Aminoglycosides

Aminoglycosides (see table: aminoglycosides), have a concentration-dependent bactericidal activity. They bind to the 30S ribosome, thereby inhibiting bacterial protein synthesis. Spectinomycin is a bacteriostatic antibiotic with aminoglycosides (spectinomycin) is chemically related. Aminoglycosides amikacin, gentamicin kanamycin, neomycin * * * streptomycin tobramycin should only be used topically or orally. Pharmacology aminoglycosides are poorly absorbed after oral administration, but are from the peritoneum of the pleural cavity and joints (and therefore should never be instilled in these body cavities) and bare skin well absorbed. Aminoglycosides are normally i.v. applied. Aminoglycosides not spread well in the extracellular fluid, but in the glass bodies in the CSF, in respiratory secretions and bile (especially in patients with biliary obstruction). In the treatment of endophthalmitis intravitreal injection is required. Intraventricular injection is often necessary to achieve adequate intraventricular levels for the treatment of meningitis. Aminoglycosides are excreted by glomerular filtration and have a serum half-life of 2-3 hours; the half-life increases with decreasing GFR (z. B. in renal failure or elderly patients) exponentially. Indications aminoglycosides are used for serious Gram-negative infections, particularly Pseudomonas aeruginosa. They are active against most Gram-negative aerobic rod-shaped bacteria, but not against anaerobes, and against most Gram-positive bacteria except most staphylococci; nevertheless there are some aminoglycoside-resistant strains also among Gram-negative bacilli and methicillin-resistant staphylococci (MRSA). Among the aminoglycosides, which are effective against P. aeruginosa include tobramycin (particularly), gentamicin and amikacin. Streptomycin, neomycin and kanamycin are not effective against P. aeruginosa. Gentamicin and tobramycin have a similar antibacterial spectrum against gram-negative rods, but Tobramycin is effective against P. aeruginosa, and gentamicin is active against Serratia marcescens. Amikacin is often still effective against gentamicin and tobramycin-resistant pathogens. Aminoglycosides are rarely used individually, unless they are used for plague and tularemia. They are usually used in combination with a broad-spectrum ?-lactam in severe infections, which are suspected to have been caused by gram-negative rods. Due to the increasing rates of aminoglycoside resistance, a fluoroquinolone may be given as initial empiric therapy also instead of the aminoglycoside, or the aminoglycoside may be discontinued unless an aminoglycoside sensitive P. aeruginosa was detected. Gentamicin, streptomycin, more rarely, can be used in combination with other antibiotics for treatment of streptococcal or enterococcal endocarditis. Aminoglycoside resistance in enterococci have become a common problem. Since the treatment of enterococcal endocarditis requires prolonged use potentially nephrotoxic and ototoxic aminoglycoside in combination with a bacterial cell wall active antibiotic (eg. As penicillin or vancomycin), in order to achieve a bactericidal synergistic effect, the choice of aminoglycoside from the specific home must vitro susceptibility testing to be aligned. A high-level in-vitro susceptibility to aminoglycosides indicates a synergistic effect of a combination therapy with a low dose of aminoglycoside and a cell wall active substance. When the strain is sensitive to high-level gentamicin and -Streptomycin, gentamicin is preferred because serum levels can easily be determined here. A high-level in-vitro resistance to gentamicin does not exclude this sensitivity Enterokokkenstammes against high doses of streptomycin, in this case, streptomycin should be used. In enterococcal endocarditis with high-level resistance to both gentamicin and streptomycin, there are few available therapeutic options; there is no synergistic cell wall substance / aminoglycoside combination with endocarditis due to such strains, but the combination of the cell wall ingredients ampicillin and ceftriaxone has been shown recently to be effective and reduces the risk of nephrotoxicity. Streptomycin is of limited use due to development of resistance and toxicity. It is used to treat tularemia and plague as well as with other antibiotics for tuberculosis. Neomycin and kanamycin are limited to local application in low doses because of their toxicity. Neomycin is available for use on the eye, ear, rectum and oral as well as for bladder irrigation. An oral application as a topically acting substance against intestinal flora is applied to the pre-operative intestinal cleansing and treatment of hepatic coma. Contraindications aminoglycosides are contraindicated in patients who are allergic to these. Use during pregnancy and lactation aminoglycosides are in pregnancy than drugs in category D (there is evidence that they pose a risk to humans, but clinical benefits to risk outweigh). Aminoglycosides pass into breast milk, but not orally absorbed. Therefore, administration during lactation is possible. Adverse effects All aminoglycosides are nephrotoxic (often reversible) and vestibulo and ototoxic (often irreversible). They also prolong the effect of neuromuscular blocking agents for symptoms or signs of a vestibular damage are vertigo and ataxia. DieRisikofaktoren of renal, vestibular and ototoxicity are frequent or very high doses very high blood levels of the drug long duration of therapy (especially> 3 days) Advanced age An existing kidney disease Coadministration of vancomycin, cyclosporine or amphotericin B When kidney damage, concomitant administration of contrast agents in Otoxizität a genetic predisposition, pre-hearing and the concomitant use of loop diuretics High doses administered over a longer period, usually lead to greater concern about kidney toxicity, but even low doses that are given for a short time, can worsen kidney function. Patients receiving aminoglycosides over> 2 weeks and those who have the risk factors for vestibular and auditory toxicity should be monitored with serial Audiographien. At the first indication of toxicity, the application is terminated (if possible) or the dose adjusted. Aminoglycosides can prolong the effect of substances that block neuromuscular transmission of excitation (eg. B. succinylcholine, curare-like substances), and muscle weakness worsen in diseases neuromuscular synaptic transmission cycle (for. Example, myasthenia gravis). These effects are especially likely when the drug is given too fast or serum levels are excessive. Occasionally, these effects lose faster i.v. Administration of neostigmine or calcium. Other neurological effects such as paresthesia and peripheral neuropathies may occur. Hypersensitivity reactions are rare, apart from contact dermatitis due to topical neomycin. High oral Neomycindosen can lead to malabsorption. Considerations dosage As the toxicity less than depend on the peak levels of the duration of the therapeutic level, and since the effect rather than a concentration-dependent time-dependent (effectiveness), a too frequent administration should be avoided. A single i.v. Application per day is preferred for most indications, except for enterococcal endocarditis. Intravenous aminoglycosides be administered slowly (30 minutes at split daily dosing or 30 to 45 minutes at once-daily dosing). In patients with normal renal function, a dose / day of gentamicin or tobramycin is from 5 mg / kg (7 mg / kg when the patients are severely ill) every 24 hours and a dose / day for amikacin 15 mg / kg every 24 h. In patients, the clinical response to a dose of 7 mg / kg gentamicin and whose renal function remains normal, the once-daily dose may be reduced to the dose of 5 mg / kg after a few days of treatment. In critically ill patients, the peak level should be determined after the first dose. Peak and trough levels should be measured after the second and third person, if the daily Aminoglykosiddosis is shared and the duration of treatment lasts> 3 days, and also when the dose is changed. Every 2 to 3 days should be determined the serum creatinine, if it remains constant, the Serumaminoglykosidspiegel need not be repeated determined. The top mirror is the mirror 60 minutes after the i.m. a Injection or 30 min after the end of the 30-minute i.v. Infusion is measured. Trough levels are determined within 30 minutes prior to the next dose. Will be sought in the serum peak levels corresponding to 10 times the MIC. The dosage must be adjusted so that therapeutic peak concentration (by concentration-dependent activity facilitate) and non-toxic trough levels are secured (see table: Dosage for aminoglycosides in adults). In critically ill patients that are likely to have a higher volume of distribution, and which initially higher doses are administered, the target peak levels are / ml for gentamicin and tobramycin, and at 56- 64 ug / ml for amikacin at 16- 24 micrograms. For gentamicin and tobramycin trough levels should 18-24 hours after the first dose for once-daily dosing <1 ug / ml and be 1-2 ug / ml when the daily dose is divided, the initial dose is the same as in patients with renal insufficiency in patients with normal renal function; it is more likely to extend the dosing interval as reducing the dose. Guidelines for maintenance doses on values ??of serum creatinine or creatinine clearance are available based (see Table: dosage for aminoglycosides in adults), but they are inaccurate and therefore the measurement of serum levels is usually preferred. occupy when patients a high dose of both a ?-lactam (z. B. piperacillin, ticarcillin) and of an aminoglycoside, the high ?-Lactamspiegel can inactivate aminoglycosides in the serum samples, when the sample is not immediately analyzed or frozen. When patients taking concomitant with kidney failure an aminoglycoside and a high-dose ?-lactam, the Aminoglykosidspiegel may be reduced because the interaction in vivo is prolonged. Aminoglycosides dosage for adults 1. Selecting an initial dose of the respective aminoglycoside in mg / kg (ideal body weight) for serum peak levels in the below mentioned range. If the real weight of the patient is due to obesity> 20% higher than the ideal weight * is used as the metering basis, the ideal weight plus 40% of excess weight (actual weight minus ideal weight). If the real body weight exceeds the ideal weight due to ascites or edema is used as dosage basis the real body weight. Aminoglycoside Typical initial doses serum peak levels (target range) trough levels (target range) Gentamicin Tobramycin 1.5-2.0 mg / kg 4-10 ng / ml 1-2 ug / ml amikacin 5.0-7.5 mg / kg 15-30 ug / ml 5-10 ug / ml 2. selection of the maintenance dose (in percent of the selected initial dose) for the above Serum peak levels, based on the desired dosing interval and adapted to the corrected creatinine clearance of the patients: required maintenance dose (in percent of the initial dose) Creatinine clearance (ml / min) ‡ 8 h (%) 12 h (%) 24 h (%) 90 84 – – 70 190 88 – 50 65 79 – 30 48 63 86 20 37 50 75 15 31 42 67 10 24 34 56 5 16 23 41 0 8 11 21 * Ideal body weight = 50 kg (male) and 45.5 kg (females) at a size of 152 cm; 0.9 kg will be deducted for each cm size <152 cm or for each cm> 152 cm to be counted. Creatinine clearance (c) for men = (140 – age) weight in kg / 70 x serum creatinine. Creatinine clearance (c) Women = 0.85 x creatinine clearance (c) for men. If CrCl (c) ? 90 ml / min, the serum levels should be measured to determine the dosage. CrCl = creatinine clearance; Creatinine clearance (c) = corrected CrCl. Modified by: Sarubbi FA Jr, JH Hull: amikacin serum Concentrations: Prediction of levels and dosage guidelines. Annals of Internal Medicine 89: 612-618., 1978

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