Commonly used antibacterial agents may be associated with various neurotoxic reactions. Central nervous system toxicities include seizure disorders, encephalopathy, bulging fontanelles, and neuropsychiatric symptoms. These abnormalities have been associated with the use of the penicillins, cephalosporins, sulfonamides, tetracyclines, chloramphenicol, colistin, aminoglycosides, metronidazole, isoniazid, rifampin, ethionamide, cycloserine, and dapsone. Cranial nerve toxicities, such as myopia, optic neuritis, deafness, vertigo, and tinnitus, have been associated with the use of erythromycin, sulfonamides, tetracyclines, chloramphenicol, colistin, aminoglycosides, vancomycin, isoniazid, and ethambutol. Peripheral nerve symptoms consisting of paresthesias, motor weakness, or sensory impairment have been associated with the use of the penicillins, sulfonamides, chloramphenicol, colistin, metronidazole, isoniazid, ethionamide, and dapsone. Neuromuscular blockade has been associated with the use of the tetracyclines, polymyxins, lincomycin, clindamycin, and aminoglycosides. Management generally consists of supportive therapy and immediate discontinuation of therapy with the offending drug.

The neurotoxicity of antibacterial agents.

Hydroxyethyl starch has recently become the subject of renewed interest because of the introduction of a new specification, hydroxyethyl starch 130/0.4, as well as the clinical availability of a solution using a previous hydroxyethyl starch type (hydroxyethyl starch 670/0.75) with a carrier other than 0.9% saline. Various types of hydroxyethyl starch show different pharmacokinetic behaviour. Since hydroxyethyl starch is a polydisperse solution acting as a colloid, pharmacodynamic action depends on the number of oncotically active molecules, not on the plasma concentration alone; therefore, solutions with a lower in vivo molecular weight contain more molecules at similar plasma concentrations. On the other hand, high plasma concentrations as well as high in vivo molecular weight can affect blood coagulation, especially factor VIII and von Willebrand factor. Hydroxyethyl starch types with a molar substitution >0.4 accumulate in plasma after repetitive administration, most pronounced with hetastarch (hydroxyethyl starch 670/0.75). Correspondingly, tissue storage as measured by (14)C tracer studies in animals showed significantly higher values for hydroxyethyl starch 200/0.5 compared with hydroxyethyl starch 130/0.4 (about 4-fold at the latest timepoint after the last administration), and considerably higher values for hetastarch compared with both hydroxyethyl starch 130/0.4 and 200/0.5. Hydroxyethyl starch 130/0.4 does not accumulate in plasma after single- and multiple-dose administration in contrast to all other available hydroxyethyl starch specifications. Plasma clearance of hydroxyethyl starch 130/0.4 is at least 20-fold higher than that for hetastarch, and considerably higher than for pentastarch. In patients with renal insufficiency, pharmacokinetic data are only available for hydroxyethyl starch 130/0.4. Cumulative urinary excretion, even in the presence of severe non-anuric renal failure, is higher for hydroxyethyl starch 130/0.4 than values published for older hydroxyethyl starch specifications. Hydroxyethyl starch 130/0.4 may be given to patients with severe renal impairment as long as urine flow is preserved. The pharmacodynamics with respect to the volume effect does not directly mirror pharmacokinetics in the case of hydroxyethyl starch solutions. Equivalent volume efficacy has been proven for hydroxyethyl starch 130/0.4 compared with 200/0.5. Prolonged persistence of hydroxyethyl starch in plasma and tissues can be avoided by using rapidly metabolisable hydroxyethyl starch types with molar substitution <0.5. Influence on coagulation is minimal with hydroxyethyl starch 130/0.4, and no adverse effects on kidney function have been observed even with large repetitive doses when used according to the product information.

Pharmacokinetics of Hydroxyethyl Starch

Delirium is a common and costly complication of hospitalization. Although medications are a known cause of delirium, antibiotics are an underrecognized class of medications associated with delirium. In this article, we comprehensively review the clinical, radiologic, and electrophysiologic features of antibiotic-associated encephalopathy (AAE). AAE can be divided into 3 unique clinical phenotypes: encephalopathy commonly accompanied by seizures or myoclonus arising within days after antibiotic administration (caused by cephalosporins and penicillin); encephalopathy characterized by psychosis arising within days of antibiotic administration (caused by quinolones, macrolides, and procaine penicillin); and encephalopathy accompanied by cerebellar signs and MRI abnormalities emerging weeks after initiation of antibiotics (caused by metronidazole). We correlate these 3 clinical phenotypes with underlying pathophysiologic mechanisms of antibiotic neurotoxicity. Familiarity with these types of antibiotic toxicity can improve timely diagnosis of AAE and prompt antibiotic discontinuation, reducing the time patients spend in the delirious state.

Antibiotic-associated encephalopathy

Dextran-70 versus albumin as plasma expanders in cirrhotic patients with tense ascites treated with total paracentesis. Results of a randomized study.

Quantitative structure-pharmacokinetic relationships and drug design.

After withdrawal of 400 ml whole blood and subsequent infusion of 500 ml of a colloidal plasma substituent, the intravascular and renal colloid elimination was investigated in 40 test subjects. The individual colloidal solutions could no longer be demonstrated in the intravascular space after the following times: 10% hydroxyethyl starch 200/0.5 (anthrone method) after six weeks, 10% dextran 40 (anthrone method) after two weeks, 6% hydroxyethyl starch 200/0.5 (anthrone method) after four weeks and 5.5% oxypolygelatine (hydroxyproline method) after two days. Colloidal plasma substitutes are polydisperse solutions with various molecular weights and degree of hydroxyethylation and therefore, also have a large number of different elimination constants. With repeated application, the intravascular colloid concentration shifts in favour of the molecules with a longer half life which are difficult to eliminate. The elimination of the clinically employed dextran 40 and oxypolygelatine solution could be best described with an open two-compartment model. As a result of its greater heterogeneity, the elimination of the moderately high molecular weight hydroxyethyl starch 200/0.5 could only be characterized approximately even assuming three elimination constants. In the first four days, the hydroxyethyl starch 200/0.5 was more rapidly eliminated compared to dextran 40. However, subsequently a very much lower elimination from the intravascular space was found for about 3% of the administered hydroxyethyl starch 200/0.5. Oxypolygelatine was eliminated especially rapidly. Accordingly, the greatest renal clearance was found for oxypolygelatine, which showed a close relation to the molecular weight. On the other hand, a rapid elimination simultaneously is followed by a correspondingly lower volume effect.

[The elimination of hydroxyethyl starch 200/0.5, dextran 40 and oxypolygelatine (author's transl)].

The effects of administration of a new, middle-molecular 10% hydroxyethyl starch 200/0.5 (HAES-steril) were compared to 10% dextran 40 (Rheomacrodex) in 20 hypovolaemic volunteers after withdrawal of 400 ml blood. The total increase of blood volume after 500 ml of 10% hydroxyethyl starch 200/0.5 was 10.19 +/- 1.1 ml/kg (754 ml), after 500 ml of 10% dextran 40 14.10 +/- 1.1 ml/kg (1032 ml), which was significantly higher (p less than 0.01) and in correspondence with the known volume expanding properties of 10% dextran 40. The volume effect after administration of both substances was stable, as demonstrated by the ability to compensate the loss of 400 ml blood for more than 8 hours. The maximal increase of the colloid osmotoc pressure after 10% hydroxyethyl starch 200/0.5 was 5.3 +/- 0.2 mm Hg, after 10% dextran 40 7.2 +/- 0.4 mm Hg and paralleled the increase of the blood volume. After 10% hydroxyethyl starch 200/0.5 an increase of serum amylase was observed. This hyperamylasemia is caused by the formation of a high molecular hydroxyethyl starch-amylase complex, which cannot be eliminated easily. Urinary volume and endogenous creatinine clearance were increased by administration of both colloids. After dextran 40 a pronounced increase of the urinary viscosity occurred.

[The effects of 500 ml 10% hydroxyethyl starch 200/0.5 and 10% dextran 40 on blood volume, colloid osmotic pressure and renal function in human volunteers (author's transl)].

After infusion of 500 ml of 6% hydroxyethyl starch into fifty-four patients an increase of serum amylase was observed which in fifty-one cases exceeded the upper limit of normal (190 U/l). In most cases serum amylase reached twice the basal value. Renal function influenced the duration of the increase in serum amylase, but not the maximum increase (201+/-15 U/l; mean+/-SEM). In patients with advanced renal failure (glomerular filtration rate (GFR) = 2-10 ml/min) serum amylase was still markedly elevated after 72 h (298+/-24 U/l; mean+/-SEM). In patients with normal renal function (GFR greater than 90 ml/min) serum amylase decreased to 183+/-40 U/l (mean+/-SEM) within 72 h without reaching basal values. After infusion of HES no changes were observed in serum lipase or in amylase or lipase activities in duodenal secretion. Amylase excretion in the urine decreased. The assumption of a macroamylasaemia caused by formation of an HES-amylase complex was confirmed by gel filtration. The elimination from plasma of this high molecular enzyme-substrate complex is slow and causes hyperamylasaemia. In no case was the macroamylasaemia associated with signs or symptoms. An awareness of this causal relationship seems to be important, to avoid the erroneous diagnosis of a pancreatic disease.

Macroamylasaemia after treatment with hydroxyethyl starch.

The neurotoxic effects of ticarcillin, methicillin, phenthicillin, oxacillin, cloxacillin and dicloxacillin were studied in the conscious rabbit. During and after intravenous administration of 1.2 and 2.4 g/kg, resp., over 50 min the blood concentrations of the drugs were determined and the neurotoxicity assessed by continuous recording of the electroencephalogram. The hydrophobia of the penicillins was characterized by determination of their partition coefficients between isobutanol and buffer solution pH 7.4. The penicillins showed quite different neurotoxic properties. A close correlation (r=0.928) was found between the neurotoxic potency of the penicillins and their partition coefficients. With increasing hydrophobia the neurotoxic potency increased in the following sequence: Ticarcillin, methicillin, oxacillin, phenethicillin, cloxacillin, dicloxacillin. It can be concluded, therefore, that determination of the partition coefficient of a penicillin gives valuable information on the neurotoxicity to be expected. The introduction of a neurotoxicity quotient revealed that penicillins may be divided into two groups: less neurotoxic penicillins with a partition coefficient below 1.0 and highly neurotoxic penicillins with a partition coefficient above 1.0.

Cerebral toxicity of penicillins in relation to their hydrophobic character

36 Patienten mit unterschiedlicher Nierenfunktion (GFR zwischen 0,5–142 ml/min) erhielten 500 ml 10%iges Dextran 40 (Rheomacrodex®). Dabei ergab sich ein relatives Verteilungsvolumen von 10,2±2,2 1/100 kg. Die Eliminationshalbwertzeiten von Dextran 40 stehen mit der Nierenfunktion (51 Cr-EDTA-Clearance) in einem Zusammenhang, der sich rechnerisch am besten durch eine Potenzfunktion darstellen last. Patienten mit normaler Nierenfunktion (GFR uber 90 ml/min) haben eine Eliminationshalbwertzeit von 573±138 min und eine 12 Std-Recovery im Urin von 48%. Ein Glomerulusfiltrat unter 10 ml/min fuhrt dagegen zur Verlangerung der Halbwertzeit auf das Funffache (Dextran 40-HWZ=2591±1022 min) und zum Ruckgang der 12 Std-Recovery auf 4%. Im Clearancebereich zwischen 30 und 142 ml/min bleiben Eliminationshalbwertzeit und Urinausscheidung im wesentlichen konstant. Dextran 40 kann deshalb bei diesen Patienten nach den bekannten Regeln dosiert werden. Bei glomerularen Filtrationswerten unter 30 ml/min ist jedoch mit einer gestorten Elimination zu rechnen. Aus der veranderten Dextran 40-Ausscheidung im Urin und aus den Eliminationshalbwertzeiten ergeben sich Dosierungsrichtlinien, die diskutiert und tabellarisch aufgefuhrt werden.

H. Köhler

Papers

[The elimination of hydroxyethyl starch 200/0.5, dextran 40 and oxypolygelatine (author's transl)].

[The effects of 500 ml 10% hydroxyethyl starch 200/0.5 and 10% dextran 40 on blood volume, colloid osmotic pressure and renal function in human volunteers (author's transl)].

Macroamylasaemia after treatment with hydroxyethyl starch.

Cerebral toxicity of penicillins in relation to their hydrophobic character

Pharmakokinetik und Dosierung von Dextran 40 in Abhängigkeit von der Nierenfunktion