Gentamicin Levels Research Articles

Pharmacokinetics of gentamicin in neonates on extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) has been used in more than 1,000 infants in 50 centers in the United States. The extracorporeal circuit contains approximately 400 ml of blood, an amount exceeding the blood volume of most full-term neonates. The effect of this additional blood volume on drug disposition is unknown. In this study, we determined the pharmacokinetic parameters of gentamicin in 10 infants on ECMO. Gentamicin concentrations were determined by a fluorescence polarization immunoassay. Pharmacokinetic parameters were determined from these concentrations by using a two-compartment model. Our study demonstrated a mean steady-state volume of distribution of 0.51 +/- 0.11 liters/kg, a figure similar to that in previous studies of full-term infants. The elimination half-life was found to be prolonged (mean, 573 +/- 263 min). The creatinine level in the plasma of the infants was found to be a statistically significant predictor of elimination half-life. Recommendations regarding initial dosing levels of gentamicin in infants on ECMO are made.

A new method for continuous intraocular drug delivery

A novel device for the continuous intraocular delivery of drugs is described. The active intraocular component of the device is made from hollow haemodialysis fibres. During operation, the drug to be administered diffuses from a small extraocular reservoir to the intraocular fibres, where it passes through the semipermeable walls and into the vitreous body. The delivery of gentamicin by the device into the vitreous body of the cat is compared with direct intraocular injection techniques. Characteristics of the process of drug delivery were influenced by the geometry and design of the device. A reservoir concentration of 10 g/L gentamicin sulphate in a device with four fibres, each 5 mm long, resulted in stable vitreal gentamicin levels of 104 to 128 mg/L at 10 hours. Intravitreal injection of 0.1 ml of a 10 g/L solution of gentamicin caused localised peaks of intravitreal gentamicin concentration in the range 1180 to 3296 mg/L, before falling to 356 to 665 mg/L at 10 hours. The device provides the opportunity of a more controlled and continuous drug delivery, thus avoiding the high localised concentrations that may occur with direct injection techniques in which the required dose is delivered as a bolus. Refinement of a device of this type may result in a clinically useful method of intraocular drug delivery for drugs which present a risk of localised retinal toxicity or require repetitive administration with conventional intraocular injection techniques.

Gentamicin nephrotoxicity in extrahepatic cholestasis: modulation by dietary calcium.

The present study was designed to test the hypothesis that the presence of a specific hepatobiliary disease, namely common bile duct obstruction, in the absence of other risk factors will exacerbate gentamicin nephrotoxicity. Furthermore, since bile duct ligation decreases urinary calcium excretion, we studied the role of calcium supplementation in the prevention of gentamicin nephrotoxicity in this model. Male Sprague-Dawley rats were allocated to sham groups and common bile duct ligation groups. Gentamicin at 40 and 100 mg per kg per day for 5 days induced a more severe azotemia in common bile duct ligation animals than in sham controls. Furthermore, higher levels of renal gentamicin were found in common bile duct ligation rats than in sham rats early in the course of therapy, at its termination and during the recovery period. Pretreatment of common bile duct ligation animals with dietary calcium supplementation significantly attenuated gentamicin nephrotoxicity and the increased renal gentamicin accumulation, whereas initiation of calcium supplementation concurrent with gentamicin administration had no salutary effect. We conclude that experimental extrahepatic cholestasis in the rat, in the absence of any other factor, potentiates gentamicin nephrotoxicity. The effect is prevented by pretreatment with dietary calcium supplementation but is not modified by concurrent administration of a high-calcium diet.

Endocarditis Due to Streptococcus faecalis with High-Level Resistance to Gentamicin

Recently, reports of Streptococcus faecalis with resistance to high levels of gentamicin have appeared in the literature, although there have been no previous reports of endocarditis due to such organisms. In this article, two cases of endocarditis--both due to Streptococcus faecalis with high-level gentamicin resistance and both presenting in an atypical manner--are described. The data suggest that a high level of suspicion regarding a diagnosis of endocarditis must be maintained in such cases and that, once a case is diagnosed, careful evaluation in the microbiology laboratory is helpful in determining the optimal antimicrobial regimen.

The in vivo behavior of gentamicin-PMMA beads in the maxillofacial region.

Gentamicin-PMMA beads were placed in maxillofacial wounds of ten dogs, and gentamicin levels from wound drain sites, serum, and urine were measured by radioimmunoassay. The results indicate extremely high wound and modest urine levels (which decrease exponentially) concurrently with negligible serum levels of gentamicin. The results of this study of a highly vascularized area were similar to other studies in which beads were placed in avascular areas.

Systemic antimicrobial therapy of nosocomial pneumonia: Monotherapy versus combination therapy

The treatment of nosocomial pneumonia is difficult because of the absence of a precise microbial etiology in a sizable fraction of cases and the severity of predisposing conditions in patients who develop these infections. Staphylococcus aureus and aerobic gram-negative rods continue to be the most common isolates in these infections. Therapy of nosocomial pneumonia is often empiric, with initial antimicrobial therapy based upon local experience and sensitivity patterns, immune competence of the patient and disease severity. Combination therapy with an aminoglycoside and a beta-lactam has long been the cornerstone of therapy, and clinical success has been correlated with peak serum bactericidal levels of 1:8 in non-granulocytopenic patients and peak gentamicin and tobramycin levels greater than 8 micrograms/ml. The introduction of new broad-spectrum antibiotics, such as monobactams, third-generation cephalosporins and imipenem, has introduced the possibility of monotherapy for the treatment of nosocomial pneumonia. In general, monotherapy has proven to be a useful alternative to combination therapy, with success rates ranging from 77 to 96%. Development of resistance during therapy, particularly by Pseudomonas, Enterobacter and Serratia spp., remains an unresolved problem.

Enhancing effect of glyceryl-1-monooctanoate on the rectal absorption of gentamicin from hollow-type suppositories in rabbits.

A hollow-type suppository containing gentamicin (GM) in its cavity was prepared using Witepsol H-15 (H-15) mixed with glyceryl-1-monooctanoate (MO) or MO alone in the body of the suppository (type I) and a suppository (type II) containing GM and MO in the cavity was constructed using H-15 in the body of the suppository. Without MO, GM (60 mg) was not absorbed (plasma GM levels less than 1 microgram/ml). However, the absorption of GM from the rectum of rabbits was enhanced by coadministered MO in types I and II. Even when the amount of GM was decreased to 6 mg (1/10), GM was observed in the plasma (Cmax, 3.5 +/- 0.3 micrograms/ml) after administration of the suppository made from MO mixed with H-15. The enhancing effect of MO on the rectal absorption of GM could not be further increased by incorporating an amount of MO larger than approximately 300 mg into the suppository. This study demonstrates that MO can be used in the two types of hollow suppositories as an effective enhancing agent of rectal absorption of poorly absorbed drugs such as GM.

Collagen-shield delivery of gentamicin and vancomycin.

The ability of collagen-shield therapeutic contact lenses to release gentamicin sulfate and vancomycin hydrochloride individually and in combination was investigated using a fluorescent polarization immunoassay. In vitro studies showed that presoaked collagen shields released the majority of gentamicin within the first 30 minutes of elution, while vancomycin was released gradually over six hours of elution. Three experiments in rabbits compared the gentamicin and vancomycin levels produced at five time points in tears, cornea, and aqueous humor by collagen shields soaked in antibiotics vs frequent-drop therapy. The collagen shields soaked in gentamicin, vancomycin, or a combination of the two produced tear, cornea, and aqueous humor levels that were generally higher or at least comparable with those achieved by frequent-drop therapy.

Prevalence and clinical implications of hypocalcemia in acutely ill patients in a medical intensive care setting: Dasai TK Carlson RW, Geheb MA. Am J Med 1988; 84:209–214

Prevalence and clinical implications of hypocalcemia in acutely ill patients in a medical intensive care setting: Dasai TK Carlson RW, Geheb MA. Am J Med 1988; 84:209–214

Absence of a postantibiotic effect in experimental Pseudomonas endocarditis treated with imipenem, with or without gentamicin.

We found an in vitro postantibiotic effect (PAE) of 3-4 h for imipenem and of approximately 5 h for imipenem plus gentamicin against Pseudomonas aeruginosa. We therefore evaluated these antibiotics in a rat model of pseudomonas endocarditis. A rapid bactericidal effect was initially observed in vegetations from rats treated with imipenem alone or in combination with gentamicin. Bacterial counts rose rapidly, however, as soon as levels of imipenem in vegetations fell below the minimal inhibitory concentration (i.e., no PAE was demonstrated). Levels of gentamicin in vegetations were similar to those that had enhanced the bactericidal effect of imipenem and had resulted in a 5-h PAE in vitro. The presence in vitro of a PAE for imipenem, with or without gentamicin, does not necessarily predict its presence in vivo in pseudomonas endocarditis in the rat.

Enhanced urinary trypsin inhibitory activity in gentamicin-induced nephrotoxicity in rats

We delineated in rats, the relationship between trypsin inhibitory activity in the urine and the nephrotoxic effects of gentamicin, eg, proteinuria and deterioration of glomerular filtration rate (GFR), measured by creatinine clearance. Gentamicin, 70 mg/kg per day, was injected intraperitoneally for 6–10 successive days. Serum and urine gentamicin levels were determined by a microbiological test. Trypsin inhibitory activity was assayed by the casein digestion method. The results showed a steady increase in urinary trypsin inhibitory activity starting from the fourth injection day. The increased levels of urinary trypsin inhibitory activity were associated with increased levels of urinary gentamicin excretion ( r = 0.36, p < 0.02, n = 50 after the fourth injection day), and were significantly higher than in control groups ( p < 0.001). The urinary trypsin inhibitory activity was inversely correlated with the GFR ( r = −0.45, p < 0.01, after the second injection day). The serum trypsin inhibitory activity remained unchanged throughout the study period in all groups. These data suggest that increased urinary trypsin inhibitory activity may be involved in the pathogenesis of gentamicin-induced nephrotoxicity.

Discussion

This report reviews our experience with inhaled high-dose gentamicin in patients with CF. A highly significant correlation between dose and peak serum gentamicin level was observed. The peak serum levels achieved with such a regimen might be sufficient to provide an antibacterial effect in unventilated but perfused lung regions.

Morphine effects on gentamicin disposition and toxicity in mice

Morphine has been shown to reduce renal and hepatic clearance of several xenobiotics in rodents. After iv administration of gentamicin, 10 to 30 mg/kg, its plasma levels were elevated in mice given morphine, 20 mg/kg sc. Plasma clearance of gentamicin was nearly halved by morphine, due primarily to lowering of the elimination constant of gentamicin from 0.03 to 0.02 min −1 ( p < 0.01). Morphine also significantly reduced urine levels of gentamicin and urine volume. In mice given naloxone, 2 mg/kg sc, morphine did not significantly raise plasma levels of gentamicin nor reduce its elimination into urine. Mice were made tolerant by morphine administration for 9 days at ascending doses to 100 mg/kg twice daily. An acute challenge with morphine, 20 mg/kg, was less effective in raising plasma levels of gentamicin or lowering its urinary elimination in tolerant mice than after chronic saline treatment. Partial tolerance to acutely administered morphine and reversal of morphine effects by naloxone suggest opioid receptor-mediated reduction of glomerular filtration by morphine in mice. Despite marked elevation of plasma gentamicin levels in morphine-treated mice, narcotic administration did not significantly increase the acute toxicity of a single dose of genatamicin. LD50 of acutely administered iv gentamicin was 51.6 mg/kg after saline and 45.3 mg/kg after treatment with morphine, 20 mg/kg sc. However, this dose of morphine enhanced the lethality of intravenously infused gentamicin. Morphine administration significantly reduced the dose of infused gentamicin needed to achieve the critical lethal plasma level.

Development of a Plant Transformation Selection System Based on Expression of Genes Encoding Gentamicin Acetyltransferases

The development of selectable markers for transformation has been a major factor in the successful genetic manipulation of plants. A new selectable marker system has been developed based on bacterial gentamicin-3-N-acetyltransferases [AAC(3)]. These enzymes inactivate aminoglycoside antibiotics by acetylation. Two examples of AAC(3) enzymes have been manipulated to be expressed in plants. Chimeric AAC(3)-III and AAC(3)-IV genes were assembled using the constitutively expressed cauliflower mosaic virus 35S promoter and the nopaline synthase 3' nontranslated region. These chimeric genes were engineered into vectors for Agrobacterium-mediated plant transformation. Petunia hybrida and Arabidopsis thaliana tissue transformed with these vectors grew in the presence of normally lethal levels of gentamicin. The transformed nature of regenerated Arabidopsis plants was confirmed by DNA hybridization analysis and inheritance of the selectable phenotype in progeny. The chimeric AAC(3)-IV gene has also been used to select transformants in several additional plant species. These results show that the bacterial AAC(3) genes will serve as useful selectable markers in plant tissue culture.

Quantitative deposition of aerosolized gentamicin in cystic fibrosis.

In cystic fibrosis (CF), the clinical effectiveness of aerosolized antibiotics is controversial. Previous investigators have not considered the type of nebulizer, droplet size, and dose to the lung in assessing the results of aerosol therapy. The present study tests the importance of these factors by standardizing an aerosol system for delivery of antibiotics and other agents to patients with CF. Particle size, distribution, and output from a commercially available nebulizer were measured. Thirteen patients with CF inhaled aerosol (MMAD = 1.1 micron) containing gentamicin (160 mg in nebulizer) and 99mTc-labeled human serum albumin. Patients' sputum and serum were analyzed for gentamicin levels by immunoenzymatic assay (Emit; Syva Corp., Palo Alto, CA). Using a gamma camera and suitable filters, central versus peripheral deposition (C/P ratio) and whole lung deposition were measured and related to sputum gentamicin levels. Gentamicin deposit averaged 12.3 mg +/- 5.9 (SD) or 7.69% of the original amount placed in the nebulizer. Peak sputum levels averaged 376.6 micrograms/ml +/- 275, whereas serum levels were undetectable in all patients. When peak sputum levels were normalized for the amount deposited, a close correlation with C/P ratio was obtained (r = 0.88, p less than 0.05). Furthermore, an inverse relationship was found between the C/P ratio and the %FEV1 (r = 0.76, p less than 0.05). Finally, a bell-shaped relationship between deposited dose and minute ventilation was seen in the patients (r = 0.88, p less than 0.05), i.e., an optimal minute ventilation was shown. These relationships may be important when designing future clinical studies.

A comparison of the effects of cisplatin and N-methyliminodiacetato-(1,2-diaminocyclohexane)-platinum(II) on renal function and gentamicin excretion in rats

N-methyliminodiacetato(1,2-diaminocyclohexane)-platinum(II) (MIDP) is a new third-generation water-soluble antitumor platinum complex. This study compares the effects of MIDP (3 injections of 25 mg/kg each on days 1, 5 and 9) on renal structure and function and the urinary excretion of gentamicin (GENT) with those of a single 6 mg/kg dose of cisplatin (DDP) in F-344 (Fischer) rats. GENT was given as a single dose of 30 mg/kg 7 days after DDP injection or the last MIDP injection. Rats given DDP and GENT had significantly different plasma urea nitrogen (BUN) levels (315 ± 79 mg/dl) and creatinine clearance (0.40 ± 0.24 ml/[min · kg]) than did the control group that was given only GENT (15 ± 1 mg/dl and 5.5 ± 0.6 ml/[min · kg]) MIDP did not affect renal function (BUN, 16 ± 3 mg/dl; creatinine clearance, 6.1 ± 1.0 ml/[min · kg]). Light microscopic examination of renal tissue from MIDP-treated rats did not reveal any evidence of cell degeneration or necrosis. Rats given GENT alone excreted 72 ± 4% of the dose in 24 h and had plasma gentamicin levels of 19 ± 2 ng/ml 24 h after injection. The group pretreated with DDP had lower urinary GENT excretion (31 ± 10%) and higher plasma GENT levels (7491 ± 3750 ng/ml). MIDP pretreatment had no effect on GENT excretion (72 ± 8%) or plasma GENT levels (16 ± 2 ng/ml). Thus, MIDP did not cause any measurable decrease in renal function or GENT excretion in our study. Since nephrotoxicity is a significant problem with DDP administration, further studies with MIDP are warranted.

A controlled study of the nephrotoxicity of mezlocillin and gentamicin plus ampicillin in the neonate

The nephrotoxicity of the aminoglycoside gentamicin was evaluated in an open, controlled study of newborn infants randomly allocated to receive either combination drug therapy with gentamicin and ampicillin or single drug therapy with mezlocillin for treatment of presumed neonatal sepsis. There were no significant differences in initial clinical characteristics between the groups. Neonates receiving gentamicin, in contrast to those receiving mezlocillin, had significant nephrotoxicity manifested by a smaller postnatal fall in mean serum creatinine concentration (-9%, P NS vs -21%, P less than 0.005, respectively) and a diminished postnatal rise in mean creatinine clearance (+ 21%, P NS vs + 51%, P less than 0.01, respectively). In neonates with a fall in creatinine clearance, the mean decline was significantly greater in those receiving gentamicin (44% vs 20%, P less than 0.01). There was no relationship between the incidence of gentamicin nephrotoxicity and either peak or trough gentamicin levels. For treatment of presumed neonatal sepsis, gentamicin proved more nephrotoxic than mezlocillin.

Influence of hydrocortisone succinate on intrarenal accumulation of gentamicin in endotoxemic rats.

Gentamicin is a commonly used antibiotic in the treatment of gram-negative infections including septicemia and pyelonephritis. Bacterial endotoxin is liberated during antibiotic therapy and may lead to endotoxemic shock. Steroids such as hydrocortisone are generally recommended in the treatment of endotoxemic shock. There are very limited data on the influence of endotoxin or corticosteroids on the pharmacology of antibiotics, especially aminoglycosides, which are nephrotoxic. We studied the influence of both Escherichia coli endotoxin and hydrocortisone succinate on the renal uptake of gentamicin in rats. Animals were injected intravenously with endotoxin (0.25 mg/kg) and/or hydrocortisone (25 mg/kg) plus gentamicin (10 mg/kg). Gentamicin levels in the serum and renal parenchyma as well as renal function and histology were evaluated. Both endotoxin and hydrocortisone given alone increased the concentration of gentamicin in the renal cortex (P less than 0.05). Normal values in serum were observed in all groups at most time intervals. When administered together, endotoxin and hydrocortisone did not potentiate each other. The combination of endotoxin and hydrocortisone gave significantly higher levels of gentamicin than endotoxin or hydrocortisone alone when endotoxin was injected 3 h before hydrocortisone (P less than 0.05). Blood pressure and cardiac frequency were normal when gentamicin was given. Endotoxin alone slightly decreased the glomerular filtration rate, and hydrocortisone alone slightly modified renal plasma flow. The combination of both drugs did not significantly affect renal function. No histological lesion was noted on light microscopy in animals receiving endotoxin. Competitive or synergistic activity of endotoxin, gentamicin, and hydrocortisone at the cellular level, especially on membranes or lysosomes, might explain in part our observation on the renal uptake of gentamicin. By increasing the total amount of drug within the kidney, endotoxin and hydrocortisone might increase the risk of nephrotoxicity associated with aminoglycosides.

Activity of LY146032 against Enterococci with and without high-level aminoglycoside resistance, including two penicillinase-producing strains.

We tested the activity of LY146032 (LY) against 57 strains of enterococci collected from Chile, Thailand, and the United States. Some of the strains were resistant to high levels of gentamicin or streptomycin (or both), and two produced beta-lactamase (Bla+). MICs of LY ranged from 0.5 to 8 micrograms/ml, and MBCs ranged from 1 to 64 micrograms/ml. In time-kill assays, a 2 to 3 log10 killing effect was observed with LY against two Bla+ strains of Streptococcus (Enterococcus) faecalis and against three strains that were highly resistant to streptomycin and gentamicin. Synergism was demonstrated with LY and streptomycin against a Bla+ strain lacking high-level streptomycin resistance. These in vitro results suggest that LY should be studied further for possible use in treatment of enterococcal infections.

Probable transmission between animals of a plasmid encoding aminoglycoside 3-N-acetyltransferase IV and dihydrofolate reductase I

Ten aminoglycoside-resistant Escherichia coli isolated from the faeces of healthy or diarrhoeic animals reared in the same herd were studied. These strains were resistant to high levels of apramycin and low levels of gentamicin. They were also resistant to streptomycin, tetracycline, trimethoprim and some to ampicillin, chloramphenicol, kanamycin or nalidixic acid. Two strains, isolated from a calf and a lamb, respectively, belonged to the same biotype. All the transconjugants resistant to gentamicin-apramycin were also resistant to streptomycin, tetracycline and trimethoprim. In all cases, these resistances were encoded by plasmids of 100 kb. Analysis of these plasmids by agarose gel electrophoresis after digestion by EcoRI or BamHI revealed their similarity. Hybridization with a 500-bp HpaI insert of plasmid pFE872 was observed with DNA from field strains and their transconjugants, demonstrating the presence on the 100-kb plasmids of the gene coding for a dihydrofolate reductase I. A single plasmid, designated pIP1831, could be observed in identical or different strains isolated from calves or lambs, suggesting the transmission of strains and plasmids between animals of different species.