Therapeutic monitoring as an aid in rationalizing aminoglycoside dosage techniques in the neonate

General pharmacokinetic parameters applicable to adults are not suitable in neonatal practice owing to wide interpatient variations in respect of fluid balance, renal clearance and metabolic rates. We attempted to determine whether acceptable blood levels of gentamicin or tobramycin are obtained with dosage regimens and dosage techniques which are generally recommended. Forty neonates receiving aminoglycosides were studied. After administration of the drug as a slow, constant intravenous infusion into the 'Y' connection of the infusion set, peak levels were found to be subtherapeutic. Trough levels were also very low. After administration of the same dose of gentamicin or tobramycin as a bolus into the butterfly connection of the infusion set, however, high therapeutic levels were obtained. We therefore recommend that gentamicin and tobramycin be administered as an intravenous bolus injection and that blood levels be monitored constantly in order to individualize therapy.     

The role of the phenomenon of the redistribution of aminoglycosides in their monitoring and dosage calculation in patients in the terminal stage of kidney failure undergoing systematic hemodialysis treatment

The kinetics of aminoglycosides (amikacin, netilmycin, gentamicin, tobramycin) were investigated in patients with end-stage renal disease who were on systemic hemodialysis. Their decrease in the blood revealed in pre-dialysis and dialysis periods was exponential. After dialysis termination there was a gradual aminoglycoside increase as compared to the end-dialysis period, which was of linear character and depended on the degree of these agents' dialysis clearance. The cause of the phenomenon is likely to be higher aminoglycoside blood elimination rate than their entering the blood from tissues. A method is proposed to calculate an additional dose of aminoglycosides, taking into account their higher concentrations in the postdialysis period, under permanent monitoring of their blood levels.     

Renal cortical uptake kinetics of gentamicin in rats with impaired renal function

The renal cortical uptake kinetics of the aminoglycoside antibiotic gentamicin was determined in the remnant kidney model. Renal failure was induced by partial ablation of the right kidney followed by left nephrectomy in female Wistar rats. The animals received a six-hour gentamicin infusion at a constant rate yielding steady-state serum concentrations ranging from 0.5 to 150 micrograms/mL. The renal cortical gentamicin concentrations were determined and related to the serum concentrations achieved. This relationship was nonlinear and followed Michaelis-Menten kinetics. Gentamicin cortical uptake rate, however, did not show clear saturation in the range of gentamicin serum levels studied as was observed in rats with normal renal function. The Michaelis-Menten parameters determined by nonlinear regression were Km = 15.0, 73.9, and 135.7 micrograms/mL; and Vmax = 149.9, 213.7, and 239.2 micrograms/g cortex/h, respectively, for controls, rats with serum creatinine levels between 0.9 and 1.2 mg/dL, and those with levels between 1.3 and 1.8 mg/dL. It is concluded that at serum levels below 100 micrograms/mL, the gentamicin renal cortical uptake is diminished in rats with renal failure. This decrease in renal cortical uptake is more pronounced in the group of rats with more severe renal failure.     

Early effects of gentamicin, tobramycin, and amikacin on the human kidney

The early alterations at the level of the proximal tubule of the human kidney caused by the three most currently used aminoglycosides, gentamicin, tobramycin, and amikacin, were studied. A prospective, randomized, and comparative approach using multidisciplinary methods was used. The patients received either no treatment or one of the three aminoglycosides at a therapeutic dose for 4 days preceding nephrectomy for neoplasia partly involving one kidney. The three aminoglycosides studied induce an early lysosomal phospholipidosis. Gentamicin and tobramycin cannot be distinguished on the basis of drug tissue accumulation, lysosomal overloading, or effect on lysosomal phospholipase A1. Amikacin induces significantly lower lysosomal overloading and no loss of phospholipase A1 activity.     

Quantitative histophotometry analysing significant inductive and alterative effects of aminoglycoside application (gentamicin, tobramycin, amikacin) upon tubular kidney proteins

In order to evaluate quantitative changes in kidney proteins, computer-assisted histophotometry of tissues was performed. Kidney marker enzyme concentrations were considered to be involved in inductive and alterative developments in the proximal tubule. These effects were caused by the administration of aminoglycosides. Indicator enzymes of the proximal tubule such as membrane-bound alkaline phosphatase (AP) and alanine-aminopeptidase (AAP) as well as lysosomal beta-glucuronidase (beta-Gl) were stained in kidney tissues. Graphic monitoring and digital display of kidney cortex sections were registered by electronic image analysis using the 'Micro-Videomat' 2 system. As an experimental design, 160 kidneys of Wistar rats were studied. Their kidneys were analyzed after one, two and three intravenous applications of gentamicin, 25 mg/kg/day, or tobramycin, 25 mg/kg/day, or amikacin, 50 mg/kg/day, on consecutive days. In a fourth test group, the kidneys were examined after the third application and a 5-day recovery period. Concentrations of tubular marker enzymes were significantly increased (2p less than 0.01, Wilcoxon test) after two applications of gentamicin: AP 37.6%, AAP 6.3% and beta-Gl 11.8%. Contrary to these findings, after two injections of tobramycin or amikacin only slight alterations were documented: tobramycin, AP 14.5%, AAP -0.1% and beta-Gl 0.4%; amikacin, AP 6.0% and AAP 4.2%. The studies indicate that tobramycin induces less severe nephrotoxic and inductive reaction than gentamicin and partly than amikacin in doses administered during our experiments. In all cases, enzyme activities studied were nearly normalized after three applications of aminoglycosides and a recovery period of 5 days. Quantitative computer-assisted evaluation of the proteins located in the tubule appears to be a tool for monitoring the degree of alterations caused by enzyme induction, enzyme release and excretion of kidney proteins.     

Atracurium and vecuronium interaction with gentamicin and tobramycin

Drug interactions between the aminoglycosides (tobramycin and gentamicin) and atracurium and vecuronium were studied prospectively in 44 patients. Twenty-two patients had therapeutic serum levels of tobramycin or gentamicin and 22 served as controls. Onset time, clinical duration, and time to spontaneous recovery of T4/T1 ratio of 0.70 after atracurium or vecuronium injection were measured. No statistically significant differences were found in onset time, but clinical duration and time to recovery were significantly longer in patients receiving tobramycin or gentamicin and paralyzed with vecuronium than for controls (P less than 0.01 for clinical duration and P less than 0.0005 for recovery). The neuromuscular block produced by atracurium was not significantly influenced by the presence of therapeutic serum levels of tobramycin or gentamicin. We conclude that for patients treated with these antibiotics, atracurium may present some advantages over vecuronium when a prolonged block is not desired.     

Pharmacokinetic monitoring of nephrotoxic antibiotics in surgical intensive care patients

An assessment of the dosage regimens prescribed for potentially nephrotoxic antibiotics (amikacin, gentamicin, tobramycin, and vancomycin) was undertaken on surgical intensive care unit patients. In 166 patients, 224 series of blood antibiotic level determinations were obtained. Using individualized pharmacokinetic determinations, the regimens were revised as necessary to provide optimal blood levels. Because of variable volumes of distribution and elimination rates, dosing according to standard clinical guidelines produced significantly lower peaks than did pharmacokinetically determined regimens for gentamicin (p less than 0.005), tobramycin (p less than 0.0001), and vancomycin (p less than 0.05). Importantly, fewer patients achieved therapeutic levels with the original regimens than with the revised regimens for gentamicin (9% vs. 91%, p less than 0.0005), tobramycin (27% vs. 92%, p less than 0.0001), and vancomycin (30% vs. 69%, p less than 0.0001). Individualized pharmacokinetic analysis of potentially nephrotoxic antibiotics in critically ill patients is essential if therapeutic, non-toxic levels are to be maintained.     

Recovery of cortical phospholipidosis and necrosis after acute gentamicin loading in rats

The recovery from gentamicin-induced phospholipidosis in the rat kidney cortex was characterized both morphologically and biochemically after a single 12-hr drug infusion. Total dosages administered were 10, 60, or 140 mg/kg, achieving constant serum concentrations of 3, 11, and 27 micrograms/ml, respectively. At the end of the 12-hr infusion, the cortical drug concentrations corresponding to the three dosages were 124, 450, and 993 micrograms/g of wet tissue. At the low dose (10 mg/kg), myeloid bodies were seen inside lysosomes of proximal tubular cells, along with a modest decrease of lysosomal sphingomyelinase activity. The cortical drug level declined steadily following first-order kinetics along with a disappearance of myeloid bodies and return of sphingomyelinase activity to control levels. At the high dose (140 mg/kg), we observed a sustained loss of sphingomyelinase activity (37% of controls), a subsequent increase of phospholipid concentration in the kidney cortex (up to 117% of controls 2 days after) and a prominent accumulation of myeloid bodies inside the lysosomes of proximal tubular cells (up to 4% of cell volume). Tubular regeneration and interstitial infiltration became detectable by histology and the increase of DNA synthesis as from day 1, along with an apparent reduction of the phospholipidosis at days 3 and 4. Drug cortical concentrations showed a sharp decline 2 days after infusion. An intermediate behavior was observed at 60 mg/kg. It is concluded that the proximal tubular cells behave in a fundamentally different way after gentamicin loading with low and high doses. At the low dose there is a regression of the drug-induced changes in the absence of any sign of necrosis-regeneration. Above a threshold in cortical drug concentration there is further development of the alterations leading to cell death-regeneration.     

Ampicillin/sulbactam versus cefazolin plus aminoglycosides for antimicrobial prophylaxis in management of Gustilo type IIIA open fractures: A retrospective cohort study

BackgroundThe antibiotic regimens for prophylaxis in the management of open fractures remain controversial. Although the use of aminoglycosides is widely accepted for treatment of Gustilo type III open fractures, aminoglycosides are often avoided in patients with risk factors. This study aimed to compare efficacy and safety of two regimens, cephazolin plus aminoglycoside (amikacin or gentamicin) and ampicillin/sulbactam (ABPC/SBT), in patients with Gustilo type IIIA open fractures.MethodsA total of 95 Gustilo type IIIA fractures in 90 patients were retrospectively reviewed in this study. The cohort was categorized into two groups that were treated in accordance with the institutional prescribed regimen in different periods: (1) cefazolin plus aminoglycoside (January 1, 2014–September 30, 2017) and (2) ABPC/SBT monotherapy (October 1, 2017–September 30, 2020). Cefazolin was used at 1–2 g every 8 h, aminoglycoside (amikacin or gentamicin) was used daily depending on body weight, and ABPC/SBT was used at 3 g every 8 h The antibiotic administration was continued within 3 days or until successful soft tissue coverage was achieved. The infection rate and the incidence of acute kidney injury (AKI) in both groups were assessed.ResultsABPC/SBT was used in 34 patients (36 fractures), and 56 patients (59 fractures) received cefazolin plus aminoglycoside for antibiotic prophylaxis. Infection developed in 2 of 36 fractures in ABPC/SBT group and 4 of 59 fractures in the cefazolin plus aminoglycoside group (p > 0.99). The average serum creatinine levels on admission, baseline, and peak during the hospital stay were not significantly different between the two groups. One case of AKI was identified in each group, indicating that incidence rate of AKI was not significantly different between the two groups.ConclusionWe demonstrated the non-inferiority of ABPC/SBT therapy over cefazolin plus aminoglycoside regimen for type IIIA open fractures. The ABPC/SBT regimen may be an alternative option for managing Gustilo type IIIA open fractures. Further prospective studies with larger samples are needed to verify these results.     

Anabolic and catabolic bone effects of human parathyroid hormone (1-34) are predicted by duration of hormone exposure

Parathyroid hormone (PTH)(1-34), given once daily, increases bone mass in a variety of animal models and humans with osteoporosis. However, continuous PTH infusion has been shown to cause bone loss. To determine the pharmacokinetic profile of PTH(1-34) associated with anabolic and catabolic bone responses, PTH(1-34) pharmacokinetic and serum biochemical profiles were evaluated in young male rats using dosing regimens that resulted in either gain or loss of bone mass. Once-daily PTH(1-34) or 6 PTH(1-34) injections within 1 h, for a total daily dose of 80 microg/kg, induced equivalent increases in proximal tibia bone mass. In contrast, 6 PTH(1-34) injections/day over 6 h for a total dose of 80 microg/kg/day or 3 injections/day over 8 h for a total of 240 microg/kg/day decreased tibia bone mass. The PTH(1-34) pharmacokinetics of the different treatment regimens were distinctive. The magnitude of the maximum serum concentrations (Cmax) of PTH(1-34) and area under the curve (AUC) did not predict the catabolic bone outcome. Compared to the anabolic pharmacokinetic profile of a transient increase in PTH(1-34) with rapid decreases in serum calcium and phosphate, the catabolic regimen was associated with PTH(1-34) concentrations remaining above baseline values during the entire 6-h dosing period with a trend toward an increase in serum calcium and a prolonged decrease in phosphate. The pharmacokinetic profiles suggest that the anabolic or catabolic response of bone to PTH(1-34) is determined primarily by the length of time each day that serum concentrations of PTH(1-34) remain above baseline levels of endogenous PTH and only secondarily by the Cmax or AUC of PTH(1-34) achieved.     

Repetition of continuous PTH treatments followed by periodic withdrawals exerts anabolic effects on rat bone

Various animal experiments and human studies have shown that intermittent injections of parathyroid hormone (PTH) exert anabolic effects on bone, whereas continuous PTH treatment decreases the bone mass and causes hypercalcemia in animals. However, limited data are available with regard to the effects of a repetitive regimen of continuous treatments of PTH followed by periodic withdrawals on the bone metabolism. We investigated the effects of this regimen by comparing the findings of intermittent and continuous PTH treatments in rats. Infusions of PTH for 24 h followed by 6-day withdrawal periods from PTH transiently increased the serum calcium levels on day 1, but these levels were within the normocalcemic range. The repetition of 4 cycles of continuous PTH infusions followed by PTH withdrawals as well as intermittent PTH treatment increased the trabecular bone thickness, osteoblast surface, and bone formation rate. Continuous PTH infusions followed by PTH withdrawals also increased the cortical thickness of the femoral diaphysis and the osteoid volume in trabecular bones, whereas the continuous treatment failed to induce these changes. These findings suggest that continuous PTH treatment followed by PTH withdrawal is a potential regimen that can induce the anabolic effects of PTH in bone metabolism without inducing hypercalcemia.     

Antimicrobial release kinetics from polymethylmethacrylate in a novel continuous flow chamber

Polymethylmethacrylate is used for local delivery of antimicrobials in the treatment of musculoskeletal infections. A novel continuous flow chamber system was designed to measure in vitro antimicrobial release. Three-millimeter beads containing amikacin, gentamicin, tobramycin, or vancomycin [concentration of 7.5% (weight per weight)] were placed individually in a continuous flow chamber with a total volume of 1 mL Kreb's Ringer buffer flowing at 1 mL/hour. Effluent was sampled hourly for 24 hours and then every 2 hours up to 48 hours; antimicrobial concentrations were measured in triplicate by bioassay. The mean peak concentrations were 40.9, 30.1, 30.0, and 19.1 microg/mL; the mean areas under the concentration time curves (Time 0 to infinity) were 263, 327, 110, and 180 hours x microg/mL of antibiotic; and the mean percentages of initial amount of antimicrobial released were 11.7%, 14.5%, 6.6%, and 10.9% for tobramycin, gentamicin, amikacin, and vancomycin, respectively. The results for each polymethylmethacrylate-antimicrobial agent combination were reproducible. In contrast to other in vitro elution systems, this novel system operates under the premise that there is dynamic flow surrounding polymethylmethacrylate in vivo and permits rapid in vitro comparison of the relative release of antimicrobial agents from polymethylmethacrylate.     

Short-course aminoglycoside therapy in patients with spinal cord injury. Standard dose versus low dose

Twenty-nine patients with spinal cord injury and asymptomatic urinary tract infection were treated with standard or reduced doses of tobramycin and amikacin. The patients received five days of intramuscular antibiotics. Most of the patients in the tobramycin groups had Pseudomonas aeruginosa infection and most of those in the amikacin group had either Proteus rettgeri or Providencia stuartii infections. Only 1 patient had a positive urine antibody coating test. High antibiotic concentrations were demonstrated in the urine of all patients during therapy. Urine cultures were obtained two and seven days after completion of therapy. Forty-eight per cent of the patients were cured, while 31 per cent showed persistence or relapse, and 21 per cent had reinfection with other bacteria. No significant differences in results were observed between the standard-dose and low-dose regimens and between the amikacin and tobramycin groups. The low success rate of the regimens used may indicate the need to evaluate alternative therapeutic regimens to treat urinary tract infections in this special group of patients.     

Blood levels of mepivacaine during continuous epidural anesthesia

Venous blood concentrations of mepivacaine were measured in 30 patients during 5 hr of surgical anesthesia following either multiple epidural injections of mepivacaine with or without epinephrine or continuous epidural infusion of mepivacaine with epinephrine. Patients were divided into three groups: group 1 initially received 10 or 15 ml followed by 10 ml of 2% plain mepivacaine at 1-hr intervals; group 2 received 10 or 15 ml followed by 10 ml of epinephrine-containing 2% mepivacaine at 1-hr intervals; group 3 received 10 or 15 ml followed by a constant infusion of 10 ml/hr of epinephrine-containing 2% mepivacaine. There were no significant differences between groups 1 and 2, but the mean blood concentration was slightly lower for the first 3 hr in group 2 than group 1. The mean blood concentration of mepivacaine in group 3 remained significantly lower than the concentrations in groups 1 and 2 from 3.5 to 5 hr. These results demonstrate that the blood concentrations of mepivacaine are not reduced by the addition of epinephrine to mepivacaine solutions when intermittent epidural injections are repeated more than four times at 1-hr intervals, but that blood mepivacaine levels are reduced below levels seen with intermittent injections by the continuous epidural infusion of epinephrine-containing mepivacaine.     

A prospective study of long-term use of amikacin in a paediatrics department. Indications, administration, side-effects, bacterial isolates and resistance

Amikacin (Amikin; B-M) was used as the only aminoglycoside for 18 months in a paediatric department within a general hospital because of high levels of resistance of Klebsiella pneumoniae, Pseudomonas aeruginosa and Enterobacter cloacae isolates to tobramycin, gentamicin and netilmicin. Between 1 February 1987 and 31 July 1988, 816 children were treated with a slow intravenous injection at a standardised dose adjusted for weight and age. Respiratory disease was present in 35.8% of 537 neonates, 56.4% of 190 infants and 70.9% of 89 older children. Escherichia coli (65 isolates), Klebsiella species (59 isolates), Enterobacter species (26 isolates) and P. aeruginosa (22 isolates) constituted the most common Gram-negative pathogens. The positive blood culture yield was 7.8%. Satisfactory median peak and trough serum amikacin levels were achieved. No significant renal side-effects were noted. Severe bilateral hearing loss in 1 low-birthweight infant resulted from inadvertent overdosage. At the end of this 18-month surveillance period 97.7% of E. coli, 98.6% of K. pneumoniae, 96.3% of E. cloacae, and 98.0% of P. aeruginosa isolates remained sensitive to amikacin, while resistance of K. pneumoniae to tobramycin, netilmicin and gentamicin decreased significantly (P less than 0.003, P less than 0.001 and P less than 0.007 respectively; chi-square test).     

Rapid individualization of gentamicin dosage regimens in 66 burn patients

Gentamicin dosage regimens were systematically calculated for each patient from serum concentration time data. Wide interpatient variations were demonstrated in gentamicin elimination rate and dosage requirements for 66 burn patients with normal renal function. The drug's half-life ranged from 0.7–6.4 h compared to previous reports of 2.5–4 h. The distribution volume ranged from 0.11–0.52 1/kg compared to reported values of 0.20–0.25 1/kg. Dosage regimens required to produce optimal serum levels demonstrated considerable variability ranging from 2.1–6.8 mg kg^?1 day^?1. Compared to the recommended regimen of 3 – 5 mg kg^?1 day^?1 75 per cent of these burn patients required higher dosages, and 6 per cent required lower dosages. These individualized regimens were initiated within the initial 12–18 h of treatment and optimal peak and trough serum concentrations were consistently obtained. Ototoxicity was not observed. Two patients had possible gentamicin associated nephrotoxicity. These results further emphasize the need to measure serum concentrations and make necessary dosage adjustments to ensure therapeutic levels. However, because of the wide interpatient variation, these increased dosage regimens are not routinely suggested without previously measuring serum concentrations and calculating each patient's regimen.     

Should aminoglycoside antibiotics be abandoned?

BACKGROUND: Aminoglycosides can cause nephrotoxicity and ototoxicity. Alternatives are available. METHODS: Surgical service antibiotic use, aminoglycoside toxicity, and perioperative culture/sensitivity results from July 1998 to June 1999 were reviewed. RESULTS: Of 289 positive cultures in 243 patients, 92 cultures (32%) grew 151 Gram-negative rods (GNRs). Aminoglycosides were used in 26 patients and 4 of 26 (15%) suffered nephrotoxicity. Of the 112 GNRs tested against ceftazidime, 111 (99%) were sensitive to it which was significantly better than amikacin (56 of 61, 92%, P = 0.038), gentamicin (116 of 134, 87%, P <0.001), and tobramycin (67 of 81, 83%, P <0.001). The proportion sensitive to cefuroxime (26 of 30, 87%) was equivalent to the proportions sensitive to gentamicin (87%, P = NS) and tobramycin (83%, P = NS). Of the 35 GNRs that were resistant to gentamicin and/or tobramycin, 15 (43%) were Pseudomonas aeruginosa. CONCLUSION: Aminoglycosides produce a significant rate of nephrotoxicity. There are antibiotics with equal or better sensitivity profiles than aminoglycosides against GNRs and Pseudomonas. Aminoglycoside use is rarely, if ever, indicated.     

The use of glycopeptides in intensive care and anaesthesia

With the objective of clarifying the modes of using glycopeptides in intensive care, a survey with a declared intention was performed in June 2001, in the form of a postal questionnaire; it was possible to exploit 742 answers. Analysis of the results showed that 15% of the doctors completing the questionnaire had not employed glycopeptides within the past six months. Preference was given to vancomycin, and 65% of practitioners prescribed this drug only, while 1% of them only prescribed teicoplanin. For vancomycin, a central route is used in 9 out of 10 cases, with a preference for continuous infusion (69% versus 48%). A loading dose is prescribed in 70% of continuous infusions (> or = 15 mg.kg-1 in 69% of cases), and in 19% of intermittent infusions (> or = 15 mg.kg-1 in 90% of cases). The mean vancomycin dosage is 30 mg.kg-1.d-1; in the case of intermittent administration this involves two (51%), three (17%) or four (27%) injections per day. The target concentrations are residual serum vancomycin levels of between 13.5 and 23.6 mg.L-1 with intermittent administration or plateau levels of 18.3 to 29.4 mg.L-1 with continuous infusion. Teicoplanin is administered intravenously (92%) and/or via the i.m. route (34%). The mean dosage is < 10 mg.kg-1.d-1 in seven out of ten cases. A loading dose is administered every 12 hours at the same dosage in 77% of cases (< or = 3 injections for 65% of prescribers). The residual teicoplanin concentrations sought are between 14.3 and 25 mg.L-1. Monitoring of serum levels is ensured at least once a week in 97% of cases with vancomycin and 66% of cases with teicoplanin. In conclusion, is seems that the methods of using glycopeptides vary considerably. The great heterogeneity of practices suggests a lack of compliance by prescribing practitioners with current recommendations. It also seems that a precise definition of the target plasma levels to be achieved in different indications is necessary.     

Renal tubular transport of gentamicin in the rat

The renal handling of gentamicin in the rat was examined by clearance, microinjection, and renal cortical-slice techniques. The steady-state renal clearance of 14C-gentamicin, when corrected for the 7.5% binding to plasma protein, was not significantly different from that of 3H-inulin. At the end of the renal clearance experiments, the cortical concentration of gentamicin was 93 +/- 7 microgram/g of tissue (N = 7), a concentration threefold greater than that of the medulla and 20-fold greater than that of serum. Absorption of 3H-gentamicin along the proximal convoluted tubule and loop of Henle was demonstrated by the tubular microinjection technique. No reabsorption of 3H-gentamicin was detected beyond the early distal convoluted tubule. The tubular absorption of 3H-gentamicin was load dependent. Fractional absorption of 3H-gentamicin averaged 30.1 +/- 2.7% when the dose of 3H-gentamicin injected into early proximal tubular convolutions averaged 132 +/- 17 pg. It was decreased to 13.6 +/- 2.6% when the microinjected dose of gentamicin was increased to 1996 +/- 388 pg. No evidence of transtubular absorption of 3H-gentamicin was detected during the microinjection experiments. Microperfusion of pertubular capillaries failed to demonstrate urinary precession of 3H-gentamicin over 14C-inulin, a finding which argues against a rapid transtubular secretory flux of gentamicin. Significant uptake of gentamicin was demonstrated by renal cortical slices incubated in medium containing 14C-gentamicin. The accumulation of 14C-gentamicin by renal cortical slices was not inhibited by probenecid or N1-methylnicotinamide but was inhibited by netilmicin and tobramycin. These data support the conclusion that the renal accumulation of gentamicin reflects transport of gentamicin across both the apical and basolateral membranes of proximal tubular epithelium.     

Gentamicin and penicillin in the treatment of severe respiratory infections.

A combination of penicillin and gentamicin has been used for severely ill patients in a respiratory intensive care ward. It has been shown that predictable mean blood levels of gentamicin can be obtained in these patients by relating the dose to surface area (60 mg/m2/8 h). When renal function was initially normal it did not deteriorate during the course of therapy (10 days); gentamicin assays are not essential for safe treatment. In patients with renal failure, increasing the interval between doses also resulted in satisfactory levels, but close monitoring of the serum creatinine level is considered necessary. No clinical difference could be detected when gentamicin was given by constant or intermittent infusion.