George R. Aronoff

Antimicrobial Therapy in Patients With Impaired Renal Function

In order to formulate a thoughtful and rational approach to drug dosing in renal failure, the nephrologist must consider several features that influence drug disposition in uremia. Drug bioavailability is generally adversely influenced in patients with renal disease. Drug distribution is frequently altered to an unpredictable degree. Drug protein binding is affected not only by changes in the amount of circulating binding protein but also by the accumulation of endogenous toxins. Renal failure frequently affects drug biotransformation. Drug-dosing tables and nomograms are important; however, they are not a substitute for an encompassing clinical approach and sound clinical judgment.

Pharmacokinetics of Common Antibiotics Used in Continuous Ambulatory Peritoneal Dialysis

To establish therapeutic guidelines for the use of antibiotics in patients receiving continuous ambulatory peritoneal dialysis (CAPD), we studied the single-dose pharmacokinetics of cefazolin, tobramycin, and vancomycin given intravenously (IV) and intraperitoneally (IP) as well as cephalexin given orally. By the IV or oral route, the antibiotics exhibited half-lives similar to those described in nondialysed, functionally anephric patients. CAPD accounted for only a negligible fraction of the total body clearance when the drugs were given by the IV route. However, when given IP, the drugs were promptly absorbed and achieved therapeutic serum concentrations. The kinetic principle of superposition was applied to predict plasma concentrations after repetitive IP dosing. Therapeutic guidelines are provided.

A note on possible limitations on the use of the harvard group scale of hypnotic susceptibility, form a

Abstract Early studies suggested that the Harvard Group Scale of Hypnotic Susceptibility, Form A (HGSHS:A), of Shor and E. Orne (1962), might have two limitations. Data are presented in support of these indications. The HGSHS: A may be insufficiently valid with male Ss, and may nominate quite different samples of hypnotically susceptible Ss and simulators than individually-administered forms of the Stanford Hypnotic Susceptibility Scales (Weitzenhoffer & Hilgard, 1959, 1962). The prudence of Ornes (1971) proposed double-check on S-selection is thus supported.

Hemodynamic, renal, and hormonal responses to lower body positive pressure in human subjects

Studies in healthy human subjects subjected to lower body positive pressure (LBPP) have failed to elucidate many of the physiologic effects of this maneuver. In 7 healthy, well-hydrated men we studied the following responses to LBPP (35 mm Hg, 1 hour, supine position): systemic and renal hemodynamics; urine volume (UV), urine osmolality (Uosm), and urine sodium level (UNaV); free water (CH20) and osmolar (Cosm) clearances; plasma renin activity (PRA); levels of aldosterone (PA), cortisol (CORT), norepinephrine (NE), atrial natriuretic peptide (ANP), and vasopressin (AVP); osmolality (Posm); and serum sodium level. Subjects were restudied on a control day with zero trouser pressure. The recorded changes (p < 0.05) when comparing the LBPP day with the control day were as follows: fractional Na+ reabsorption increased (98.7% +/- 0.2% to 99.3% +/- 0.1%) and UNaV decreased (0.19 +/- 0.03 mEq/min to 0.10 +/- 0.01 mEq/min), with concomitant increases in PRA (1.7 +/- 0.2 ng/ml/90 min to 4.5 +/- 1.8 ng/ml/90 min), PA (7.7 +/- 0.7 ng/dl to 9.3 +/- 1.5 ng/dl), and CORT (13.0 +/- 2.6 mg/dl to 19.2 +/- 3 mg/dl); the increase in blood pressure with LBPP (96 +/- 3 mm Hg to 112 +/- 4 mm Hg) was greater than that during control conditions. Renal plasma flow tended to display an interactive pattern across days, with a slight decline during LBPP (5%) and a slight elevation under control conditions (9%). On the LBPP day only, filtered Na+ declined (15 +/- I mEq/min to 12 +/- 1 mEq/min) as a function of reduced glomerular filtration rate (112 +/- 5 ml/min to 91 +/- 7 ml/min), blood volume decreased (by 2.7% +/- 0.7%), CO decreased (5.5 +/- 0.3 L/min to 4.7 +/- 0.3 L/min), and stroke volume declined (101 +/- 6 ml to 84 +/- 3 ml). On both days, NE increased (control, 221 +/- 23 pg/ml to 340 +/- 33 pg/ml; LBPP, 236 +/- 17 pg/ml to 369 +/- 31 pg/ml) and ANP increased (control, 47 +/- 7 pg/ml to 97 +/- 21 pg/ml; LBPP, 49 +/- 10 pg/ml to 104 +/- 30 pg/ml). We concluded that LBPP reduces renal sodium excretion. The mechanism for this reduction is not known, although it did occur in association with an increase in plasma renin activity, which in turn results from mechanical reduction of renal perfusion, stress-related CORT stimulation, a reflex-based elevation in peripheral vascular resistance leading to a reflex increase in plasma renin activity, or a combination of these.

Interactions of ceftazidime and tobramycin in patients with normal and impaired renal function.

We studied the in vivo interaction of ceftazidime and tobramycin in normal volunteers and anuric patients given each drug separately or both drugs in combination. Kinetic analysis of plasma concentration data showed minor changes in the disposition of these agents when they were given concurrently. However, the resulting clearance of both tobramycin and ceftazidime was unchanged when these drugs were given concurrently. The volume of distribution of tobramycin at steady state was increased by 20% in normal volunteers when given with ceftazidime. The increase in distribution was accompanied by a slight decrease in ceftazidime elimination rate. No additional alteration in dosing over those necessary to adjust for a decrease in renal function is necessary when giving this combination.

Effects of moxalactam and cefotaxime on rabbit renal tissue.

To determine and compare the effects of moxalactam and cefotaxime on kidneys, we gave these drugs in doses of 750 and 1,500 mg/kg to rabbits for 7 days. Cephaloridine was included as a positive control. Neither moxalactam nor cefotaxime at either dose caused lysosomal enzymuria, changes visible by light microscopy or increased plasma creatine. Both drugs caused minor alterations in glomerular ultrastructure at the higher dose. Cephaloridine, on the other hand, caused widespread renal functional and morphological damage. We conclude that in rabbits, both moxalactam and cefotaxime are remarkably nonnephrotoxic. Images

Ceftazidime nephrotoxicity in rats

The nephrotoxicity of ceftazidime compared with that of cefazolin or cephaloridine and the capacity of ceftazidime to enhance the nephrotoxicity of tobramycin were evaluated in rats. Only cephaloridine and tobramycin given alone altered creatinine clearance or caused significant histological injury. Our data suggest that ceftazidime is no more nephrotoxic than cefazolin and does not enhance the nephrotoxicity of tobramycin.

Microbiology, Pharmacology, and Clinical Use of Mezlocillin Sodium

The acylureido penicillin mezlocillin is active against gram‐positive, gram‐negative, and anaerobic bacteria. It easily penetrates the outer membrane of gram‐negative bacteria, and it has a strong affinity for penicillin binding protein 3. Its stability to 3‐lactamases is weak. Mezlocillin is synergistic when given in combination with aminoglycoside antibiotics. In pharmacokinetic studies mezlocillin conforms to a two compartment open model; its pharmacokinetic properties are dose‐dependent. The half‐life of the drug is about 1 hour after intravenous injection and 1.5 hours after intramuscular injection. Protein binding ranges from 16 to 42%, and 55% of a dose is excreted in the urine. Biliary excretion ranges from 0.5 to 25%. Clinical trial cure rates were as follows: bacteremia (78%), respiratory tract (62%), urinary tract (81%), gynecological (86%), bone and joint (55%), intraabdominal (67%) and skin and soft tissue (59%). The frequency of adverse reactions was 7.7%. Interstitial nephritis, CNS toxicity, and bleeding have not been reported.

Management of Amikacin Overdose

A woman with subarachnoid hemorrhage inadvertently received 18 g of amikacin over a 4-hr period, 20 times the recommended total daily dose. Intravenous fluids were administered to expedite renal excretion of the amikacin, and a peritoneal dialysis was performed to augment drug elimination. Drug levels were measured sequentially in serum, urine, and peritoneal dialysate. Renal clearance of the drug was increased compared to clearance following a standard dose and the drug was rapidly excreted in the urine. Amikacin was not detected in the peritoneal dialysate. There were no apparent toxic effects from the overdose. A patient with normal renal function who receives a potentially toxic dose of amikacin can be appropriately managed by careful hydration and maintenance of a generous diuresis.