Carbenicillin therapy in patients with normal and impaired renal function.

Optimun therapy with carbenicillin entails the use of high serum concentrations and the risk of significant dose-related toxicity. We report a study of serum clearance method of dose adjustment of carbenicillin patients with normal and imparied renal function. This method was found to provide serum concentrations considered to be satisfactory in every instance, by either constant-rate or intermittent infusion, and should enable greater precision in the use of the antibiotic. Implications of these findings aimed at providing dosage schedules for patients with renal failure are discussed.

Piperacillin kinetics.

Piperacillin was administered to normal, healthy volunteers by an intravenous infusion over 30 min at dosage regimens of 12 gm daily (4 gm every 8 hr) and 24 gm daily (6 gm every 6 hr) for 5 consecutive days. Mean peak serum level after 12 gm daily was 244 +/- 24 (SE) microgram/ml and after 24 gm daily, 353 +/- 7 microgram/ml. After infusion the serum level declined monoexponentially in most subjects. On the 12-gm daily dosage mean values were 60 min for half-life (t1/2), 16 1 for volume of distribution, 188 ml/min for body clearance, and 139 ml/min for renal clearance. The same values on day 4 were 47 min, 12 1, 181 ml/min, and 125 ml/min; the volume of distribution was lower than on day 1. On the 24-gm daily dosage regimen, t1/2 was 60 min; volume of distribution, 16 1; body clearance, 183 ml/min; and renal clearance, 101 ml/min on day 1 compared to 68 min, 15 1, 148 ml/min, and 71 ml/min on day 4, the last 2 being significantly lower than on day 1. High renal clearance values were observed at low serum concentrations and vice versa, suggesting saturation of the tubular secretion process at high piperacillin concentrations in serum.

Pharmacokinetics of sulbenicillin, a new broad-spectrum semisynthetic penicillin.

In a pharmacolinetic study on a new semisynthetic penicillin, alpha-sulfobenzylpenicillin, sulbenicillin, serum level, serum half-life, apparent distribution volume, renal clearance, urinary excretion, and metabolism were determined after a 4-gm intravenous dose and compared to that of carbenicillin in 5 patients with normal renal function. In the case of sulbenicillin, the mean serum concentration at 1 hr was 157 plus or minus 25 mug/ml, the mean serum half-life was 70 plus or minus 10 min, the renal clearance was 95 plus or minus 25 ml/min, and the total urinary recovery after 24 hr was about 80% of the dose. The only metabolite detected in the urine was the penicilloic acid derivative, in an amount usually less than 5% of the dose. Serum values, serum half-live, renal clearances, and excretion pattern did not differ significantly from that of carbenicillin. In 8 patients with decreased renal function (creatinine clearance less than 50 ml/min) there was an inverse correlation between creatinine clearance and serum half-life.

Significance of antimicrobial synergism for the outcome of gram negative sepsis.

Amikacin plus penicillin (A+P) was compared to amikacin plus carbenicillin (A+C) in a double-blind study. Therapy with one of these combinations was given, as soon as servere infection was suspected, to 117 patients with proved gram negative infection, none of whom was granulocytopenic. Gram negative bacteremia was documented retrospectively in 52 patients; 25 had received A+P and 27 had been treated with A+C. All the isolated gram negative pathogens were sensitive to amikacin (MIC less than 12 microng/ml). In the A+P group, 55 per cent of the patients responded favorably while in the A+C group 63 per cent did respond; the difference was more striking for bacteremic patients: 52 per cent responded in the A+P group and 70 per cent in the A+C group. This difference, however, was not statistically significant. The outcome of patients whose infection was treated by synergistic combinations against the offending pathogen was better (66 per cent) than that observed in patients who received nonsynergistic combinations (48 per cent) (p less than 0.05). Once again the results were more striking in the bacteremic patients (p less than 0.01). A favorable outcome was associated also with a high (larger than or equal to 1/8) bactericidal activity of the diluted serum of the treated patient against the offending pathogen (p less than 0.05). This study suggests that the optimal therapy in gram negative septicemia might be the administration of synergistic combinations of antibiotics.

Development and validation of an LC method for the quantitation of carbenicillin in human serum.

An LC method for the quantitation of carbenicillin in human serum has been developed and validated. After protein precipitation with acetonitrile and evaporation, the residue was taken up by citric acid at pH 1.9. Carbenicillin and the internal standard (I.S.), piperacillin, were extracted with ethyl acetate, evaporated to dryness and reconstituted with a buffer solution. The separation of carbenicillin,, the I.S., and matrix peaks was achieved on a Microsorb C18, 3 microns column with a mobile phase of acetonitrile-tetrabutylammonium-phosphate buffer (pH* 6.6). The detection was by UV at 208 nm. The run time was 8 min. The established linearity range was 0.25-20 microgram ml-1 (r2 > 0.99) with a limit of quantitation of 0.25 microgram ml-1. Interday precision (RSD) and bias over the entire range were 1.1-6.9% and -1.83 to +2.80%, respectively. The interday precision (RSD) and bias for the QC samples at 0.75, 3.0 and 12 micrograms ml-1 were 5.9-7.9% and -2.80 to +2.30%, respectively. Stabilities of on-system, bench top, freeze-thaw cycles and sample storage were established.

Use of carbenicillin in two species of tortoise (Testudo graeca and T hermanni).

A preliminary investigation of the blood levels of carbenicillin, after the administration of a single intramuscular injection, suggests that the tortoise's bladder may act as a reservoir of antibiotic that is available for resorption. This phenomenon could confound the establishment of a safe, effective dose regime for antibiotics, in tortoises, which are excreted in an unchanged active form in urine.

Chronic polymicrobial bacteremia.

A 13-year-old girl had chronic polymicrobial bacteremia with Enterobacter hafnia and Enterobacter agglomerans in the absence of any demonstrable underlying illness, use of immunosuppressive drugs, or discovery of portal of entry of the bacteria. She was treated successfully with a prolonged course of carbenicillin and aminoglycoside antibiotics which were tolerated well. The only side effect of the therapy was a transient episode of vestibular dysfunction which was reversible following cessation of gentamicin. The principles of management of polymicrobial bacteremia are presented.

[Antibiotic therapy and renal insufficiency. Pharmacokinetics of pivampicillin, cephaloridin and streptomycin in chronic uremic patients undergoing conservative or hemodialytic treatment]. / Terapia antibiotica ed insufficienza renale. Rilievi intorno alla farmacocinetica di alcuni antibiotici (pivampicillina, cefaloridina, streptomicina) in pazienti con uremia cronica in terapia conservativa od emodialitica

The plasma kinetics of some antibiotics (pivampicillin, cephaloridine, streptomycin) has been studied in patients with chronic renal failure. The oral administration of pivampicllin promptly increases the plasma levels of the antibiotic, without any toxic side effect: this antibiotic is to be chosen in chronic uremic patients, also during regular dialytic treatment (R.D.T.). Cephaloridine has some renal toxic effects in high concentration; in the renal failure it is advisable to calculate the exact dose of the antibiotic by the use of nomograms when the creatinine clearance is known. These nomograms must absolutely be employed when administrating some toxic antibiotics, as gentamycin and streptomycin in chronic uremic patients. Some formulas have been experimentally determined, which allow a calculation of the exact dose of the antibiotic, also during R.D.T. If a kidney or urinary tract infection is present in patients with low G.F.R. (creatinine-clearance less than 30 ml/min.), it is necessary to administer only those antibiotics which can reach an active urinary concentration (i.e. penicillin and derivatives, cephaloridine).

Pharmacokinetics of intramuscular carbenicillin.

A 500 mg intramuscular dose of carbenicillin produced peak levels averaging 147 microgram/ml after three hours in the first day full-term newborn infants, and 172 microgram/ml after one to two hours in infants five days of age. The fall of blood levels thereafter was delayed and serum half-life averaged 4.2 and 2.2 hours in both groups, almost four times and twice as long, respectively, as that reported in adults. Absorption from the injected site was also delayed in young newborns, as was shown by the delayed serum peak and small estimated absorption rate constant. This must be taken into consideration if the intramuscular route is chosen in young newborn infants. On the basis of serum half-life, an administration interval of 12 hours was recommended for newborns younger than four days, and eight hours for those five days of age or more.