Is there any interaction between gentamicin (Garamycin) and ampicillin?/nThis is a general question

Fråga: Is there any interaction between gentamicin (Garamycin) and ampicillin?

This is a general question.

Sammanfattning: Ampicillin may inactivate gentamicin, and they should not be given in the same infusion. This inactivation may also occur in patients with end-stage renal disease but in patients with normal renal function no significant interaction occurs.

Svar: Penicillins are often given in combination with aminoglycosides for treatment of various infections (1).

Penicillins, for example ampicillin, may inactivate aminoglycosides in vitro by complex formation. The sugar in the amine group in aminoglycosides binds to the betalactam ring in penicillin and forms an inactive complex (2, 3). Tobramycin and gentamicin appears to be the aminoglycosides most prone to be inactivated by penicillins. Netilmicin is less sensitive and amikacin seems to be the least sensitive aminoglycoside (4, 5). Carbenicillin and ticaricillin are the penicillins that are most studied in this regard. The interaction has, in vitro, also been reported to occur with ampicillin, mecillinam, azlocillin, mezocillin, penicillin G and piperacillin. The interaction is temperature-, time-, concentration- and medium dependent. The interaction seems to appear when the penicillin/aminoglycoside concentration ratio is 20:1 or more (5).

No reports of an interaction between gentamicin and ampicillin in patients have been found. In patients with normal renal function, no effect of ampicillin on the Cmax of gentamicin could be seen (6). One in vitro study found ampicillin to deactivate gentamicin to a higher extent than carbecillin when mixed in intravenous infusion fluids. If ampicillin and gentamicin should be mixed in an infusion, the dose the patient would receive would be one quarter of the original dose. If carbenicillin and gentamicin were mixed the same way the patient would receive approximately half of the intended gentamicin dose. Carbenicillin at therapeutic concentration decreased the concentration of gentamicin in serum more than ampicillin at therapeutic concentration (7).

This interaction occurs to a clinically significant degree when aminoglycosides and, at least some, penicillins are given as a mixed infusion. In one patient no gentamicin concentration could be detected in blood after doses of up to 31 mg/kg had been administered. The patient received carbenicillin in the same infusion. The carbenicillin concentration measured was much lower than expected (8).

A clinically significant interaction between carbencillin/ticaricillin/piperacillin and tobramycin/gentamicin has in several case reports and in prospective studies been described in patients with end stage renal disease. In these cases the drugs have been given separately (9,10,11,12,13,14,15).

The reason why this interaction is only seen in patients with end-stage renal disease is because they will have higher plasma concentrations of the drugs during a longer time. The rate of elimination of both penicillins and aminoglycosides is much higher than the rate of inactivation in subjects with normal renal function and the effect of inactivation is negligible (6).

One possible bias in these studies is that the inactivation of aminoglycosides may continue in test tubes and a lower concentration than the actual concentration in patients may be observed (16).

Subtheraputhic concentrations of gentamicin have been reported in several cases. One hemodialysis patient with end-stage renal disease received gentamicin in doses up to 1.8 mg/kg without reaching a peak concentration above 2 ug/ml during concomitant treatment with carbenicillin 15 g/d. When carbenicillin was withdrawn, the peak concentration of gentamicin reached 7-8 ug/ml when 0.9 mg/kg was administered (9). In one, carbenicillin treated patient with end-stage renal disease the plasma concentration of gentamicin was 1 ug/ml one hour after infusion of 80 mg gentamicin (10). In four other hemodialysis patients, concomitantly treated with carbenicillin, no gentamicin concentration above 2 ug/ml could be detected 3-24 hour after gentamicin administration (0.6-2.1 ug/kg/d). One of the patients became temporarily deaf even tough his gentamicin concentration was below 2 ug/ml. The concentration ratio between carbenicillin/gentamicin varied between 125:1 and 360:1.The gentamicin concentration rose to 2.5-7.6 ug/ml after withdrawal of carbenicillin (11). In three other studies including totally twenty patients with end-stage renal disease, no markedly decrease in peak concentration has been observed but a significant decrease in half-life by 52-70% has been observed (12,13,14). Similar results have been described for the combination of tobramycin with carbenicillin and piperacillin (11,15).

Concomitant treatment with carbenicillin and amikacin did not cause any significant change in the half-life of amikacin (12). Netilmicin and ticaricillin have also been reported to not interact in patients with end-stage renal disease (17).

Ampicillin and gentamicin can be given together in patients with normal to moderately decreased renal function. The combination should not be given in the same infusion. If the combination is given to patients with end-stage renal disease the peak and trough concentration of gentamicin should be closely monitored. Use of amikacin instead of gentamicin may be considered. Brunton LL, Lazo JS, Parker KL, editors. Goodman & Gilman´s The pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill; 2006 Jorgensen JH, Crawford SA. Selective inactivation of aminoglyosices by newer beta-lactam antibiotics. Curr Ther Res Clin Exp 1982;32(1):25-35. Perenyi T, Graber H, Arr M. Reciprocal effects of penicillins and aminoglycoside antibiotics. Int J Clin Pharmacol 1974;10(1):50-5. Pickering LK, Gearhart P. Effect of time and concentration upon interaction between gentamicin, tobramycin, Netilmicin, or amikacin and carbenicillin or ticarcillin. Antimicrob Agents Chemother 1979;15(4):592-596 Farchione LA. Inactivation of aminoglycosides by penicillins. J Antimicrob Chemother 1981;8 Suppl A:27-36 Riff LJ, Jackson GG. Laboratory and clinical conditions for gentamicin inactivation by carbenicillin. Arch Intern Med 1972;130(6):887-891 Noone P, Pattison JR. Therapeutic implications of interaction of gentamicin and penicillins. Lancet 1971;2(7724):575-578 McLaughlin JE, Reeves DS. Clinical and laboratory evidence for inactivation of gentamicin by carbenicillin. Lancet 1971;1(7693):261-264 Weibert RT, Keane WF. Carbenicillin-gentamicin interaction in acute renal failure. Am J Hosp Pharm 1977;34(10):1137-1139 Eykyn S, Phillips I, Ridley M. Gentamicin plus carbenicillin. Lancet 1971;1(7698):545-546 Weibert R, Keane W, Shapiro F. Carbenicillin inactivation of aminoglycosides in patients with severe renal failure. Trans Am Soc Artif Intern Organs 1976;22:439-443. Blair DC, Duggan DO, Schroeder ET. Inactivation of amikacin and gentamicin by carbenicillin in patients with end-stage renal failure. Antimicrob Agents Chemother 1982;22(3):376-379 Ervin FR, Bullock WE, Jr., Nuttall CE. Inactivation of gentamicin by penicillins in patients with renal failure. Antimicrob Agents Chemother 1976;9(6):1004-1011 Thompson MI, Russo ME, Saxon BJ, tkin-Thor E, Matsen JM. Gentamicin inactivation by piperacillin or carbenicillin in patients with end-stage renal disease. Antimicrob Agents Chemother 1982;21(2):268-273 Uber WE, Brundage RC, White RL, Brundage DM, Bromley HR. In vivo inactivation of tobramycin by piperacillin. DICP 1991;25(4):357-359 Russo ME. Penicillin-aminoglycoside inactivation: another possible mechanism of interaction. Am J Hosp Pharm 1980;37(5):702-704 Matzke GR. Netilmicin disposition is not altered by concommitant piperacillin administration. Clin Pharmacol Ther 1985;??:210 (abstract II-D)