Daily Gentamicin Research Articles

Pyrogenic reactions associated with single daily dosing of intravenous gentamicin.

To identify risk factors associated with an unexpected outbreak of pyrogenic reactions (PR) following intravenous gentamicin. We conducted two cohort studies. PRs were defined as chills, rigors, or shaking within 3 hours after initiating the gentamicin infusion during the preepidemic (December 1, 1997-January 15, 1998) or epidemic (May 1-June 15, 1998) periods. We tested gentamicin vials for endotoxin using the limulus amebocyte lysate assay. Inpatient services of a large community hospital in Los Angeles, California. During the epidemic period, 22 (15%) of 152 patients developed documented PRs following intravenous gentamicin. PRs were more likely among patients receiving single daily dosing (SDD) than multiple daily dosing gentamicin (20/73 [27%] vs. 2/79 [3%]; relative risk, 10.8; 95% confidence interval, 2.6 44.7). Laboratory analysis of gentamicin vials found endotoxin levels that were higher among Fujisawa-brand gentamicin (implicated brand) than gentamicin used after the outbreak terminated (non-implicated brand). Although endotoxin levels in the vials did not exceed US Pharmacopeia limits (1.7 endotoxin units/mg gentamicin), the use of SDD gentamicin may place patients at greater risk of receiving doses of endotoxin above the threshold for PRs in humans. Reassessment of the acceptable amounts of endotoxin in gentamicin and other parenteral products should be considered when dosing intervals used in clinical practice change.

Therapeutic drug monitoring of once daily gentamicin in serum and saliva of children.

Gentamicin is widely used in paediatric medicine and therapeutic monitoring is mandatory due to the narrow margin of safety. Saliva sampling may be of potential interest, especially in children in whom blood sampling is often difficult. Experience with once daily intravenous administration of aminoglycosides has grown in recent years. Gentamicin levels were measured in serum and saliva of 55 children treated with the drug (5 mg/kg per day), administered intravenously in three different regimens: thrice (n = 19), twice (n = 18), and once daily (n = 18). No correlation was found between serum gentamicin concentrations and saliva levels when the drug was administered twice or thrice daily, however, there was good correlation when the drug was administered once daily (r2 = 0.96, P < 0.0001). In children with uncomplicated infections treated with once daily gentamicin, trough concentrations of the drug can be monitored in saliva.

Pharmacokinetics of once daily gentamicin dosing in pediatric patients.

Pharmacokinetics of once daily gentamicin dosing in pediatric patients.

Toxicity of single daily dose gentamicin in stem cell transplantation.

To determine the safety of single daily dose (SDD) gentamicin in recipients of stem cell transplantation (SCT), we evaluated all adult patients at MD Anderson Cancer Center who received SDD gentamicin for treatment of febrile neutropenia. Thirty-three patients received gentamicin 5 mg/kg i.v. every 24 h. Mean duration of therapy was 7 days (range 3-32 days). All patients received vancomycin and 17 received cisplatinum. All patients had normal renal function prior to therapy. Serum gentamicin levels were monitored only when renal function deteriorated. The incidence of nephrotoxicity and clinically significant ototoxicity was 3% and 12%, respectively. All four patients who developed ototoxicity had normal renal function before and during therapy. The mean duration of gentamicin therapy was significantly longer in patients who developed ototoxicity, 20 days vs 9 days (P = 0.001). Patients treated with SDD gentamicin for >10 days were more likely to develop ototoxicity (P = 0.045). Single daily dosing of gentamicin was associated with clinically significant ototoxicity in 12% of our patients. A larger randomized EORTC trial evaluating SDD vs MDD amikacin failed to detect a difference in ototoxicity. However, the median duration of therapy was only 8 days. The increased incidence of ototoxicity in our study may be due to prolonged therapy, type of aminoglycoside used, concomitant ototoxic agents, small sample size, or a combination of the above.

Pharmacokinetics of single daily dose gentamicin in children with cancer.

To study the pharmacokinetics of single daily dose (SDD) gentamicin in children with cancer. Serum concentrations of gentamicin were prospectively measured at 0.5, 8, 16, and 24 hours after a single daily dose of gentamicin 6 mg/kg, given as a 30-minute infusion in 18 febrile children with cancer and a central venous catheter. Then the peak (0.5-hour) and 12-hour serum concentrations of gentamicin were prospectively measured after a SDD of 7 mg/kg during 73 febrile episodes in 54 pediatric cancer patients with suspected infections. The aim was to achieve a peak serum concentration of 15 to 20 microg/mL 10 times the minimum inhibitory concentration (MIC) for sensitive Pseudomonas strains, resulting in good bactericidal activity and a long post-antibiotic effect (PAE) after a SDD of gentamicin. The mean serum peak gentamicin concentration 30 minutes after the end of the infusion of 6 mg/kg was 13.3 +/- 4.0 microg/mL. The mean serum concentration 16 hours after the infusion was 0.3 +/- 0.2 microg/mL. The mean peak and 12-hour serum concentration after SDD of 7 mg/kg was 17.2 +/- 3.9 microg/mL and 0.9 +/- 0.7 microg/mL, respectively. The mean peak serum concentration after SDD of 7 mg/kg in children younger than 5 years of age (16.1 +/- 3.5 microg/mL ) was significantly lower than that of children over 5 years of age (18.2 +/- 3.9 microg/mL; P = 0.02). The desired peak serum concentration was achieved in 67% of children younger and 84% of those older than 5 years of age. Adequate peak serum concentrations of gentamicin in children may be obtained with a SDD of 7 mg/kg. Children younger than 5 years of age achieve lower peak serum gentamicin concentration after SDD of 7 mg/kg than those older than 5 years.

Population pharmacokinetics of gentamicin in patients with cancer.

The purpose of this study was to describe the population pharmacokinetics of gentamicin in patients with cancer, to identify possible relationships between clinical covariates and population pharmacokinetic parameter estimates and to examine the relevance of existing dosage nomograms in light of the population model developed in these patients. Data were collected prospectively from 210 patients with cancer and were analysed with package NONMEM. Data were split into two sets: a population data set and an evaluation set. Creatinine clearance was estimated using measured creatinine concentrations and using 'low' creatinines set to a minimum of 60 micromol l(-1), 70 micromol l(-1) or 88.4 micromol l(-1) A two compartment model was fitted to the concentration-time curve. Two best models were obtained, one that related clearance to estimated creatinine clearance (minimum creatinine value 60 micromol l(-1)) and the other that related clearance to age, creatinine concentration and body surface area. Volume of the central compartment was influenced by body surface area and albumin concentration. For both models 90% of measured concentrations lay within the 95% confidence interval of the simulated concentrations and the mean prediction errors were -7.2% and -6.6%, respectively. A final analysis performed in all patients identified the following relationship CL (1 h(-1))=0.88 x (1 + 0.043 x creatinine clearance) and central volume of distribution V1 (1)=8.59 x body surface area x (albumin/34)(-0.39). The mean population estimate of intercompartmental clearance (Q) was 1.301 h(-1) and peripheral volume of distribution (V2) was 9.801. Coefficient of variation was 18.5% on clearance and 28.2% on Q. Residual error expressed as a standard deviation was 0.36 mg l(-1) at 1.0 mg l(-1) and 1.32 mg l(-1) at 8.0 mg l(-1). The mean population estimate of clearance was 4.21 h(-1) and volume of distribution (Vss) was 24.61 (0.381 kg(-1)). The mean population estimates of half-lives were 1.8 h and 8.0 h. In the context of published nomograms this analysis indicated that both the traditional approach and the new, 'once daily' approach should achieve satisfactory concentrations in cancer patients although serum concentration monitoring is required to confirm optimal dosing in individual patients.

Once daily ceftriaxone & gentamicin (CRO/GEN) in paediatric haematology & oncology patients: R.H. George and J. Gray, Department of Microbiology, Birmingham Children's Hospital, Birmingham, B16 8ET, UK

Once daily ceftriaxone & gentamicin (CRO/GEN) in paediatric haematology & oncology patients: R.H. George and J. Gray, Department of Microbiology, Birmingham Children's Hospital, Birmingham, B16 8ET, UK

Gentamicin Usage and Monitoring in a Sydney Teaching Hospital

Objective: To determine gentamicin usage and monitoring patterns at St George Hospital.Method: A random audit was performed on the medical records of 200 patients who received gentamicin whilst in hospital between July 1994 and July 1995.Results: The amount of gentamicin patients received per course of therapy ranged from 60 to 6080 mg (median 670 mg). A course of gentamicin therapy ranged from 1 to 27 days (median 4 days) and the total daily gentamicin dose ranged from 60 to 360 mg (median 160 mg). Once‐daily administration of gentamicin increased from 4.9% of gentamicin courses to 25.8% following the introduction of hospital guidelines outlining the benefits of once‐daily gentamicin usage. Serum gentamicin concentrations were monitored in 134 (67%) patients with assays being performed within the first two days of therapy in 65 (48.5%) of these patients. Elevated serum trough concentrations (≥2.0 mg/L) occurred in 40 patients; of these, 47.5% had levels between 2.0 and 4.0 mg/L (median 3.1 mg/L, range 2 to 11 mg/L). No clinically recognisable cases of gentamicin toxicity occurred. Significant independent predictors of elevated gentamicin concentrations were baseline serum creatinine levels(β = 0.353, p = 0.0001), duration of gentamicin therapy (β = 0.572, p = 0.008) and the total daily dose of gentamicin (β = 0.186, p = 0.02).Conclusion: Once‐daily gentamicin use at this hospital is still below that recommended in the antibiotic policy/guidelines set by the hospital. The routine monitoring of gentamicin concentrations to reduce the risk of toxicity is of questionable value when gentamicin therapy is given once daily and the duration of therapy is restricted to less than seven days. Considerable savings could be made (approximately $63 000 per annum at St George Hospital) if suitable patients received once‐daily gentamicin dosing, and monitoring of gentamicin was deferred until the third day of therapy in patients with normal renal function.Aust J Hosp Pharm. 1997; 27: 133–7.

A randomized, prospective study comparing once daily gentamicin with thrice daily gentamicin in the treatment of puerperal endometritis

A randomized, prospective study comparing once daily gentamicin with thrice daily gentamicin in the treatment of puerperal endometritis

The pharmacokinetics of once daily gentamicin in neutropenic adults with haematological malignancy.

Seven febrile neutropenic adults with normal renal function were treated with intravenous gentamicin 4.5 mg/kg once a day in combination with azlocillin. Gentamicin serum concentrations 1, 2, 4, 8, and 24 h after a 30 min infusion were 10.9 +/- 0.6, 7.1 +/- 0.4, 4.2 +/- 0.2, 1.8 +/- 0.1 and 0.16 +/- 0.003 mg/L respectively. The pharmacokinetics were best described by a triphasic plot including a distribution phase (about 1/2 h) and two elimination phases, an early and late.

Protective Effect of KCl Loading in Gentamicin Nephrotoxicity

Aminoglycoside nephrotoxicity in experimental animals can be reduced by calcium loading, inducing diabetes, and giving thyroid hormone, while a potassium deficient diet enhances aminoglycoside nephrotoxicity. This study investigated whether potassium loading protects against gentamicin nephrotoxicity in the rat. In part I, group GK ate a diet containing 3.5% potassium and drank 0.2 mol/L KCl. Pair-fed rats eating a standard diet, group G, ate a 1% potassium diet and drank water. After 10 days, each group received gentamicin subcutaneously, 60 mg/kg twice daily for 8 days. The control groups, K and C, received the high or normal potassium diet, respectively. To control for a protective effect from a high solute load, the effect of equimolar NaCl loading was studied in group GNa and Na. At the end of the 8 days of gentamicin, inulin clearance was significantly higher in GK compared with G(0.6 +/- 0.1 v 0.3 +/- 0.1 mL/min per 100 g body weight [BW], P less than 0.05), but group GNa (0.4 +/- 0.1 mL/min per 100 g BW) was not different from group G. Morphological studies demonstrated that potassium-loaded rats (group GK) had significantly less proximal tubular necrosis compared with rats on a standard potassium diet, group G. Sodium loading did not protect against cellular necrosis. Part II studied renal function, cortical Na,K-adenosine triphosphatase (ATPase) and gentamicin accumulation after 2 days of gentamicin to determine the early functional and biochemical effects of potassium loading before overt renal functional impairment.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Dietary protein as a risk factor in gentamicin nephrotoxicity.

The effects of dietary protein on renal function and structure, both prior to and after initiation of daily gentamicin treatment, were investigated. Male Sprague-Dawley rats were pair-fed on low-protein (LP, 5%), normal-protein (NP, 20%), or high-protein (HP, 60%) diets for 10 days prior to gentamicin treatment. Gentamicin was administered as daily subcutaneous injections (150 mg/kg) for 6 days. Immediately after beginning daily gentamicin injections some of the rats on NP diets were switched to LP or HP diets, and some of the rats on HP diets were switched to LP diets. Renal function was monitored by evaluating serum creatinine levels and 24-h urine volumes; renal histology was evaluated by light and electron microscopy; and gentamicin uptake was determined using radioimmunoassay. Our findings indicate that conditioning to higher dietary protein prior to gentamicin administration results in less uptake of gentamicin by the kidneys. If rats on HP diets are placed on LP coincident with gentamicin administration, there is a significant improvement in survival. Switching rats from NP to LP protein coincident with gentamicin administration does not improve renal function, histology, or survival. However, switching rats from NP to HP coincident with gentamicin administration significantly increases mortality. Maintaining rats on LP both prior to and after gentamicin administration results in a significant improvement in survival but does not improve renal function. These results indicate that dietary protein both prior to and following the administration of gentamicin can significantly affect the nephrotoxicity of gentamicin.

Benefit from high intrarenal levels of gentamicin in the treatment of E. coli pyelonephritis

The importance of high intrarenal levels of gentamicin on the outcome of experimental pyelonephritis was studied in rats receiving either a short course (three days) of gentamicin (G) alone or combined with a longer course (14 days) of ampicillin (A), cephalothin (C), or trimethoprim (T), or two weeks of therapy with ampicillin, cephalothin, trimethoprim and gentamicin given alone. While ampicillin, cephalothin and trimethoprim were undetectable in the medulla within six hours of cessation of therapy, gentamicin was still detectable in levels six folds above the MIC up to six months after treatment had ceased. Six months after the end of treatment, the percentage of sterile left kidneys in animals treated with ampicillin (50%), cephalothin (15%), trimethoprim (20%) was lower than the percentage of animals receiving 14 days of gentamicin (100%), or the combinations AG:89%, CG:67% and TG:60%, P less than 0.01. Following three days of gentamicin, 50% of the left kidneys were sterilized. When compared to ampicillin, cephalothin or trimethoprim alone, combined therapies significantly reduced the number of CFU in the kidneys P less than 0.01. These combinations were almost as effective as two weeks of therapy with gentamicin. Short-term therapy (three days) with an aminoglycoside which concentrates in the renal parenchyma, combined with an antibiotic which will accumulate in other parts of the nephron, may result in "pharmacological synergy". This new approach to therapy of pyelonephritis may be promising.

Comparative clinical evaluation of ticarcillin plus clavulanic acid versus clindamycin plus gentamicin in treatment of post-cesarean endomyometritis

A new single-antibiotic combination of ticarcillin and clavulanic acid was compared with the standard two-drug regimen of clindamycin and gentamicin in the treatment of post-cesarean endomyometritis. The regimens were as follows: 3 g of ticarcillin plus 100 mg of clavulanic acid intravenously every four hours; or 600 mg of clindamycin intravenously every six hours plus 3 to 5 mg/kg per day of gentamicin intramuscularly. The prospective randomized schedule was calculated such that half the patients were assigned to each treatment group. The diagnosis of endomyometritis was based upon an elevated oral temperature of 100.4°F or higher on any two occasions, excluding the first 24 hours after delivery, uterine tenderness, and the absence of other foci of infection. Lochial discharge was foul in most cases. Forty-seven patients were treated. Treatment was successful in all patients who received clindamycin and gentamicin; ticarcillin plus clavulanic acid failed in two of 23 (9 percent) patients. Patients in whom treatment failed did not appear to be different from those in whom treatment was successful on demographic variables or in terms of risk factors for endomyometritis. The difference between the treatment failure rates was not statistically significant. This study suggests that the single-drug combination of ticarcillin plus clavulanic acid is effective in the treatment of post-cesarean endomyometritis when compared with the standard regimen of clindamycin and gentamicin.

Treatment of streptococcal infective endocarditis

Patients with infective endocarditis caused by penicillin-sensitive streptococci (minimal inhibitory concentration for penicillin of 0.1 μg/ml or less) may be treated successfully with one of the following regimens: aqueous penicillin G administered intravenously for four weeks, intravenous aqueous penicillin G for four weeks combined with streptomycin for the first two weeks of therapy, or parenterally administered penicillin plus streptomycin for two weeks. A cure rate of at least 98 percent may be anticipated with each of these regimens. During a 12-year period among 142 patients treated for two weeks with penicillin and streptomycin, one (0.7 percent) had relapse and four (3 percent) had vestibular toxicity. The major advantage of the two-week regimen is that it is more cost-effective than the four-week regimens. The major disadvantage of the use of streptomycin is the relatively low risk of vestibular toxicity. Patients with enterococcal endocarditis were treated initially for four weeks with aqueous penicillin G together with either streptomycin (streptomycin-susceptible enterococci, 36 patients) or gentamicin (streptomycin-resistant enterococci, 20 patients). Compared with patients who had symptoms for less than three months, patients with symptoms for longer than three months had a higher relapse rate (0 percent versus 44 percent; p <0.001) and mortality (2.5 percent versus 25 percent; p <0.001). Patients with mitral valve endocarditis had a significantly higher relapse rate (25 percent) than patients with aortic valve infection (0 percent; p <0.01). Gentamicin-associated nephrotoxicity was more frequent (p <0.001) among patients treated with more than 3 mg/kg per day of gentamicin than among those treated with 3 mg/kg per day or less (100 percent versus 20 percent). Relapse and mortality rates did not differ significantly between patients treated with low-dose or high-dose gentamicin regimens. Patients who have had symptoms of enterococcal endocarditis for longer than three months or perhaps patients with mitral valve Infection should receive at least six weeks of penicillin therapy together with an aminoglycoside; patients without either high-risk factor may be treated successfully for four weeks.

Renal cortex ion composition and Na-K-ATPase activity in gentamicin nephrotoxicity.

Abnormalities of potassium and magnesium homeostasis have been reported following the use of gentamicin, and potassium depletion enhances gentamicin nephrotoxicity. The present study investigates these relationships in the dog by assessing changes in renal cortex ion composition and renal cortex Na-K-ATPase activity occurring during gentamicin nephrotoxicity. Gentamicin (15 mg/kg i.m. twice daily) was administered for 4 to 7 days to potassium-depleted or potassium-supplemented animals. The results show that gentamicin nephrotoxicity was characterized by a significant reduction in renal cortex content of potassium (17%), magnesium (19%), and phosphorus (12%) in all groups of animals given gentamicin. However, only potassium-depleted animals exposed to 7 days of gentamicin experienced a significant rise in plasma creatinine (from 1.3 +/- 0.1 to 4.3 +/- 1.0 mg/dl). Accompanying this increase in plasma creatinine was a significant rise in the renal cortex content of sodium (from 25 +/- 0.5 to 27.9 +/- 1.7 meq/100 g fat-free dry solid wt) and calcium (from 1.2 +/- 0.1 to 2.6 +/- 0.3 mM/100 g fat-free dry solid wt). Na-K-ATPase activity in the renal cortex fell only in potassium-depleted animals after 4 days (from 11.5 +/- 0.9 to 7.8 +/- 0.1 microM Pi.mg protein-1.h-1) and 7 days (5.9 +/- 0.8 microM Pi.mg protein-1.h-1) of gentamicin treatment. Thus, gentamicin nephrotoxicity is characterized by sequential changes in renal cortex ionic composition, sodium pump activity, and renal function.

Dosing implications of altered gentamicin disposition in patients with cystic fibrosis

A pharmacokinetic approach was used for gentamicin dosing in 19 children and young adults with cystic fibrosis. A one-compartment open-model analysis of steady-state gentamicin pharmacokinetics revealed a significantly larger apparent volume of distribution and total plasma clearance for patients with CF as compared to a similar population of children without the disease. The increase in the apparent volume of distribution for patients with CF produced a larger daily gentamicin dose requirement to maintain similar steady-state levels as compared to children without the disease. Significant differences in the elimination rate constant and half-life for gentamicin were not found between these populations. Linear correlations between creatinine clearance and kel for gentamicin, and total body body weight and the apparent volume of distribution were demonstrated for children with varying degrees of stable renal function but not patients with CF. Altered gentamicin disposition peculiar to CF precludes application of currently used dosing nomograms or guidelines derived from normal populations, and emphasizes the need for individualized gentamicin therapy guided by a pharmacokinetic approach in these patients.

Concurrent pharmacist monitoring of gentamicin therapy

The results of concurrent monitoring of gentamicin therapy by a clinical pharmacist are reported. All patients in a 332-bed teaching hospital who were started on gentamicin therapy during a 72-day period were monitored. Predetermined criteria concerning maximum daily gentamicin dose based on serum creatinine and acceptable precautions for avoiding toxicity (i.e., serum creatinine, gentamicin serum level determinations) were used. Deviations from these criteria resulted in contact with the patient's physician, and specific recommendations were made by the pharmacist at that time. During this period, 120 courses of gentamicin therapy were monitored in 101 patients. Major criteria deviations were found in 15 (12.5%) courses, resulting in the contact of 10 physicians. Physicians responded to the pharmacists' recommendations in 9 (60%) of the 15 courses. It is concluded that a clinical pharmacist can interact effectively with physicians in monitoring drug therapy in the hospital.

Topical gentamicin cream as prophylaxis against burn-wound sepsis

Summary One hundred and thirty patients with fresh burns involving over 10 per cent of the body surface have been treated with daily prophylactic topical gentamicin cream. Pseudomonas aeruginosa colonized 30 per cent of these patients' wounds while on topical treatment and a further 20 per cent after daily applications were stopped. Over half of these patients colonized with a gentamicin-resistant Ps. aeruginosa at some time during their treatment course. No death was due to Ps. aeruginosa septicaemia. Two patients died of Candida albicans fungaemia and one died of Ps. maltophilia septicaemia following prophylactic gentamicin therapy. Compared with the preceding 5-year period in which no topical prophylactic antibacterial agent was used, a modest improvement in patient survival in burns involving less than 60 per cent of the body surface was observed, but mortality in larger burns did not decrease significantly. This slight improvement in survival must be weighed against the appearance of gentamicin-resistant Ps. aeruginosa in 25 per cent of patients who received a course of prophylactic therapy. As prophylaxis against burn-wound sepsis due to Ps. aeruginosa, gentamicin was not found to be particularly effective.