Protective effect of piperacillin against nephrotoxicity of cephaloridine and gentamicin in animals.

The protective effect of piperacillin against the nephrotoxicity of cephaloridine and gentamicin was examined in experimental animals. In rabbits, piperacillin was infused at a dose of 1 mg/kg (body weight) per min over 225 min and cephaloridine (300 mg/kg) was intravenously administered as a bolus 45 min after the start of a drip infusion. Blood urea nitrogen, serum creatinine, and N-acetyl-beta-D-glucosaminidase (NAG) in urine were measured as the renal toxicological parameters before and 24 h after cephaloridine dosing. Although the single administration of cephaloridine significantly elevated these parameters, the elevation was prevented by the concomitant administration of piperacillin. The protective effect of piperacillin was superior to those of cephalothin and fosfomycin. In rats, piperacillin (1,000 mg/kg) was intravenously administered and immediately followed by the intramuscular administration of gentamicin (100 mg/kg) every 24 h for 5 days. When piperacillin was concomitantly administered with gentamicin, the elevations of blood urea nitrogen, serum creatinine, and urinary NAG were significantly lower than when gentamicin was given alone. The concomitant administration of piperacillin resulted in a significant protective effect against the nephrotoxicity of cephaloridine in rabbits and of gentamicin in rats. Histopathological observation also supported the protective effect of piperacillin. The protective mechanism of piperacillin might be the inhibition of transport from the peritubular side to tubular cells for cephaloridine and from both the peritubular and luminal sides for gentamicin.     

Multiple-dose ciprofloxacin dose ranging and kinetics

We injected multiple doses of intravenous ciprofloxacin over 10 minutes every 12 hours for 1 week to nine healthy subjects, while three other subjects received placebo. Ciprofloxacin doses of 25, 50, and 75 mg were evaluated with a 1-week washout between each dose level. Mean (+/- SD) terminal excretion t1/2S were 3.56 +/- 0.66, 4.15 +/- 0.68, and 3.46 +/- 0.42 hours for the 25, 50, and 75 mg doses. Serum clearances were 35.4 +/- 6.8, 31.8 +/- 3.0, and 31.3 +/- 5.4 L/hr/1.73 m2 for these doses. Urine concentrations remained above the minimal inhibitory concentration of most urinary tract pathogens for the full 12-hour dosing interval at each dose. Renal clearance accounted for 65% to 70% of the serum clearance, but because biologically active renally excreted metabolites have been identified, our values exceed the true values. The doses of ciprofloxacin we intravenously injected were well tolerated and appeared adequate for treatment of urinary tract infections. For serious hospital-acquired sepsis, however, larger doses should be evaluated.     

Gentamicin penetration into cerebrospinal fluid in experimental Haemophilus influenzae meningitis.

We studied the effect of meningitis and the method of parenteral gentamicin administration (intramuscular injection, a 30-min intravenous infusion, or intravenous bolus administration) on achievable concentrations of drug in cerebrospinal fluid (CSF). In normal animals, only intravenous bolus administration of 2 to 8 mg/kg produced a gentamicin concentration of greater than 0.1 microgram/ml in CSF in some animals. All CSF samples contained less than the limit of detection (0.1 microgram/ml) after the intramuscular administration of 6 mg/kg. In animals with meningitis, gentamicin penetration into cisternal CSF was increased significantly after a bolus administration of 6 mg/kg (mean, 0.197 +/- 0.063 microgram/ml in normal animals versus 1.68 +/- 0.38 micrograms/ml in animals with meningitis; P less than 0.01). In meningitic animals that received 6 mg/kg as an intravenous bolus, lumbar CSF had the highest maximum concentration (4.25 +/- 1.08 micrograms/ml), in comparison with ventricular CSF (3.10 +/- 0.66 micrograms/ml). The gentamicin concentration in cisternal CSF decreased more slowly than it did in serum (elimination half-life, 238.70 +/- 64.56 min in cisternal CSF versus 82.73 +/- 2.91 min in serum), yielding a relative increase in the percentage of penetration. We conclude that maximum penetration by gentamicin into CSF occurs after intravenous bolus administration and that the maximum concentration occurs in lumbar CSF.     

Multiple-dose pharmacokinetics of ciprofloxacin administered intravenously to normal volunteers.

We administered multiple doses of ciprofloxacin intravenously over 30 min every 12 h for 1 week to nine healthy volunteers. Three volunteers received a placebo (vehicle) intravenously. Doses of 100, 150, and 200 mg were evaluated with a 1-week wash-out period intervening between each dose level. Terminal excretion half-lives averaged 3.67 +/- 0.65, 3.60 +/- 0.26, and 4.00 +/- 0.69 h for the 100-, 150-, and 200-mg doses, respectively. Serum clearances were 30.1 +/- 3.4, 29.8 +/- 4.0, and 26.9 +/- 4.1 liters/h per 1.73 m2 for these doses. Urine concentrations remained in excess of the MIC for 90% of the relevant urinary tract pathogens for the full 12-h dosing interval at each dose. Renal clearance accounted for 56 to 71% of the serum clearance. However, because a microbiologic assay was used and biologically active, renally excreted metabolites were identified, the renal clearance determinations are likely to be in excess of the true values. The doses of ciprofloxacin administered intravenously were well tolerated, and the drug concentrations appeared adequate for the treatment of the vast majority of cases of nosocomially acquired sepsis and urinary tract infections. For patients with serious Pseudomonas infections and perhaps staphylococcal infections, either an 8-h dosing schedule or larger doses on a 12-h schedule should be considered.     

A comparison of four buprenorphine dosing regimens in the treatment of opioid dependence.

OBJECTIVES: This study compared 24-, 48-, 72-, and 96-hour buprenorphine dosing regimens in opioid-dependent outpatients. METHODS: Fourteen subjects received buprenorphine in a double-blind, placebo-controlled crossover trial. Daily sublingual maintenance doses were 4 mg/70 kg (n = 5) and 8 mg/70 kg (n = 9). After a stabilization period of maintenance administration, subjects received, in a random order, four dosing regimens for five repetitions of each regimen: a maintenance dose every 24 hours, a doubled maintenance dose every 48 hours, a tripled maintenance dose every 72 hours, and a quadrupled maintenance dose every 96 hours. In the latter three dosing regimens, subjects received placebo on the interposed day(s). Study participation was contingent on opioid abstinence and daily clinic attendance. Measures of subjective opioid agonist and withdrawal effects were assessed daily. RESULTS: Relative to standard maintenance dosing, none of the higher doses induced agonist effects. Changes in indices of subjective withdrawal effects were noted as the time since the last active dose increased during intermittent dosing regimens, but the magnitude of these effects was relatively low and was comparable to those found in other alternate-day dosing studies. CONCLUSIONS: These results support the feasibility and safety of twice weekly buprenorphine dosing regimens.     

Acetazolamide therapy for hypochloremic metabolic alkalosis in pediatric patients with heart disease

BACKGROUND: Pediatric patients with heart disease are often treated with high doses of diuretics, which can lead to hypochloremic metabolic alkalosis. There are no data in children regarding the efficacy and safety of acetazolamide to treat hypochloremic metabolic alkalosis. METHODS: Patients from January 2004 to June 2005 who received acetazolamide were identified. Inclusion criteria were: age less than 18 years, being a cardiology patient, diuretics use, and had received a 3-day course of acetazolamide. Demographic information was collected along with serum electrolytes, serum creatinine/blood urea nitrogen, urine output, pH, acid-base excess, concurrent medications, cardiac lesion/surgery, and incidence of adverse effects. Efficacy of acetazolamide was determined by comparing variables before and after the 3-day course. Statistical comparisons were made using Student's t-test. RESULTS: A total of 28 patients were identified, 7 of whom received oral acetazolamide, 21 intravenous acetazolamide. Patients were a median of 2.5 (range, 0.3-20) months of age, and 57% (17/28) were female. Seventy-one percent of the cohort received acetazolamide after cardiac surgery. There was no significant difference in any electrolyte, blood urea nitrogen, or serum creatinine from baseline, except for serum bicarbonate, which decreased (36.2 +/- 4.6 vs. 30.9 +/- 4.5 mmol/L, P < 0.001), and chloride, which increased (91.1 +/- 6.8 vs. 95.4 +/- 6.2, P < 0.03). Acid-base excess values and pH decreased during therapy in patients who had the laboratory values drawn (n = 22). No change in urine output at 8 hours (5.2 +/- 2.3 vs. 4.9 +/- 2.3 mL/kg/hr, P = 0.6) or 24 hours (4.7 +/- 1.5 vs. 4.3 +/- 1.4 mL/kg/hr, P = 0.18) occurred after administration of acetazolamide. CONCLUSION: Acetazolamide was safely used in pediatric patients with heart disease to lower serum bicarbonate and acid-base excess values and raise chloride values in hypochloremic metabolic alkalosis.     

Nizatidine disposition in subjects with normal and impaired renal function

To test the hypothesis that renal insufficiency alters nizatidine disposition, we determined the pharmacokinetics of nizatidine and its major metabolite after a single oral dose in normal volunteers and patients with various degrees of renal dysfunction, after a single intravenous dose in normal volunteers and patients with severe renal failure and during hemodialysis. After intravenous administration the elimination half-life increased from 1.5 +/- 0.2 hours in normal volunteers to 6.9 +/- 3.3 hours in patients with renal failure. The plasma clearance decreased from 0.59 +/- 0.07 L/kg/hr in normal volunteers to 0.14 +/- 0.02 L/kg/hr in patients with renal failure. Nizatidine bioavailability was nearly 100% in normal volunteers but decreased to 75% in patients with renal failure. The volume of distribution was 1.3 +/- 0.1 L/kg in normal volunteers and was not different in patients with renal failure. Nizatidine protein binding was about 30% in normal and uremic plasma. The drug was not substantially removed by hemodialysis. Patients with creatinine clearances less than 50 ml/min/1.73 m2 should receive 150 mg nizatidine once each evening. Patients with creatinine clearances less than 20 ml/min/1.73 m2 should receive 150 mg nizatidine every other night.     

Systemic absorption of endotracheally administered aminoglycosides in seriously ill patients with pneumonia.

A study was performed with 10 hospitalized patients to determine the percentage of an aminoglycoside dose (tobramycin or gentamicin) that is absorbed systemically after being instilled into the endotracheal tube at steady state. All patients were on respirators, had indwelling urinary catheters, and had creatinine clearances estimated to be greater than or equal to 40 ml/min. Tobramycin or gentamicin (40 mg) was instilled every 4 h directly into the endotracheal tube. Nine patients also received systemically a different aminoglycoside from that administered through the endotracheal tube. Urine was collected over a 4-h dosing interval at steady state (after at least 5 doses of the drug). The amount of aminoglycoside excreted over the 4-h interval was measured and expressed as percentage of the dose administered over that period. The range of percentage of dose absorbed was 1.5 to 34%, with a mean of 16.7 +/- 11.4% standard deviation and a median of 16.5%. The coefficient of variation was 68%. Levels of the endotracheally administered aminoglycoside in serum were measured, and all were less than 1.0 microgram/ml. While a large degree of variability in absorption was observed in this study, significant amounts of aminoglycosides could be absorbed in some patients. However, levels apparently did not accumulate in sera of patients with adequate renal function, and an empirical dosage reduction in intravenous aminoglycoside should not be necessary with the addition of endotracheally instilled aminoglycoside in patients with creatinine clearances greater than 40 ml/min.     

Target site concentrations after continuous infusion and bolus injection of cefpirome to healthy volunteers

BACKGROUND: Recent data indicate a higher level of effectivity of beta-lactam antibiotics if serum concentrations are kept above the minimal inhibitory concentration (MIC) of the pathogen. This concept would favor continuous infusion over bolus dosing. However, it is usually not the serum concentration but the free interstitial concentration in the target tissue that determines antibiotic activity. We therefore set out to measure effective drug concentrations in the interstitial space of muscle and subcutaneous adipose tissue and to compare trough levels and times above the MIC after bolus versus continuous infusion of cefpirome. METHODS: Twelve healthy volunteers received a single dose of 2 g cefpirome as an intravenous bolus or as a continuous infusion over 8 hours in a crossover design, and the resulting free interstitial tissue concentrations were measured with use of microdialysis. RESULTS: After bolus injection, mean interstitial trough concentrations were 3.0 +/- 1.9 microg/mL and 2.1 +/-1.0 microg/mL for muscle and subcutaneous tissue, respectively; continuous infusion resulted in trough levels of 10.1 +/- 6.8 microg/mL and 10.1 +/- 4.6 microg/mL for muscle and subcutaneous tissue, respectively. This resulted in significantly longer times above the MIC with continuous infusion for Staphylococcus epidermidis and Enterobacter cloacae. Bacteria with an MIC < or =1 would be covered by either method, whereas higher doses seem to be necessary for Pseudomonas aeruginosa. CONCLUSION: Although susceptible organisms will usually be covered sufficiently with standard dosing regimens, soft tissue infections with bacteria that have MIC values of 2 to 8 may profit from continuous application. Coverage of P aeruginosa, however, would be inadequate with conventional daily doses of 4 g cefpirome regardless of the method of application.     

Randomized comparison of serum teicoplanin concentrations following daily or alternate daily dosing in healthy adults

Trough serum teicoplanin concentrations were compared in healthy adults following intravenous administration of one of two regimens: (i) 12 mg/kg of body weight every 12 h for 3 doses and then 15 mg/kg every 48 h for 4 doses (n = 16 subjects) or (ii) 6 mg/kg every 12 h for 2 doses and then 6 mg/kg every 24 h for 9 doses (n = 8 subjects). The mean +/- standard deviation trough concentrations in serum on day 11 (24 and 48 h after administration of the last dose for the daily and alternate-day dosing schedules, respectively) were 16.0 +/- 2.1 and 17.9 +/- 3.5 mg/liter for subjects receiving the two regimens, respectively, by a fluorescence polarization immunoassay. The limits of the 95% confidence interval of the difference (-0.2, 3.6 mg/liter) determined by a nonparametric test were situated above the -1.3-mg/liter maximum set difference and indicated a noninferiority of the alternate-day dosing to the daily dosing. Throughout the study the individual trough concentrations in serum in the alternate-day dosing group constantly exceeded 10 mg/liter, the presently recommended target concentration for the treatment of severe infections. The trough concentrations in the sera of all subjects were bactericidal for six Staphylococcus aureus strains for which teicoplanin MICs are between 0.5 and 4 mg/liter. The bactericidal activity of serum was related to total teicoplanin (protein bound and unbound). In conclusion, an alternate-day dosing schedule (15 mg/kg on alternate days following administration of a 12-mg/kg loading dose three times every 12 h) could be considered for further efficacy and safety studies.     

Intraoperative concentrations of ofloxacin in serum, bile fluid, and gallbladder wall tissue.

To evaluate concentrations of ofloxacin in serum, bile fluid, and gallbladder wall tissue after intravenous administration, patients greater than or equal to 16 years old diagnosed with acute cholecystitis were randomly assigned to receive ofloxacin (400 mg) intravenously every 12 h or ceftazidime (2 g) intravenously every 8 h. Doses of each regimen were given preoperatively. Serum, bile fluid, and gallbladder wall tissue samples of consecutive patients in the ofloxacin group were obtained intraoperatively. The samples were frozen at -70 degrees C until analyzed by high-pressure liquid chromatography. Twenty-three patients (6 males and 17 females) were evaluated. The mean (+/- the standard deviation) ofloxacin concentrations in serum, bile fluid, and gallbladder wall tissue were 2.9 +/- 2.4 and 6.0 +/- 7.9 micrograms/ml and 3.1 +/- 2.9 micrograms/g, respectively. The mean number of doses each patient received before surgery was 5.3 +/- 3.0, and the mean delta time (time elapsed between last antibiotic administration and when intraoperative samples were obtained) was 9.6 +/- 7.5 h. The mean tissue-to-serum ratio was 1.2 +/- 0.5, and the mean bile-to-serum ratio was 2.3 +/- 1.4. The mean serum ofloxacin concentrations were not statistically different from the concentrations in bile (P = 0.1) and tissue (P = 0.7) at the mean delta time. The study revealed that concentrations of ofloxacin in serum, bile fluid, and gallbladder tissue after intravenous dosing were adequate against susceptible organisms found in the biliary tract.     

Multiple-dose pharmacokinetics of rectally administered acetaminophen in term infants

OBJECTIVE: To investigate pharmacokinetics and pharmacodynamics of rectally administered acetaminophen (INN, paracetamol) in term neonates directly after birth. METHODS: In this prospective clinical trial, term neonates wtih painful conditions or who were undergoing painful procedures received multiple-dose acetaminophen. Serum concentrations were determined serially with an HPLC method, and pharmacokinetic analysis was performed. Pain assessment was performed by means of a validated pain score. RESULTS: Ten consecutive term neonates received four rectal doses of acetaminophen, 20 mg/kg body weight, every 6 hours. Mean peak serum concentrations (+/-SD) during multiple-dose administration were 10.79 +/- 6.39 mg/L, 15.34 +/- 5.21 mg/L, and 6.24 +/- 3.64 mg/L for the entire group, boys, and girls, respectively. There was a significant difference between the boys and the girls (P = .01). No serum concentrations associated with toxicity (>120 mg/L) were found. Median time to peak serum concentration was 1.5 hours after the first dose and 15 hours for multiple doses. Mean (+/-SD) half-life was 2.7 +/- 1.4 hours in eight patients. There was no correlation between dose and serum concentration or between pain score and serum concentration. There was a significant inverse relationship between the preceding pain score and peak serum concentrations. CONCLUSIONS: In term neonates, multiple rectal doses of acetaminophen, 20 mg/kg body weight, led to widely varying serum concentrations but did not result in therapeutic concentrations in all infants. Boys had higher peak concentrations. Because accumulation was not found, a dose of 30 mg/kg followed by doses of 20 mg/kg at 6- to 8-hour administration intervals are appropriate to reach therapeutic concentrations. A concentration-effect relationship could not be determined.     

Amikacin and gentamicin accumulation pharmacokinetics and nephrotoxicity in critically ill patients.

Twenty-five critically ill adults receiving blood level-adjusted doses of amikacin were prospectively studied with serum, urine, and, when possible, tissue amikacin concentrations. These data were fitted to a two-compartment pharmacokinetic model. Prolonged urine collections or postmortem tissues (or both) were used to confirm predicted tissue accumulation. Nephrotoxicity was also investigated. Patients were defined as having renal damage if they showed an increase in serum creatinine of greater than 0.5 mg/100 ml, an increase in urine beta 2-microglobulin of greater than 50 mg/day, and presence of urinary casts of greater than 500/ml. Renal damage was attributed to amikacin if there was, in addition to the above, tissue accumulation of amikacin of greater than 600 mg. These patients were matched with 25 patients treated with gentamicin during the same time period. There were no statistical differences between the gentamicin- and amikacin-treated patients in age, sex, weight, base-line creatinine clearance, concurrent cephalosporins or diuretics, treatment duration, site of infection, normalized (amikacin/gentamicin dosing ratio of 3:1) total dose, mortality, or tissue accumulation. More amikacin-treated patients (19 of 25) than gentamicin-treated patients (9 of 25) received prior aminoglycosides (P less than 0.01). The only pharmacokinetic parameter that differed between amikacin and gentamicin was a greater K21 for gentamicin. Nephrotoxicity was observed in 4 gentamicin was a greater K21 for gentamicin. Nephrotoxicity was observed in 4 gentamicin-treated patients (16%) and 5 amikacin-treated patients (20%). At a 3:1 dosing ratio, there were no significant differences between amikacin and gentamicin two-compartment pharmacokinetics and nephrotoxic potential in matched critically ill patients, but the trend of these data showed greater amikacin tissue accumulation. However, at an amikacin/gentamicin dosing ratio of 4:1, their tissue accumulation potential appeared to be almost identical.     

Once-daily dosing decreases renal accumulation of gentamicin and netilmicin

The pathogenesis of aminoglycoside nephrotoxicity is intimately related to the extent of drug accumulated in the renal cortex. In the framework of searching for preventive measures of aminoglycoside-induced nephrotoxicity, we investigated the influence of dosage regimen on the renal cortical accumulation of gentamicin and netilmicin in humans. Patients with a tumor partly involving one kidney, with normal renal function, and scheduled for nephrectomy received one dose of either gentamicin (4.5 mg/kg) or netilmicin (5 mg/kg) as a single short-term infusion or as 24-hour continuous infusion. Treatment started 24 hours before surgery. Serum aminoglycoside pharmacokinetics were examined during treatment and renal cortical tissue was sampled at the moment of operation for drug determination. The short-term infusion schedule yielded cortical concentrations of 103.2 +/- 36.3 and 137.4 +/- 34.6 micrograms/gm for gentamicin and netilmicin, respectively. Tissue levels after continuous infusion were 158.1 +/- 52.9 and 178.5 +/- 21.8 micrograms/gm for gentamicin and netilmicin, respectively. For each aminoglycoside, a single short-term infusion resulted in significantly lower renal drug levels than did a continuous infusion of the same dose. From the nephrotoxicity point of view, these data support the administration of gentamicin and netilmicin as once-daily injections. This also supports the appropriateness of further studies to determine clinical efficacy of once-a-day dosing for aminoglycosides.     

Pharmacodynamic modeling of the acid inhibitory effect of ranitidine in patients in an intensive care unit during prolonged dosing: characterization of tolerance.

OBJECTIVE: To characterize the relationship between the pharmacokinetics and the acid inhibitory effect of ranitidine during prolonged dosing on the basis of a physiologic indirect-response model. METHODS: Multiple doses of ranitidine were administered to 18 patients in an intensive care unit in an open randomized trial. All patients received an initial intravenous dose of 50 mg ranitidine; after 12 hours repeated injections (50 mg every 6 hours) or a primed continuous infusion (50 mg plus 0.125 mg/kg/h) was administered. Intragastric pH was monitored continuously for at least 42 hours. RESULTS: After the initial injection a time lag was observed between the increase of plasma concentration and the increase of pH. With the indirect-response model the rate of onset of effect (kout) could be estimated adequately by relating the inhibitory effect on acid secretion to the concentration according to a sigmoid Emax model. For administration of a single dose, estimated pharmacodynamic parameters were 4.5 +/- 0.9 h(-1) for kout, 1.4 +/- 0.1 for baseline pH, 0.051 +/- 0.012 mg/L for 50% inhibition constant, and 7.0 +/- 1.5 for Hill factor (mean +/- SEM; n = 18). Tolerance developed during subsequent dosing that could be described as a linear increase (beta) of 50% inhibition constant with time (beta = 0.0030 and 0.0045 mg/L/h for repeated and continuous administration, respectively). Conclusions: The developed physiologic indirect-response model may be used to quantify the pharmacokinetic-pharmacodynamic relationship of ranitidine during single and multiple dosing. During prolonged intravenous dosing, tolerance developed within 42 hours and could be characterized on the basis of the developed indirect-response model.     

Disposition of ceftazidime in surgical patients with intra-abdominal infection.

The disposition of ceftazidime was assessed in 11 surgical patients with suspected intra-abdominal infection. All patients had normal hepatic function, and creatinine clearances ranged from 43 to 186 ml/min. Patients received 2 g of ceftazidime intravenously every 8 h. Trough and peak concentrations in serum were measured on day 2, and trough and postdose concentrations in serum were determined on 10 samples collected during a dosage interval between days 3 and 6 of therapy. Ceftazidime peak and trough concentrations in serum at steady state determined by high-performance liquid chromatography were 257.4 +/- 122.0 (mean +/- standard deviation) and 13.1 +/- 20.6 mg/liter. The serum-concentration-versus-time profile was multiexponential. The elimination half-life, steady-state volume of distribution, and total body clearance were 2.52 +/- 1.39 h, 0.31 +/- 0.12 liter/kg, and 0.11 +/- 0.05 liter/h per kg, respectively. Total predicted body clearance significantly correlated with the measured values (r = 0.868; P = 0.001). The disposition of ceftazidime is dependent on creatinine clearance and is not significantly altered by surgery or acute infectious processes.     

Gentamicin effects on urinary electrolyte excretion in healthy subjects

BACKGROUND: Symptomatic hypomagnesemia, hypocalcemia, and hypokalemia caused by renal electrolyte wasting occasionally develop in patients treated with aminoglycosides. This phenomenon has been attributed to aminoglycoside tubular injury. However, rats administered a single dose of gentamicin show immediate dose-related calcium and magnesium renal wasting without sodium or potassium wasting days before other evidence of tubular dysfunction or structural injury can be shown. The mechanism is undefined but transient and is not dependent on the presence of parathyroid hormone. OBJECTIVE: To determine whether gentamicin administration to humans causes renal electrolyte wasting. DESIGN: Five healthy volunteers ingested a 400-mg calcium, 100-mEq sodium diet for 1 week before the study. After a 90-minute baseline period, 5 mg/kg gentamicin was administered intravenously over 30 minutes. Urine and serum were collected for 5 hours after gentamicin administration. RESULTS: Peak serum gentamicin levels ranged from 12.8 to 20.6 microg/mL. There was no change in serum electrolytes. The urinary fractional calcium excretion rose from a baseline of 1.8% +/- 0.5% to 6.8% +/- 1.4% (P < .01), and the magnesium fractional excretion rose from 3.4% +/- 0.8% to 11.8% +/- 6.4% (P = .03). These effects were transient. Gentamicin caused no change in renal excretion of sodium, potassium, or phosphate. CONCLUSIONS: Gentamicin administered at the standard clinical dose causes immediate and transient renal calcium and magnesium wasting in normal humans. The mechanism of gentamicin-associated urinary magnesium wasting and calciuria is undefined. However, the pattern of electrolyte excretion after gentamicin administration suggests that the site of action of these gentamicin effects is the distal convoluted tubule.     

Evaluation of methods of administering tyramine to raise systolic blood pressure

To compare the relative merits of two different administration regimens, tyramine was administered intravenously in ascending doses to 12 healthy subjects to raise systolic blood pressure slightly more than 30 mm Hg. Six subjects received tyramine by bolus injection and six other subjects received tyramine by infusion. The bolus dose of tyramine needed was 4.34 +/- 1.51 mg (X +/- SD) and the infusion rate needed was 1.11 +/- 0.33 mg/min. Four blood pressure response patterns to continuous tyramine infusion were observed. Because different units were measured for the quantity of tyramine administered, the between-subject variance estimate to within-subject variance estimate ratios were calculated. The two techniques had equivalent consistency. With the bolus method, in contrast to the infusion procedure, the dose-response relationship was obvious in most subjects. Therefore the bolus method was judged to be more useful than the infusion method.     

Single versus multiple doses of acetazolamide for metabolic alkalosis in critically ill medical patients: a randomized, double-blind trial.

OBJECTIVE: To compare two dosing regimens of acetazolamide for the reversal of metabolic alkalosis in mechanically ventilated patients with asthma or chronic obstructive pulmonary disease. DESIGN: A randomized, double-blind, placebo-controlled trial. SETTING: A 35-bed medical intensive care unit in a tertiary care teaching hospital. PATIENTS: Forty mechanically ventilated patients with a metabolic alkalosis (arterial pH > or = 7.48 and serum bicarbonate concentration > or = 26 mEq/L) resistant to fluid or potassium therapy (serum potassium concentration, > or = 4 mEq/L) not receiving acetazolamide or sodium bicarbonate in the previous 72 hrs. INTERVENTIONS: Stratified by previous diuretic use and randomized to receive intravenous administration of acetazolamide, one dose of 500 mg or 250 mg every 6 hrs for a total of four doses. MEASUREMENTS AND MAIN RESULTS: Serum bicarbonate and potassium concentrations were drawn every 6 hrs for 72 hrs, arterial blood gases were drawn every 12 hrs for 72 hrs, and both urine chloride and pH were drawn at hours 0, 6, 12, 18, 24, 48, and 72. By using generalized estimating equation techniques, no difference was found between the two dosing regimens at any point over the study period for serum bicarbonate, serum potassium, or urine chloride end points. Results did not differ between diuretic- and nondiuretic-treated patients. Serum bicarbonate concentrations remained significantly decreased in both treatment groups 72 hrs after administration of the first acetazolamide dose (31.8 +/- 4.9-25.3 +/- 3.8 mEq/L, p < .0001 [250 mg x 4]; 31.9 +/- 25.4-25.4 +/- 3.6 mEq/L, p < .0001 [500 mg x 1]). CONCLUSIONS: We conclude that a single 500-mg dose of acetazolamide reverses nonchloride responsive metabolic alkaloses in medical intensive care unit patients as effectively as multiple doses of 250 mg. Studies to examine the prolonged duration of action of acetazolamide observed in this study as well as the effect of acetazolamide on clinical end points, such as duration of mechanical ventilation, are warranted.     

Validation and nephrotoxicity of a simplified once-daily aminoglycoside dosing schedule and guidelines for monitoring therapy.

There is no established dosing schedule for once-daily aminoglycoside dosing regimens, and accepted guidelines for monitoring therapy are lacking. We derived a simplified schedule from the Hull and Sarubbi (J. H. Hull and F. A. Sarubbi, Ann. Intern. Med. 85:183-189, 1976) nomogram, for which efficacy and safety in a once-daily dosing regimen were previously demonstrated, and prospectively followed serum aminoglycoside levels in patients. The standard treatment was gentamicin or tobramycin at 4 mg/kg of body weight given intravenously once daily. When the renal function was decreased, the daily dose was reduced, as follows: for an estimated creatinine clearance of between 50 and 80 ml/min, the daily dose was 3.25 mg/kg, for an estimated creatinine clearance of between 30 and 50 ml/min, the daily dose was 2.5 mg/kg, and for an estimated creatinine clearance of below 30 ml/min, the daily dose was 2 mg/kg. A total of 221 patients were studied (184 received gentamicin and 37 received tobramycin). First trough levels above 2 mg/liter were recorded in 11% of the patients, and they all had a baseline creatinine clearance below 50 ml/min, or a substantial decrease in clearance between enrollment and the day that the trough level was obtained. A peak level below 6 mg/liter was recorded in 6% of the patients, and half of them received the lowest daily dose. Twenty-five of the 179 evaluable patients (14%; 95% confidence interval, 9 to 19%) fulfilled the criteria for nephrotoxicity. In a multiple regression analysis, the duration of treatment and the use of other nephrotoxic antibiotics or high-dose furosemide, but not trough levels, were significant risk factors. Since the meaning of low peak levels is unclear and since most studies with multiple daily regimens confirm the lack of an association between trough levels and toxicity, we believe that monitoring of serum drug levels can be restricted to monitoring of trough levels in patients with a creatinine clearance below 50 ml/min or with a deteriorating renal function.