Animal model distinguishing in vitro from in vivo carbenicillin-aminoglycoside interactions

Possible antibiotic inactivation was studied in 12 subjects with end-stage renal disease who were undergoing thrice-weekly hemodialysis. The study was a randomized three-way crossover. Subjects received (i) gentamicin as a single intravenous dose of 2 mg/kg, (ii) 4 g of piperacillin intravenously every 12 h for four doses or 2 g of carbenicillin intravenously every 8 h for six doses, and (iii) gentamicin as described in (i) plus piperacillin or carbenicillin as described in (ii). Subjects were studied on their off-dialysis days, and each treatment phase was separated by a 3-week wash-out period. Gentamicin was inactivated to a greater extent by carbenicillin than by piperacillin (P < 0.05). In the six subjects in the carbenicillin group, the terminal elimination-phase half-life (t1/2p) of gentamicin was 61.6 h when gentamicin was administered alone, and it was 19.4 h when gentamicin was administered with carbenicillin. In six subjects in the piperacillin group, the mean t1/2p of gentamicin when gentamicin was given alone was 53.9 h, and it was 37.7 h when gentamicin was given with piperacillin. The inactivation rate constant (k,) of gentamicin was 0.0251/h for the carbenicillin group and 0.0064/h for the piperacillin group, demonstrating that carbenicillin inactivated gentamicin four times faster than did piperacillin. No inactivation of either ,3-lactam could be measured. Control samples verified that no in vitro inactivation occurred.

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confidence: 99%

Gentamicin inactivation by piperacillin or carbenicillin in patients with end-stage renal disease

Thompson¹,

Russo²,

Saxon³

et al. 1982

“…In the face of such limited published data, we undertook this clinical evaluation of the action of piperacillin on tobramycin, which appears to be the aminoglycoside most susceptible to inactivation (7). Tobramycin concentrations were determined by radioimmunoassay, which minimizes potential aminoglycoside inactivation during analysis (16). Our aim was to determine the clinical significance of this interaction and whether tobramycin dosing adjustments would be warranted in patients with normal renal function who are also receiving piperacillin.…”

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confidence: 99%

Effect of piperacillin on tobramycin pharmacokinetics in patients with normal renal function

Lau

Lee

Flascha

et al. 1983

Aminoglycosides are inactivated by extended-spectrum penicillins in vitro and in patients with end-stage renal failure. In this prospective controlled study, we determined the effect of piperacillin on tobramycin pharmacokinetics. In 10 clinically stable male patients with calculated creatinine clearances of greater than or equal to 60 ml/min, serial levels in serum of tobramycin alone and after single 4-g intravenous doses of piperacillin were determined. No statistically significant changes in the concentration of drug in serum, the half-life (t1/2), the elimination rate constant (Ke), the volume of distribution (Vd), or the area under the serum concentration-time curve (AUC0-oo) occurred when tobramycin was used concurrently with piperacillin. Therefore, this antibiotic combination will not result in a clinically significant interaction in patients with normal renal function.

“…Of particular interest has been aminoglycoside inactivation by the newer broad-spectrum penicillin derivatives, such as carbenicillin, azlocillin, ticarcillin, etc. (9)(10)(11)(12)(13)(14)(15).…”

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confidence: 99%

“…The in vivo inactivation of aminoglycosides by betalactam antimicrobial agents may be of clinical significance only in patients with severe renal failure (3,12,14,15). However, the nature of the antagonistic relationship between these compounds dictates caution in the procedures used to administer such antibiotic combinations and in the protocol required for handling serum specimens submitted to, and processed by, the laboratory (9, 13).…”

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confidence: 99%

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In vitro inactivation of aminoglycosides by apalcillin

Wright¹,

Hale²,

Saxon³

et al. 1986

Apalcillin, at concentrations of 75, 150, 300, and 600 ,ug/ml, was combined in vitro with amikacin, gentamicin, netilmicin, or tobramycin. Incubation at 37C resulted in an apalcillin concentration-dependent and time-dependent decrease of aminoglycoside activity of up to 60%. Amikacin was the most stable and tobramycin was the least stable aminoglycoside under the conditions tested.The in vitro inactivation of aminoglycoside antibiotics by beta-lactam antibiotics has often been reported (2-4, 9-15). The extent of such inactivation has been shown to vary as a function of various experimental parameters, such as time, temperature, solvent, method of assay, and antibiotic concentration (2,4,9,11,14). Of particular interest has been aminoglycoside inactivation by the newer broad-spectrum penicillin derivatives, such as carbenicillin, azlocillin, ticarcillin, etc. (9-15).Apalcillin is a relatively new semi-synthetic penicillin with activity against a broad spectrum of gram-negative bacteria (1,7,8). This naphthyridine derivative of ampicillin has particularly good activity against Pseudomonas aeruginosa (5) and will likely be used in combination with other broadspectrum antimicrobial agents, such as the aminoglycosides, in therapy against gram-negative infections. In view of the prospective combination of apalcillin use and the inactivation of aminoglycoside antibiotics by other beta-lactam antibiotics, we determined to measure the in vitro effect of apalcillin on aminoglycoside activity when these compounds are mixed together.The stability of the aminoglycosides amikacin (Bristol Laboratories, Syracuse, N.Y.), gentamicin and netilmicin (Schering Corp., Bloomfield, N.J.), and tobramycin (Eli Lilly & Co. Indianapolis, Ind.) was evaluated when they were mixed in combination with apalcillin (Wyeth Laboratories, Philadelphia, Pa). Each antibiotic solution was prepared from a standard reference powder and diluted in pooled, drug-free human serum. The final apalcillin concentrations in the reaction mixture were 0, 75, 150, 300, and 600 ,ug/ml. The concentration of gentamicin, netilmicin, and tobramycin used in combination with each apalcillin concentration was 10 ,ug/ml, and amikacin was prepared at 20 ,ug/ml.The antibiotic pairs were combined, mixed, and then placed at 37°C in a water bath shaker. Duplicate samples for assay were removed from each mixture at 0, 8, 24, and 36 h after mixing. These samples were immediately frozen. The aminoglycoside concentration in each sample was determined by thawing the samples and immediately measuring the aminoglycoside by fluorescence polarization immunoassay (TDX; Abbott Laboratories) according to the specifications of the manufacturer (6). Possible changes in apalcillin concentration during antibiotic interaction were not determined. Assays were done in duplicate on each sample. The data, analyzed by using a two-way analysis of variance, were * Corresponding author. significant to greater than the 95% confidence level, both as a function of time and of apalcillin concentration. Tabl...