susceptible to attack by aminoglycoside acetyltransferases... 

Indiscriminate use of amikacin may lead to bacterial resistance due to R-factor coding for several enzymes inactivating aminoglycosides, including kanamycin acetyltrans-ferase (5 ). 

Amikacin is mainly of value because it is more resistant to aminoglycoside-inactivating bacterial enzymes than is gentamicin. Since it is more costly, amikacin is reserved for treatment of infections with gentamicin-resistant organisms. Peak plasma concentrations should be kept between 20-30 mg/1 and trough concentrations below 10 mg/1. 

In a leading cancer center in Houston, 24% of 758 Gram negative clinical isolates were resistant to tobramycin and 12% were resistant to amikacin (138). In 3144 bacterial isolates causing urinary tract infections in Chile, 74% were identified as Escherichia colv, 4.2% of these strains were resistant to gentamicin, and 1.3% were resistant to amikacin (139). In contrast, the resistance levels were 30% and 17% respectively, in the other enterobacterial strains. In Brazil, all isolates of methicillin-resistant S. aureus were also resistant to gentamicin, amikacin, kanamycin, neomycin, and tobramycin (140), and 97% of such strains from Spain were resistant to tobramycin (141). 

Amikacin is derived from kanamycin and has the broadest spectrum of activity of the aminoglycosides. It is less susceptible to bacterial enzyme inactivation than the other aminoglycosides, so it is usually reserved for therapy of gentamicin-resistant bacterial infections. 

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