Renal disposition of gentamicin, dibekacin, tobramycin, netilmicin, and amikacin in humans

Using a rabbit model of aortic valve endocarditis, we studied the efficacy of vancomycin alone or in combination with netilmicin and/or rifampin against a methicillin-and gentamicin-resistant strain of Staphylococcus aureus (MGRSA). Antibiotics were given for 6 or 12 days, as follows: vancomycin (15 mg/kg of body weight every 12 h [BID] intravenously), vancomycin plus netilmicin (2.5 mg/kg BID intramuscularly), vancomycin plus rifampin (10 mg/kg BID intramuscularly), and vancomycin plus netilmicin plus rifampin at the same routes, dosages, and schedules mentioned above. Netilmicin was given to two additional groups at a higher dosage (6 mg/kg every 24 h intramuscularly) alone or in combination with vancomycin (15 mg/kg BID intravenously) for 12 days. All regimens resulted in undetectable bacterial counts in a significant proportion of vegetations (except netilmicin alone) or reduced the bacterial counts in the vegetations compared with the counts in the untreated controls (P < 0.01 to P < 0.001). No resistance to rifampin or netilmicin developed during therapy. It is concluded that in the treatment of experimental aortic valve endocarditis caused by MGRSA (i) vancomycin as monotherapy is as efficacious as the triple combination, (ii) the addition of netilmicin (once daily or BID) to vancomycin does not improve the efficacy of the latter antibiotic, even in the presence of rifampin, and (iii) a 12-day course is more effective than a 6-day one, but not at a statistically significant level.Staphylococcus aureus is the second most common cause of infective endocarditis. It affects either native (25 to 35%) or prosthetic valves and is the most common organism (70%) recovered from intravenous drug addicts with endocarditis (23). Methicillin-resistant S. aureus (MRSA) strains have spread worldwide, and the frequency of their isolation has recently increased steeply (5, 12). MRSA isolates should be considered resistant to all ␤-lactams, and very often these organisms are cross resistant to gentamicin; however, they are uniformly susceptible to vancomycin and are usually susceptible to rifampin (5, 23).Vancomycin is clearly the drug of choice for the treatment of infections caused by MRSA as well as an alternative to betalactam antibiotics for the treatment of methicillin-susceptible S. aureus infections, particularly in patients allergic to ␤-lactams (8, 24). Nevertheless, there have been several reports of therapeutic failures in patients with S. aureus endocarditis treated with vancomycin as monotherapy (18,33,35). Even in animal models, vancomycin has been found to be ''surprisingly unsuccessful'' against MRSA endocarditis (9). On the other hand, the therapeutic role of rifampin in MRSA endocarditis is controversial (4), and today the majority of MRSA endocarditis strains are also gentamicin resistant (23). Because netilmicin (i) has been found to be active in vitro against MRSA strains cross resistant to gentamicin (16a), (ii) it possesses decreased nephrotoxic potential in comparison with that of gentamicin (11,22,...

Section: Vol 39 1995 Vancomycin Plus Netilmicin For S Aureus Endocmentioning

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Vancomycin or vancomycin plus netilmicin for methicillin- and gentamicin-resistant Staphylococcus aureus aortic valve experimental endocarditis

Perdikaris

Giamarellou

Pefanis

et al. 1995

“…In order to reduce aminoglycoside toxicity, some investigators suggested the use of low doses of gentamicin (30) or other aminoglycosides with lower toxicities, such as netilmicin (4,15). This is the aminoglycoside of choice in our institution, precisely because of its lower toxicity (6,13), and therefore was the aminoglycoside evaluated in the present experimental study. Another way to attenuate aminoglycoside toxicity would be to inject the antibiotic once daily, since this dosing regimen is well tolerated in humans (24,25) and is less ototoxic and nephrotoxic than conventional dosing regimens in animal studies (1, 10, 25, 31).…”

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Importance of the aminoglycoside dosing regimen in the penicillin-netilmicin combination for treatment of Enterococcus faecalis-induced experimental endocarditis

Fantin

Carbon

1990

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The penicillin-aminoglycoside combination is recommended for the treatment of systemic enterococcal infections. However, the optimal dosing regimen of the aminoglycoside remains to be elucidated. We evaluated the efficacy of penicillin, alone or in combination with various dosing regimens of netilmicin, for the treatment of experimental left-sided Enterococcusfaecalis endocarditis in rabbits. Animals were injected intramuscularly for 4 days with penicillin alone or in combination with netilmicin in one of the following regimens: netilmicin at a low dose (2 mg/kg of body weight every 8 h), netilmicin at a high dose (4 mg/kg every 8 h), or netilmicin at a single daily high dose (12 mg/kg every 24 h). MICs and MBCs were 3.1 and 6.2 ,ug/ml and 8 and 8 ,ug/ml for penicillin and netilmicin, respectively. A netilmicin concentration of 4 ,ug/ml was the lowest concentration that achieved synergism with penicillin, as shown by the kill-curve method. Mean peak levels of netilmicin in serum were 5.6 (netilmicin at 2 mg/kg), 9.8 (netilmicin at 4 mg/kg), and 20.6 (netilmicin at 12 mg/kg) ,g/ml.Mean penicillin levels in serum were constantly above the MIC. Penicillin plus netilmicin at a high dose given three times daily was more effective (P < 0.05) than any other regimen in reducing bacterial titers in vegetations and was the only treatment that induced a significant bactericidal activity in rabbit serum during the trough. We concluded that divided doses of aminoglycoside are more effective than the same total dose given once daily in combination with penicillin. Our data suggest that prolonged levels of aminoglycoside in serum might be important to exhibit the greatest in vivo efficacy of the combination against E. faecalis. They also indicate that use of a reduced total daily dose of aminoglycoside or an increase in the interval between each dose might reduce the efficacy of therapy in animals with this type of infection.

“…These two antibiotics are not metabolized in humans and are mainly cleared through urinary excretion. They differ in their degrees of binding to serum albumin, i.e., 0% for gentamicin and 82% for cefazolin (6,9). This fact allowed us to study independently the roles of increased vascular permeability and of altered protein binding in the hypothyroid state.…”

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Alteration of gentamicin and cefazolin kinetics with control of the hypothyroid state in humans

Chanson¹,

Joly²,

Contrepois³

et al. 1987

Self Cite

We studied the effect of the control of the hypothyroid state in humans on the pharmacokinetic parameters of cefazolin and gentamicin after a single intravenous inJection. These two antibiotics were chosen because of their different patterns of binding to serum albumin (0% for gentamicin and 82% for cefazolin). In hypothyroidism, the behavior of cefazolin only was altered, with a decrease in the total body clearance, possibly due to reduced urinary excretion, and a decrease in the volume of distribution without a significant alteration of cefazolin binding to serum protein.The extravascular accumulation of albumin and fluid in primary myxedema was previously assessed by Parving et al. (10). This increased extravasation of albumin, fluid, and presumably all other plasma proteins could change the pharmacokinetic behavior of drugs. Furthermore, the binding of drugs to plasma proteins may be altered in thyroid disease. Feely et al. (8) reported that the degree of binding of propranolol (basic compound) increased in hypothyroid patients, whereas that of warfarin (acidic compound) decreased in hyperthyroid patients. Usually, drug adminstration does not take the thyroid state into account. The effect of hypothyroidism on the pharmacokinetic behavior of antibiotics has never been reported. The purpose of this study was to evaluate the pharmacokinetic parameters of cefazolin and gentamicin in humans before and after the control of the hypothyroid state. These two antibiotics are not metabolized in humans and are mainly cleared through urinary excretion. They differ in their degrees of binding to serum albumin, i.e., 0% for gentamicin and 82% for cefazolin (6,9). This fact allowed us to study independently the roles of increased vascular permeability and of altered protein binding in the hypothyroid state.Five women (mean age, 59 ± 19 years) participated in the study after giving informed consent. They were treated for thyroid cancers (two by radiotherapy and three by surgery). They were studied initially when they were rendered hypothyroid and then at least 3 months later when they became euthyroid through replacement hormonetherapy. Euthyroidism was assessed by the normalization of serum thyrotrophin, tri-iodothyronine, and thyroxine, with normal values being 0 to 7 mU/liter, 60 to 190 ng/dl, and 4.5 to 11 ,ug/dl, respectively. Before each step, serum samples were taken to measure creatinine, albumin, tri-iodothyronine, thyroxine, and thyrotrophin. At each step, each subject received an intravenous bolus injection (over 3 min) of 2 mg of gentamicin and 15 mg of cefazolin per kg. An indwelling butterfly cannula was used to withdraw blood samples at 3,5,10, 15, 20, 30, 45, 60, and 120 min after the injection.Although a sampling period of 2 h only is inadequate to * Corresponding author.define the elimination character with any accuracy when the terminal half-life of the antimicrobial agent approaches 2 h, samples were not taken beyond 2 h for ethical reasons, this study being performed in cancer patients during dynamic t...