Serum Gentamicin Levels Research Articles

Aminoglycoside ototoxicity: prevention in sight?

Despite the development of new antibiotics, the aminoglycosides are still indispensable in the treatment of life-threatening diseases. Worldwide they are the most commonly used antibiotics, and their use is expected to increase in the wake of the rising incidence of tuberculosis. The most prominent side effects of aminoglycoside treatment--cochlear, vestibular, and renal impairment--are a limiting factor in the utility of these drugs. A novel mechanism of gentamicin ototoxicity is based on observations of iron chelation and free radical formation. Predictions from this mechanism have led to successful therapeutic prevention of ototoxicity by use of iron chelators and radical scavengers in guinea pigs. The drugs used for this interventive treatment affect neither serum levels of gentamicin nor its antibacterial efficacy. Because these drugs are in clinical use, the suggested protective treatment should lend itself to clinical trials.

Influence of diagnostic and treatment factors in the population pharmacokinetics of gentamicin.

Using the NONMEM program, the population kinetics of gentamicin were retrospectively studied in a series of 51 patients with different pathologies undergoing treatment (single or three daily doses) with gentamicin whose serum gentamicin levels were being monitored. Renal function, the type of treatment and cancer proved to be the covariates which affected drug clearance, while patient weight was found to govern the distribution volume. The distribution coefficient of gentamicin in the patients was 0.37 litres/kg, justifying gentamicin doses higher than those used conventionally. The optimized population model allowed us to simulate drug serum levels at 8 and 12h, as well as the area under the curve of gentamicin and its variability in patients with high distribution volumes when dosage regimens based on a single daily dose administration are implemented.

Supplemental iron exacerbates aminoglycoside ototoxicity in vivo

There is increasing evidence to suggest that free radical generation is central to a variety of pathological processes, including drug toxicity. Studies demonstrating the ability of gentamicin to facilitate the generation of radical species suggest that this process plays an important role in aminoglycoside-induced ototoxicity. Because transition metals, particularly iron, play an important role in the production of free radicals and the generation of reactive oxygen species, we sought to determine whether gentamicin-induced ototoxicity is exacerbated by increases in serum iron levels. To this end, we assessed the effects of supplemental iron administration (2 mg/kg/day and 6 mg/kg/day) on changes in auditory function induced by co-administration of gentamicin (100 mg/kg/day for 30 days). Experiments were carried out on pigmented guinea pigs initially weighing 250–300 g. Changes in cochlear function were characterized as shifts in compound action potential (CAP) thresholds, estimated every third day throughout the treatment period by use of chronic indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. Results showed that animals receiving iron in combination with gentamicin demonstrated a more rapid and profound elevation in CAP thresholds compared with animals receiving gentamicin alone. This effect occurred in a dose-dependant manner. Animals receiving supplemental iron alone maintained normal CAP thresholds throughout the treatment period. There was no statistically significant difference in serum gentamicin levels between groups receiving gentamicin alone or gentamicin plus iron. These results provide further evidence of the recently reported intrinsic role of iron in aminoglycoside ototoxicity, and highlight a potential risk of aminoglycoside administration in patients with elevated serum iron.

Communications: Gentamicin Concentrations in Toadfish and Goldfish Serum

Abstract Previous work in our laboratory has demonstrated that goldfish Carassius auratus produce new nephrons in response to gentamicin-induced nephrotoxicity. The oyster toadfish Opsanus tau, however, does not undergo nephron neogenesis. To explore possible reasons for the differences in the formation of new nephrons, we evaluated the elimination of gentamicin from the serum of both species. Fish (20 toadfish and 20 goldfish) were given intramuscular injections of 3.5 mg gentamicin/kg of body weight or an equal volume of sterile water. Blood samples were taken by venipuncture from goldfish at days 1, 2, 3, and 4 postinjection and from toadfish at days 1, 2, 7, 14, 28, and 49 postinjection. Gentamicin levels were measured in serum via a competitive binding immunoassay. Gentamicin levels in serum declined rapidly in goldfish, reaching near baseline levels 4 d after the injection, with a half-life of 49.6 h for the β component. Toadfish had a much longer gentamicin retention time with a half-life of 602 h ...

A comparison of once-daily and 8-hour gentamicin dosing in the treatment of postpartum endometritis

To evaluate whether once-daily gentamicin dosing is as effective as the traditional 8-hour regimen for the treatment of postpartum endometritis. Postpartum women with endometritis were randomized to receive gentamicin 5 mg/kg as a single daily dose or 1.75 mg/kg every 8 hours. All subjects also received clindamycin. Each participant had a peak serum gentamicin level of at least 5.0 micrograms/mL within the first 24 hours. The dosing regimens were compared by analyzing the number of hours that patients were febrile, the length of hospital stay, occurrence of complications, pharmacy costs, and nursing time required to administer the regimens. The study group (n = 62) and the control group (n = 65) were similar in demographic characteristics and the presence of endometritis risk factors. No differences were found between the groups in the number of patients who completed therapy without complications, required changes in antibiotics, or required readmission for endometritis. The groups did not differ in the number of hours that patients remained febrile after the start of therapy or in the length of hospital stay. No patient in the study group had an initial peak serum concentration less than 5.0 micrograms/mL, whereas 24 patients in the control group had initial peak serum concentrations less than 5.0 micrograms/mL and required dose adjustment, a statistically significant difference (P < .001). Pharmacy costs averaged $16.12 +/- 5.68 for the study group and $41.75 +/- 17.41 for the control group, also a significant difference (P < .001). Nurse tasking time averaged 13.62 +/- 2.56 minutes for the study group and 28.06 +/- 8.77 minutes for the control group (P < .001). In patients with postpartum endometritis, once-daily gentamicin dosing provides consistently high peak serum levels of gentamicin, requires less nurse tasking time, costs less, and is as effective as the 8-hour dosing regimen.

Variable efficacy of radical scavengers and iron chelators to attenuate gentamicin ototoxicity in guinea pig in vivo

Recent studies from our laboratory have suggested that the ototoxic side effects of gentamicin are caused by a metabolized or ‘activated’ form of the drug. Furthermore, we have postulated that the activation proceeds via the formation of an iron-gentamicin complex and that this complex produces free radicals. The present study assessed the protective effects of free radical scavengers and iron chelators on gentamicin-induced ototoxicity in guinea pigs in vivo. Gentamicin (120 mg/kg per day for 19 days) caused progressive threshold shifts reaching 50–65 dB at 18 kHz. Co-therapy with different radical scavengers yielded results ranging from no protection (with allopurinol, dimethyl sulfoxide, benzoate, lazaroid U74389G) to a moderate attenuation of hearing loss (with mannitol, 4-methylthiobenzoate, WR-2721). This finding agrees well with previous reports of inconsistent effects of scavengers on aminoglycoside-induced ototoxicity although it should be cautioned that only a single dose and route of application was tested. Two iron chelators, deferoxamine and 2,3-dihydroxybenzoate, significantly reduced the gentamicin-induced threshold shifts to about 10 dB or less. Iron chelators markedly decreased total serum iron levels while gentamicin treatment alone had no influence. There were no differences in serum gentamicin levels among all treated groups. This study confirms that iron plays a critical role in gentamicin ototoxicity and suggests that iron chelators, which are well-established drugs in clinical therapy, may be promising therapeutic agents to reduce aminoglycoside ototoxicity.

Reduced nutritional status enhances ototoxicity

This study investigates whether the nutritional state of guinea pigs is a risk factor for the ototoxic side effects of cisplatin, gentamicin, and gentamicin in combination with ethacrynic acid. A normal nutritional state was maintained with a standard 18.5% protein diet while nutritional deficiency was produced by feeding a 7% protein diet. Hearing loss was measured by auditory evoked brainstem responses. Guinea pigs on the low protein diet had a significantly higher drug-induced hearing loss. Cisplatin-induced hearing loss was 32 dB in undernourished animals but 10 dB in normal animals (18 kHz). The difference for gentamicin was 74 dB versus 42 dB (18 kHz). Gentamicin in combination with 20 mg ethacrynic acid/kg body weight produced a hearing loss of 95 dB in animals on a low protein diet and 12 dB in animals on a full protein diet. The enhanced ototoxicity was not based on differences in drug pharmacokinetics since serum levels of platinum and gentamicin did not differ between the groups. These results demonstrate that the severity of ototoxic side effects is influenced by nutritional factors. They also imply that animals on a restricted diet may be a more appropriate model for severely compromised patients undergoing pharmacotherapy.

Glutathione protection against gentamicin ototoxicity depends on nutritional status

This study demonstrates that gentamicin ototoxicity depends on dietary factors and correlates with tissue glutathione levels. After 15 days of gentamicin injections (100 mg/kg/day s.c.) guinea pigs on a regular protein diet (18.5% protein) had an average hearing loss of 9 dB at 3 kHz, 31 dB at 8 kHz and 42 dB at 18 kHz. Guinea pigs on a 7% protein diet showed an increased hearing loss of 52 dB at 3 kHz, 63 dB at 8 kHz and 74 dB at 18 kHz. Supplementing the low protein diet with either essential or sulfur-containing amino acids did not protect against gentamicin ototoxicity. Glutathione levels in the cochlear sensory epithelium were decreased in animals on a low protein diet and could be restored to normal by oral administration of glutathione monoethyl ester (1.2 g/kg/day) in combination with vitamin C (100 mg/kg/day). Glutathione supplementation significantly reduced the magnitude of hearing loss in the low protein diet group at all frequencies (43 dB reduction at 3 kHz, 27 dB reduction at 8 kHz and 21 dB reduction at 18 kHz). In animals on a full protein diet, dietary glutathione neither increased cochlear glutathione levels nor attenuated hearing loss. Serum gentamicin levels did not differ between animals on the various diets with or without glutathione supplement. These results suggest that gentamicin toxicity and detoxifying mechanisms are affected by the metabolic state of the animal and the glutathione content of the tissue. Thus, compounds that could potentially protect against gentamicin ototoxicity may be more correctly assessed in animal models of deficient nutritional states in which endogenous detoxifying mechanisms are compromised. This animal model might also be more realistically related to the clinical situation of a critically ill patient receiving gentamicin treatment.

Gentamicin vestibulotoxicity.

We reviewed 36 patients with gentamicin vestibulotoxicity to determine its relationship to gentamicin dosage, serum gentamicin levels, and the development of gentamicin nephrotoxicity. Thirty of the patients had received intravenous or intramuscular gentamicin; six had received intraperitoneal gentamicin. Sixteen of the 30 patients treated with intramuscular or intravenous gentamicin had received less than the recommended maximum dose of 5 mg/kg/day for less than the recommended maximum period of 10 days. Nephrotoxicity as well as vestibulotoxicity developed in 16 of these 30 patients. Gentamicin vestibulotoxicity was not recognized before discharge from hospital in 32 of the 36 patients. We conclude that as far as the vestibular system is concerned there is no safe gentamicin dose and no safe serum gentamicin level, and there is an increased risk of vestibulotoxicity in patients in whom nephrotoxicity develops. Physicians who use gentamicin should become more aware of the clinical features of vestibulotoxicity because stopping gentamicin as soon as symptoms of vestibulotoxicity appear could prevent permanent impairment of vestibular function.

Serum Gentamicin Concentrations in Postpartum Endomyometritis

Gentamicin in combination with other antibiotics is frequently used in the treatment of postpartum endomyometritis. The need to monitor and maintain therapeutic concentrations, however, is controversial. To assess the role of monitoring, serum gentamicin concentrations were prospectively studied in an obstetric population treated for postpartum endomyometritis. Clinical course was correlated to serum gentamicin levels obtained using a 1 mg/kg/dose regimen. No patient demonstrated therapeutic concentrations. Sixteen of 18 obstetric patients (88%) exhibited a clinical response despite subtherapeutic serum gentamicin concentrations. The two failures included one case of septicemia and one wound seroma. Serum gentamicin levels of this obstetric population when compared to those from a gynecologic population treated for benign disease demonstrated no statistical difference. These data suggest that clinical response provides an accurate indication of the efficacy of therapy and that gentamicin doses of 1 mg/kg/dose provide sufficient antibiotic coverage in most cases. These results do not support the use of increased gentamicin dosages and the need to attain therapeutic levels in the obstetric patient, as previously suggested.

Population pharmacokinetics of gentamicin in premature infants.

The population kinetics of gentamicin were studied in 97 newborn patients with a gestational age ranging between 28 and 43 weeks and a postnatal age ranging between 2 and 30 days undergoing routine therapeutic monitoring of their serum gentamicin levels. The individual kinetic analysis of serum drug levels was performed using a single-compartment model. The clearance and apparent distribution volume were calculated in each patient. The population model employed assumes the existence of residual variability in the serum concentrations and interindividual variability in the pharmacokinetic parameters. The effects of demographic variables on the clearance, distribution volume, and optimum daily dose of gentamicin were established using multiple linear regression. Gestational age is the best predictive variable of the clearance and the optimum dose/day in the whole population studied. In the premature infant patients, the predictive capacity increases with postconceptional age. Weight is a good predictive variable of all of the parameters, especially of the apparent distribution volume in the overall population of newborns. Analysis of the population kinetic behavior and optimum dose/day in each subgroup recommends that the interval of drug administration should be increased, keeping the same dose/day ratio, due to the tendency of the drug to accumulate its long half-life, especially in premature babies.

The Role of Gentamicin Iontophoresis in the Treatment of Burned Ears

Ear cartilage heals slowly, and limited vascularity in cartilage precludes use of systemic antibiotics. Iontophoresis electrically induces drugs in solution to migrate into target tissues. Fifteen patients were randomized to receive gentamicin iontophoresis (n = 7) plus dressing changes every 6 hours and cleaning or routine care alone (n = 8) for treatment of ear burns. There were no differences between the groups in incidence of chondritis (43% vs 50%) or cartilage loss (11% vs 16%). However, gentamicin-resistant organisms developed in 29% of the patients who received iontophoresis, but in none of the patients in the control group (p less than 0.05). To identify the etiology of the resistant organisms, 10 New Zealand white rabbits receive 7 cm2 contact burns to each ear. Gentamicin iontophoresis was performed on one ear, and the other ear served as the control. Serum gentamicin levels were always subtherapeutic. Additionally, gentamicin tissue levels in both the treated and control ears were subtherapeutic. Gentamicin iontophoresis appears to offer no additional salutary effects beyond those that are provided by routine care and may encourage the development of antibiotic resistance.

Ciprofloxacin versus gentamicin in prophylaxis against bacteremia in transrectal prostate needle biopsy

Consecutive patients with abnormal rectal examinations underwent transrectal needle prostate biopsy at VA Medical Center, New Orleans. Each patient was randomized to receive either gentamicin 1.5 mg/kg intravenously (IV) or 500 mg ciprofloxacin (Cipro-Miles) p.o., before and after the biopsy. Serum and prostate tissue levels of ciprofloxacin and gentamicin were measured by high-pressure liquid chromatography and by competitive binding immunoassay, respectively. Blood cultures were obtained, and the patients were observed for twenty-four hours after biopsy. After discharge the patients were followed up by telephone. The incidence of bacteremia and postbiopsy symptoms were less with ciprofloxacin. Prostate tissue levels of this drug were higher than gentamicin, while serum levels were roughly equivalent. Ciprofloxacin is less nephrotoxic, can be given orally, and has a better antimicrobial spectrum. We, therefore, recommend it as prophylaxis against bacteremia in transrectal prostate needle biopsy. Furthermore, it appears that prostatic drug levels are more important than serum levels in preventing bacteremia.

Changes in Gentamicin Serum Levels and Pharmacokinetic Parameters in the Newborn in the Course of Treatment with Aminoglycoside

Gentamicin serum levels were determined in an unselected group of newborns treated with standard doses of the drug to study the changes in pharmacokinetic parameters (trough and peak serum levels/dose ratio, serum level increases/dose ratio, elimination half-life, and distribution volume) 48, 96, and 144 h after commencing treatment. However, no significant changes in the pharmacokinetic parameters were found in different groups of neonates, classified according to gestational age and days of life during the study period. It appears that the dose of gentamicin once it has been individually established does not have to be changed, at least during the first week of treatment.

Monitoring Serum Levels of Gentamicin to Develop a New Regimen for Gentamicin Dosage in Newborns

The newborns studied had gestational ages ranging between 23-44 weeks, weights ranging between 725-4510 g, and were treated with standard doses of gentamicin (5.2 +/- 1.0 mg/kg/day). The gentamicin serum peak and trough levels were unrelated to administered doses, and a large proportion of patients had low (peak less than 4 micrograms/ml in 12%) or potentially toxic concentrations (trough greater than 2 micrograms/ml in 55%). The pharmacokinetic parameters (t1/2e, 8.2 +/- 4.8 h and Vd, 0.64 +/- 0.22 L/kg) varied markedly between patients. The newborn's weight, age, gestational age, and serum creatinine were factors of importance for the variability of gentamicin serum levels. The newborns were divided into four groups: gestational period less or more than 37 weeks and age below or above 7 days. These groups had different gentamicin serum levels and pharmacokinetic parameters. The results suggest that a gentamicin dosage regimen based on the division of newborn patients into subgroups or calculated from individual pharmacokinetic characteristics would decrease the risk of obtaining potentially toxic or subtherapeutic gentamicin concentrations after the use of standard doses.

Serum levels of gentamicin at peak and trough in neonates and infants

The peak and the trough levels of serum gentamicin were determined in 50 cases of neonates and infants by microbiological assay method. The peak levels in the neonates and the infants were 5.98 +/- 0.48 and 4.63 +/- 0.31 mcg/ml respectively. The trough levels in the corresponding group were 1.06 +/- 0.19 and 0.94 +/- 0.23 mcg/ml. The mean values of the peak and trough levels of the antibiotic were 5.57 and 1.02 mcg/ml respectively. It was observed that there was a significant lower peak concentration in the infants than in the neonates. A significantly higher peak concentration of gentamicin was observed in babies aged under 7 days than in those above 7 days. The route of administration (between I/M and I/V) did not seem to have any effect on the peak and trough levels of the antibiotics.

Effect of Gentamicin on the Auditory Brainstem Evoked Response in Term Infants: A Preliminary Report

Seven essentially healthy term infants who received gentamicin starting on the 1st day of life for prolonged rupture of membranes and maternal fever were compared with nine healthy term infants to determine whether this drug induces alterations in the auditory pathway. The auditory pathway was studied on the 3rd day of life by analyzing brainstem auditory evoked potentials elicited by a click stimulus presented at the infant's ears. Latencies of components III and V, interval I-III, and interval I-V were significantly prolonged in the gentamicin group, indicating impairment of the central component of the auditory pathway. Peak and trough serum gentamicin levels all fell within the recommended therapeutic range. The study indicates that short course gentamicin therapy in healthy newborn infants can lead to abnormality of auditory function.

Enhanced gentamicin nephrotoxicity after experimental biliary obstruction in rats.

To explore whether bile duct ligation increased the risk for gentamicin nephrotoxicity, male Wistar rats were subjected to bile duct ligation or sham surgery and given either gentamicin 20 mg/kg or saline twice daily intraperitoneally for 8 days. Bile duct ligated and gentamicin injected rats elicited a decline in renal function and tubular cell necrosis after 8 days of treatment whereas equal dosage regimen in sham operated rats exhibited no evidence of renal dysfunction. In addition, though serum and kidney gentamicin levels were higher in bile duct ligated rats (1.84 +/- 0.11 micrograms/ml versus 0.20 +/- 0.03 microgram/ml, and 1453 +/- 164 micrograms/g versus 698 +/- 138 micrograms/g of cortex, respectively, P less than 0.05). The data indicate that complete biliary obstruction enhances renal sensitivity to gentamicin.

Gentamicin dosage in newborn infants

Sixty nine pairs of trough and peak serum levels of gentamicin were determined in sixty three cases of gentamicin therapy of suspected sepsis in newborn babies (dosage 3.46 +/- 0.42 mg/kg/day given once a day). Eighty four percent of the trough levels were below 2 mg/l (mean: 1.39-0.60 mg/l). Ninety three percent of the peak levels were between 4 mg/l and 12 mg/l (mean: 7.38-2.35 mg/l). Three peak levels (four percent) were in the potentially toxic range (above 12 mg/l) and eleven trough levels (sixteen percent) were in the potentially toxic range (above 2 mg/l). On the basis of these observations the recommended gentamicin doses during the first two weeks of life is 3-4 mg/kg/day applied once a day. In immature babies with birth weights below 1500 g the daily doses should not exceed 3 mg/kg were as term babies especially during the second week of life should be treated with a daily gentamicin doses of near to 4 mg/kg/day.

Gentamicin dosing in postpartum women with endometritis

Postpartum women receiving gentamicin for endometritis were studied to determine if selective determination of gentamicin serum levels was cost-effective in terms of safety and efficacy. The women were randomized into two groups of 30 patients each. In the control group gentamicin serum levels were determined after the third dose. In the study group, levels were determined only if renal dysfunction was evident or if the patient failed to respond to therapy. Determination of serum levels did not assure a better therapeutic outcome in either group, as measured by hospital stay, duration of treatment, total cost of antibiotics, and hospital readmissions. Although pharmacokinetic dosing equations were used, the use of 1.75 mg/kg every 8 hours based on actual body weight in patients with average heights and weights would have produced acceptable results. We conclude that routine monitoring of gentamicin serum levels is not required in otherwise healthy postpartum women with endometritis. (AM J OSSTET GVNECOL 1989;160:309-13.)