Laboratory and Clinical Conditions for Gentamicin Inactivation by Carbenicillin

Riff, Louise J.

doi:10.1001/archinte.1972.03650060077013

Cited by 79 publications

(65 citation statements)

References 18 publications

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“…Pharmacokinetic interactions between j-lactam and aminoglycoside antibiotics have been studied extensively (2,3,10,11,25). Concurrent administration of a penicillin and an aminoglycoside significantly shortens the t1,2 of the latter group of antibiotics (11,19,25), particularly in patients with renal impairment.…”

Section: Resultsmentioning

confidence: 99%

“…Concurrent administration of a penicillin and an aminoglycoside significantly shortens the t1,2 of the latter group of antibiotics (11,19,25), particularly in patients with renal impairment. Recently, pharmacokinetic interactions between a cephalosporin (ceftazidime) and tobramycin have been reported in a study in normal volunteers (3).…”

Section: Resultsmentioning

confidence: 99%

“…Chemical inactivation of 1-lactam and aminoglycoside antibiotics occurs in vitro (18). Phamacokinetic interactions between these two classes of antibiotics have been reported in patients with normal and impaired renal functions (3,10,11,14,19,25). Since cefepime, as a 3-lactam, could be used in such a combination therapy, it was deemed * Corresponding author.…”

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Lack of pharmacokinetic interaction between cefepime and amikacin in humans

Barbhaiya

Knupp

Pfeffer

et al. 1992

Antimicrob Agents Chemother

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The interaction potential between cefepime and amikacin was investigated in a steady-state pharmacokinetic study in 16 healthy male subjects. Eight subjects (group A) received a first course of 2,000 mg of cefepime; this was followed by a second course of 2,000 mg of cefepime with 300 mg of amikacin and a third course of 2,000 mg of cefepime. Eight other subjects (group B) received a first course of 300 mg of amikacin, a second course of 300 mg of amikacin with 2,000 mg of cefepime, and a third course of 300 mg of amikacin. Each course consisted of four consecutive doses administered every 8 h as 30-min intravenous infusions. Serial plasma and urine samples, which were collected after administration of the fourth dose of each course, were assayed for cefepime and/or amikacin by validated high-performance liquid chromatographic assays. Trough levels of cefepime and amikacin indicated that these antibiotics attained a steady state prior to administration of the fourth dose of each course. Key pharmacokinetic parameters for each antibiotic were determined by noncompartmental methods. The peak concentrations of cefepime and amikacin in plasma when the drugs were given alone were about 160 and 27 ,g/ml, respectively. Levels of each antibiotic in plasma declined, with an apparent half-life of approximately 2.2 h. Urinary recovery of cefepime and amikacin accounted for more than 85% of the administered dose of each antibiotic. Mean renal clearances for cefepime and amikacin ranged from 79 to 95 ml/min and suggested that glomerular filtration is the primary excretion mechanism. The results of the statistical analyses indicated that the pharmacokinetic parameters of cefepime following the concurrent administration of amikacin and following the discontinuation of the amikacin therapy were not significantly altered. Similarly, the pharmacokinetic parameters of amikacin following the concurrent administration of cefepime and following the discontinuation of the cefepime therapy were not significantly altered. Cefepime and amikacin can be coadministered to patients with normal renal function by using the standard recommended dosing regimens.Cefepime (BMY-28142) is a new parenteral cephalosporin with significant potential advantages over other new cephalosporins and nontraditional ,3-lactam antibiotics with respect to its antimicrobial spectrum of activity (12,15). In addition, cefepime appears to have a low affinity for chromosomally derived P-lactamases (23). Clinical experience indicates that cefepime is safe and well tolerated when single or multiple (every 8 or 12 h) doses of 250 to 2,000 mg are given by the intravenous (4, 5) or intramuscular (9) routes of administration. The pharmacokinetics of this cephalosporin are linear (4, 5, 9). Over 80% of the administered dose of cefepime is recovered in urine in an unchanged form (4, 5, 7-9).In the most severely infected patients, empiric therapy consists of the administration of antibacterial therapy before pathogen identification. The standard approach has been to use an ant...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Lack of pharmacokinetic interaction between cefepime and amikacin in humans

Barbhaiya

Knupp

Pfeffer

et al. 1992

Antimicrob Agents Chemother

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“…The last of these factors is particularly important when broad-spectrum penicillins are combined with aminoglycosides. In this situation, significant inactivation can occur in vitro (147,177) as well as in vivo (41,151).…”

Section: Checkerboard Titrationsmentioning

confidence: 99%

Antibiotic combinations: should they be tested?

1988

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When antibiotic combinations are used to provide a broader spectrum of antimicrobial activity or in an attempt to prevent the emergence of resistant organisms, it is rarely necessary or practical to perform tests of drug interactions in vitro. In vitro testing of combinations may be useful when combinations are used in an attempt to attain synergistic interactions. In some cases, screening methods can be used as substitutes for formal synergy testing. This paper examines the mechanisms of antibiotic interaction leading to synergism or antagonism, surveys attempts to correlate in vitro observations with efficacy in animal models, and reviews clinical data providing evidence for or against a useful role of synergistic antibiotic interactions in the treatment of human infections.

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“…5,6 The rate of aminoglycoside inactivation is dependent on temperature, time, concentration of the b-lactam and composition of the medium. [7][8][9] Another important factor to consider is the pH of the solution. As the degree of protonation of an amino group increases, it should become less nucleophilic.…”

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Structural characterization of the tobramycin–piperacillin reaction product formed at pH 6.0

Pagano¹,

Gong²,

Kong

et al. 2011

J Antibiot

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Tobramycin is an aminoglycoside antibiotic that loses a significant amount of activity in the presence of Zosyn at pH 6. As part of our investigation into ways to improve the compatibility of tobramycin with Zosyn (which contains piperacillin and tazobactam in an 8:1 ratio buffered at pH 6 by sodium citrate) by lowering the pH, we identified the reaction product of tobramycin and piperacillin at pH 6.0 and the order of the pK a values of tobramycin. The structure of the main reaction product of tobramycin and piperacillin at pH 6.0 was determined by 2D NMR to be the product of 3 00 -NH 2 reacting with the b-lactam of piperacillin. The order of the pK a values of the nitrogens of tobramycin was determined by 1 H and 15 N NMR titrations to be 6¢-NH 2 42¢-NH 2 41-NH 2 E3 00 -NH 2 43-NH 2 . At pH 4.0, the reaction between tobramycin and Zosyn was almost negligible for a period of up to 2 h. The pH can be lowered by adding an acid such as HCl or citric acid to Zosyn to make a pH 4.0 buffer. The Journal of Antibiotics (2011) 64, 673-677; doi:10.1038/ja.2011.72; published online 3 August 2011Keywords: piperacillin; protonation constants; structure elucidation; tobramycin; Y-site co-administration; Zosyn INTRODUCTION Tobramycin (Figure 1) is an aminoglycoside antibiotic produced by Streptomyces tenebrarius 1 used to treat infections caused by susceptible Gram-negative microorganisms. 2 It is often used in combination with penicillins, such as piperacillin (Figure 2), to treat severe infections caused by Gram-negative bacteria. 3 It is well known that tobramycin reacts with b-lactams, including piperacillin, causing a significant loss of aminoglycoside activity. 4 The inactivation mechanism is thought to involve nucleophilic attack and ring opening of the penicillin b-lactam ring by an amino group of the aminoglycoside. 5,6 The rate of aminoglycoside inactivation is dependent on temperature, time, concentration of the b-lactam and composition of the medium. [7][8][9] Another important factor to consider is the pH of the solution. As the degree of protonation of an amino group increases, it should become less nucleophilic. The amino groups of tobramycin have different pK a values, 10,11 hence, it is logical to assume the reaction would be affected by pH of the solution. Therefore, knowledge of the protonation constants of the amino groups and their order is important in understanding the reactivity of tobramycin with piperacillin at different pHs.Zosyn is an intravenously administered antibiotic, which contains piperacillin and tazobactam (a b-lactamase inhibitor) in an 8:1 ratio. It also contains EDTA and sodium citrate, which is used to buffer the solution at around pH 6. 12 It has been approved for Y-site coadministration with the aminoglycosides amikacin and gentamicin. 13 It has not been approved for co-administration with tobramycin,

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Laboratory and Clinical Conditions for Gentamicin Inactivation by Carbenicillin

Cited by 79 publications

References 18 publications

Lack of pharmacokinetic interaction between cefepime and amikacin in humans

Lack of pharmacokinetic interaction between cefepime and amikacin in humans

Antibiotic combinations: should they be tested?

Structural characterization of the tobramycin–piperacillin reaction product formed at pH 6.0

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