Stability of gentamicin, tobramycin, and amikacin in combination with four beta-lactam antibiotics

Glew, Richard H.; Pavuk, Rosemary A.

doi:10.1128/aac.24.4.474

Cited by 21 publications

(15 citation statements)

References 16 publications

(24 reference statements)

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“…The relative ability of particular beta-lactam compounds to inactivate aminoglycosides found in our study agrees with previous reports describing piperacillin, carbenicillin, azlocillin, and ticarcillin as having greater inactivating activity on aminoglycosides than the other beta-lactam agents tested (1,6,7,15). A direct comparison of an order of inactivating capacity of beta-lactam agents between our study and previous ones is difficult because of the different test conditions used, such as different concentrations and types of aminoglycosides (15), incubation times, temperature, media (6), and assays (6,15).…”

Section: Discussionsupporting

confidence: 82%

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Comparative inactivation of isepamicin, amikacin, and gentamicin by nine beta-lactams and two beta-lactamase inhibitors, cilastatin and heparin

Walterspiel¹,

Feldman²,

Van³

et al. 1991

Antimicrob Agents Chemother

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This study was undertaken to compare the susceptibility to inactivation of isepamicin with amikacin and gentamicin when. exposed to different beta-lactams, ,I-lactamase inhibitors, and heparin. The aminoglycosides (5; 10, 20, and 50 ,g/ml) were incubated in human serum with ampicillin, azlocillin, aztreonam, carbenicillin, ceftazidime, piperacillin, and ticarcillin (100 and 600 ,ug/ml) and with clavulanate, cilastatin, 1:1 imipenemcilastatin? oxacilin, and sulbactam (20 and 120 ,ug/ml) for 48 h at 37°C. Aminoglycoside concentrations were measured by fluorescence polarization immunoassay (FPI) after 0, 8, and 48 h of incubation and by radial difibsion bipassay after 48 h of incubation. Each of the three aminoglycosides was also added to whole blood tontaihing either hebarin (100 U/ml) or 0.5% EDTA as a control and assayed after 6 h by FPI. The degree of inactivation of isepamicin by the beta-lactams was significantly less than that by amikacin (P < 0.003) and gentamAicih,(P < O.0.X2) when determined by bioassay. Piperacillin, carbenicillin, and azlocillin produced the greatest amount of inactivation, and cilastatin and oxacillin produced the least. A similar pattern was observed when the degree of inactivation ywvs measured by FPI. A significant difference in the degree of inactivation was noted between isepanticin and gentamicin (P < 0.003 at 8 h and P < 0.006 at 48 h) but not between isepamicin and amikacin (P> Q.7 at 8h and P > 0.08 at 48 h). Aminoglycoside determinations by FPI were not influenced by the,pirestnce of heparin. In summary, isepamicin was found to be at least as stable as amikacin against inactivration by beta-lactam compounds and Il-lactamase inhibitors. Heparin (100 U/ml) did not influence aminoglycoside determinations by FPL Aminoglycoside antibiotics interact with beta-lactam compounds and heparinr (11,12,14). The mechanism for the interaction with beta-lactams is thought to consist of a nuc1 ophilic opening of the beta-lactam ring by an amino group, leading to formation of. an amide, with loss of biological activity of both (2). Heparin in contrast binds by ionic ijiteraction only, a process that is reversible by dilution (12). The concentrations of heparin that are used therapeutically are too low for this to occur in vivo, but sufficient concentrations can be reached in blood collection tubes (12).The inactivation of aminoglycosides by beta-lactam antibiotics is clinically relevant for patients with renal failure, in whom beta-lactams can accumulate to high concentrations and inactivate an aminoglycoside given concomitantly (4,11,16). Loss of the aminoglycoside due to in vitro inactivation can also occur when specimens containing both compounds are processed after delay (14). Tissue culture media frequently contain both types of antibiotics, and inactivation can limit the time for storage and exchange of media.Isepamicin is an aminoglycoside with increased stability against enzymatic degradation and low oto-and nephrotoxicity (9). Its sensitivity to inactivation by beta-lactam compounds ...

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Section: Discussionsupporting

confidence: 82%

“…Amikacin's stability against inactivation has been shown previously (5,6,8,13,15). We further demonstrated that heparin at a concentration as high as 100 U/ml did not interfere with the determination of isepamicin levels by automated FPI immunoassay when compared with 0.5% EDTA as an anticoagulant control.…”

Section: Discussionmentioning

confidence: 99%

Comparative inactivation of isepamicin, amikacin, and gentamicin by nine beta-lactams and two beta-lactamase inhibitors, cilastatin and heparin

Walterspiel¹,

Feldman²,

Van³

et al. 1991

Antimicrob Agents Chemother

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“…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.…”

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confidence: 99%

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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“…This can be especially significant in patients with severe renal failure, since accumulation of APPs, as well as AMGs, can occur in serum, resulting in significant inactivation of both agents (5,23). However, amikacin demonstrates the greatest stability in vitro when combined with various concentrations of beta-lactams (12), as well as resistance to inactivation in vivo (5). In addition, piperacillin has been shown to have an increased rate of nonrenal elimination in renal failure patients (27,28).…”

Section: Resultsmentioning

confidence: 99%

“…However, by assessing the data (5,12,23,28). This can be especially significant in patients with severe renal failure, since accumulation of APPs, as well as AMGs, can occur in serum, resulting in significant inactivation of both agents (5,23).…”

Section: Resultsmentioning

confidence: 99%

In vitro activity of piperacillin, ticarcillin, and mezlocillin alone and in combination with aminoglycosides against Pseudomonas aeruginosa

Lyon¹,

Smith²,

Saag³

et al. 1986

Antimicrob Agents Chemother

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A total of 103 isolates of Pseudomonas aeruginosa were studied to compare the in vitro effectiveness of three beta-lactam antibiotics (piperacillin, ticarciflin, and meziocillin) when used alone and in combination with four aminoglycosides (tobramycin, gentamicin, amikacin, and netilmicin). All drugs were tested as single agents against a standard inoculum (5 x 105 CFU/ml). The three antipseudomonal penicillins were also tested against the isolates at a higher inoculum concentration (107 CFU/ml). Synergy testing was performed by the two-dimensional checkerboard method and was defined by (i) a fractional bactericidal index of -0.5 and (ii) bacterial killing accomplished at antibiotic concentrations no greater than those achievable in serum. All combinations were assessed for synergy. The degree of synergy was further'analyzed by dividing the isolates into groups based on their susceptibility and resistance to the individual agents in the combination. The overall effectiveness of the various aminoglycoside-antipseudomonal penicillin combinations was assessed regarding their ability to kill the isolates either as single agents or through synergy. Piperacillin was the most active antipseudomonal penicillin, and tobramycin and amikacin were the most active aminoglycosides when used as single agents. When tested against isolates at a higher inoculum concentration, ticarcillin was significantly more active than the other beta-lactams. The highest degree of overall synergy was noted with gentamicin-ticarcillin (78.2% of strains) and amikacin-piperacillin (77% of strains). When assessed for overall effectiveness, all combinations containing amikacin were the most active. The combination of amikacin-piperacillin was the most effective, with activity against 96% of all isolates.The newer semisynthetic penicillins have been shown by previous investigators to demonstrate increased antibacterial activity against a wide range of organisms (3,17,26,29), including strains of members of the family Enterobacteriaceae and Pseudomonas aeruginosa that are multiply resistant to other antimicrobial agents (3, 10). Moreover, these antimicrobial agents have been found to be especially useful when combined with an aminoglycoside (AMG) in the treatmnent of severe infections with gram-negative bacilli (1, 2), perhaps reflecting their in vitro synergistic activity (10,11,13,15,16,19,24).The purpose of this study was to compare the in vitro synergistic activity of the four most commonly used AMGs with that of three of the newer semisynthetic antipseudomonal penicillins (APP) against 103 hospital strains of P. aeruginosa. Only results demonstrating synergy at clinically attainable concentrations in serum of both antimicrobial agents were considered to be synergistic. In addition, we examined each drug combination for overall effectiveness in vitro. Analyses of these results took into consideration synergistic responses as well as single-drug activities.MATERIALS AND METHODS Organisms. Altogether, 103 P. aeruginosa strains were obtained from th...

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Stability of gentamicin, tobramycin, and amikacin in combination with four beta-lactam antibiotics

Cited by 21 publications

References 16 publications

Comparative inactivation of isepamicin, amikacin, and gentamicin by nine beta-lactams and two beta-lactamase inhibitors, cilastatin and heparin

Comparative inactivation of isepamicin, amikacin, and gentamicin by nine beta-lactams and two beta-lactamase inhibitors, cilastatin and heparin

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

In vitro activity of piperacillin, ticarcillin, and mezlocillin alone and in combination with aminoglycosides against Pseudomonas aeruginosa

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