Drugs
Gentamicin; Amikacin; Framycetin (aka Neomycin, Soframycin); Tobramycin; Streptomycin; Paromomycin; Kanamycin; Sisomicin; Netilmicin. Of these only gentamicin is relevant for systemic therapy in adult horses. Amikacin is very expensive, and tends only to be used systemically in newborn foals. Amikacin is a popular medication for intra-articular use, either as a treatment of synovial sepsis or as a preventative co-factor when other medications are used. Framycetin and tobramycin are used in ophthalmic preparations in Australia.
Mechanism of Action
Aminoglycosides are concentration dependent antibiotics and only require a brief contact time to kill susceptible bacteria. They do need to cross the bacterial cell wall where they inhibit protein synthesis by binding on to the 16S ribosomal RNA of the 30S ribosome. This causes errors in protein synthesis causing the wrong amino acids to be assembled into polypeptides, that after release, damage the bacterial cell membrane and other bacterial cell components.
Aminoglycoside antibiotics also demonstrate a post-antibiotic effect that lasts for 2-8 hours post exposure, and therefore permits greater dosing intervals than would be predicted by the drug half-life. Originally gentamicin was dosed at 8 hour intervals, this has changed to once daily dosing at a much higher dose rate. This prolonged duration of effect is enhanced by the host leukocyte response, and it is believed that leukocytes demonstrate enhanced killing activity after exposure to aminoglycosides.
Spectrum of activity
Although primarily used to target Gram-negative bacteria, newer generation aminoglycosides are broad spectrum antibiotics. They are most effective against the Enterobacteriaceae family, including Escherichia coli, Klebsiella species, Enterobacter, Proteus, and Serratia species. In addition, most Staphylococcus species are susceptible, including both methicillin-resistant and vancomycin-resistant species, but Streptococcus species are typically resistant. Aminoglycosides are not effective against many anaerobes. Gentamicin has been advocated in foals with resistant Rhodococcus equi infections.
The activity of aminoglycosides is enhanced through synergy with other drugs, particularly the β-lactams which are active against bacterial cell walls.
Aminoglycoside resistance
Aminoglycoside resistance is complex, and can involve several different mechanisms. Firstly, aminoglycoside-modifying enzymes (AMEs) can be found on bacterial plasmids and can cause damage to the aminoglycoside molecule to decrease its ability to bind targets rendering it ineffective. Target site modification can also occur through 16S rRNA methyltransferases. These enzymes prevent aminoglycosides from binding to their target. They can also be encoded by bacterial plasmids. A third mechanism involves intrinsic efflux systems that are found naturally in certain bacteria.
Toxicity
Aminoglycosides have the potential to be nephrotoxic. The drugs are freely filtered across the glomerulus with almost all of the drug excreted in urine. However, approximately 5-15% of the dose are taken up and sequestered by proximal tubule cells, reaching intracellular concentrations much higher than serum concentrations. This effect is saturable, such that single large doses result in less toxicity than more frequent smaller doses. After uptake by the proximal tubule cells a number of cellular processes are disturbed, resulting in apoptosis (programmed cell death). This can lead to a loss of renal tubular epithelium and kidney dysfunction. This dysfunction is characterized by a nonoliguric and even often polyuric fall in creatinine clearance. Progression to oliguric or anuric renal failure is uncommon, and recovery upon drug discontinuation is likely. Damage to the proximal tubules will produce casts in the urine. These are microscopic cylindrical structures. The concentration of gamma-glutamyl transferase will also increase in the urine. These changes occur before the rise in serum creatinine. Nephrotoxicity is enhanced by dehydration or concurrent diuretic treatment.
Ototoxicity is a feature of aminoglycoside dosing in non-equids. A recent publication from the University of Davis examined the effect of gentamicin at 6.6 mg/kg intravenously once daily for 7 days on hearing in 10 research horses. They used a technique known as brainstem auditory evoked responses (BAER) to assess the hearing pathways. This dosing schedule is used very commonly around the world. They reported that 7 of the 10 horses had some hearing loss, one had complete loss in both ears, two had complete loss in one ear, and four horses had partial loss in one ear. After 30 days hearing was restored in 4 horses only, both horses with total loss in one ear and 2 of the four horses with partial loss in one ear. These are clearly interesting findings that require more research. The dose rate may be important in determining this effect.
Dosing
Dosing information is intended for use by registered veterinarians or veterinary nurses. Equiimed assumes no responsibility for the information detailed below. Equiimed shall not be liable for any damages resulting from reliance on any information provided below, or by reason of any misstatement or typographical errors. Ultimately veterinarians should consult information provided by the manufacturer prior to use.
Tags: Pharmacology