Changing Strategies in Aminoglycoside Dosing; the Result of Research on Antimicrobial Pharmacodynamics

Zbl. Bakt. 279, 447-449 (1993) © Gustav Fischer Verlag, Stuttgart· Jena . New York

Changing Strategies in Aminoglycoside Dosing; the Result of Research on Antimicrobial Pharmacodynamics GEORGE G. ZHANEL

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Faculty of Pharmacy and Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

Aminoglycosides continue to be used for the treatment of serious infections, despite the well documented nephrotoxicity and ototoxicity and the development of new and potent antimicrobial classes (fluoroquinolones, monobactams and carbapenems). The reasons for their continued use include the fact that they rapidly and extensively eliminate a broad range of gram-negative and gram-positive pathogens, the limited resistance that emerges during treatment, and the lack of an inoculum effect (5). Due to their continued use, investigators have focused on ways to minimize nephrotoxicity, such as the use of poly-L-aspartic acid. Agents such as poly-L-aspartic acid block the cascade of events leading to aminoglycoside nephrotoxicity (3). However, even though early results have been promising, the clinical use of these agents is at best, several years away. Thus, several groups including ours have focused on the pharmacodynamic properties of aminoglycosides in an effort to enhance clinical efficacy, while decreasing toxicity. Unlike the beta-Iactams, aminoglycosides display very rapid bactericidal activity and concentration-dependent antimicrobial activity over a wide range of concentrations (9). The greater the aminoglycoside concentration to MIC ratio, the greater the rate and extent of bacterial killing. In addition to concentration-dependent antimicrobial activity, factors such as the postantibiotic effect (PAE) should be considered. The PAE (persistent suppression of bacterial growth after antimicrobial exposure) is an important parameter in the design of antimicrobial dosage regimens (1). Aminoglycosides against gram-negative bacilli, demonstrate long (> 3 hours) PAE's (1, 7). In addition, aminoglycosides demonstrate concentration-dependent PAE's which are even further prolonged by biological fluids such as human serum or human cerebrospinal fluid (10, 6). In addition to concentration-dependent bactericidal activity and prolonged and concentration-dependent PAE, aminoglycosides display activity at concentrations below their MIC (8). Subinhibitory concentrations of aminoglycosides influence bacterial virulence by altering adherence to epithelial cells, affecting susceptibility to host defense mechanisms and by producing changes in toxin or enzyme production. Finally, it has been shown that after exposure to aminoglycosides (low or high concentrations), bacteria develop a period of "adaptive resistance". During the adaptive resistance period, bacteria down-regulate an energy-dependent transport mechanism responsible

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for conveying aminoglycosides into the bacterial cell (2). Thus it may be best to expose bacteria with a large initial concentration in order to maximize killing and then allow a long period of time for the adaptive resistance period to wear off. The sum of these effects suggested to investigators that aminoglycosides should be administered as a single daily dose (SDD). If these agents were given in considerably higher doses (on a mg/kg basis), a higher peak serum concentrationiMIC ratio would be obtained. This higher ratio would result in greater bacterial killing. In addition, the prolonged PAE and activity at subinhibitory concentrations would allow aminoglycoside concentrations to fall below the MIC for several hours while maintaining residual antimicrobial activity. Also the long period between repeated dosing would allow the adaptive resistance period to wear off such that the organisms would again be very susceptible to aminoglycosides upon re-exposure. Although SDD of aminoglycosides had sound scientific foundations, animal and human studies were required to confirm or reject these findings in vivo. Numerous animal studies have assessed the efficacy and toxicity of SDD of aminoglycosides versus more frequent dosing (6). Several animal model systems have been investigated including E. coli pyelonephritis in rats, P. aeruginosa acute pneumonia in neutropenic and non-neutropenic guinea pigs, P. aeruginosa chronic pneumonia in rats, P. aeruginosa endocarditis in rabbits, K. pneumoniae pneumonia in mice, P. aeruginosa subcutaneous abscess in rats and P. aeruginosa thigh infection in neutropenic mice. Aminoglycosides used included gentamicin, tobramycin and netilmicin. Dosage schedules have varied from once daily, twice daily, every four, six or eight hours to continuous infusion with treatment durations up to 20 days. Summary of these animal data suggests that although the majority of animal studies reported equal or greater efficacy with single daily versus more frequent dosing, results are inconsistent. Extrapolation of these data to humans is difficult since marked variability exists in terms of aminoglycoside pharmacokinetic disposition. The half life of aminoglycosides in animals is relatively short (guinea pigs and mice < 30 minutes: rats < 20 minutes) when compared to humans with normal renal function (2-3 hours). With regards to nephrotoxicity, animal studies suggest that multiple daily doses of animoglycosides result in more frl(quent or more severe nephrotoxicity than do less frequent or single daily doses of these agents. Human studies assessing the efficacy and toxicity of SDD of aminoglycosides date back to the mid-1970's (5, 4). These studies included various types of infections (urinary, intra-abdominal, bacteremias); have studied various aminoglycosides (gentamicin, netilmicin, amikacin and sisomicin) and compared SDD to twice-daily or thricedaily administration. A summary of these human data suggests that single daily dosing (SDD) aminoglycoside regimens are as effective as more frequent dosing regimens. In addition, the incidence of nephrotoxicity or ototoxicity is not increased and may in fact be reduced with SDD versus multiple daily dosing aminoglycoside regimens. Well, where do we go from here? Animal and human studies clearly show that SDD of aminoglycosides is as efficacious and no more toxic than traditional multiple dosing. However, we should realize that few studies have been performed dealing with infections at sites other than intra-abdominal and the urinary tract. In addition, these results should not be extrapolated to patients who are immunocompromised as the efficacy of single daily aminoglycoside dosing in this patient population has not been proven. Further studies need to be performed to answer the above questions. Also, the issue of single daily dosing in patients with renal dysfunction needs to be addressed. Finally,

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what do these new dosage guidelines do to our presently accepted peak and trough ranges? Clinical trials need to establish new peak and through guidelines. I anticipate that in the future, we will not administer aminoglycosides once daily in all patients, but we will use the rationale of single daily dosing in all patients. That is, attempts will be made to maximize the peak serum concentration/MIC ratio while altering the dosing interval. Variables such as half-life and volume of distribution will be used to adjust the dosing interval to a spectrum of dosing intervals from every 12 hours of every several days.

Acknowledgement. Dr. Zhanel is supported by the Medical Research Council to Canada (MRC). The author would like to thank Mrs. Macleod for expert secretarial assistance.

References

1. Craig, W. A. and S. Gudmundsson: Postantibiotic Effect. In: Antibiotics in Laboratory Medicine, 3rd edition, Lorian, V., Ed (1991), pp. 403--431. Williams and Wilkins, Baltimore, MD 2. Daikos, G. L., G. G. Jackson, U. T. Lolans, and D. M. Livermore: Adaptive resistance of aminoglycoside antibiotics with implications for dosing. ]. Infect. Dis. 162 (1990) 414--420 3. Gilbert, D. N., C. A. Wood, S. J. Kohlhepp, P. W. Kohnen, D. C. Houghton, H. C. Finkbeiner, J. Lindsay, and W. M. Benett: Polyaspartic acid prevents experimental aminoglycoside nephrotoxicity. ]. Infect. Dis. 159 (1989) 945-953 4. Tulkens, P. M.: Efficacy and safety of aminoglycosides once a day: Experimental and clinical data. Scand. J. Infect. Dis. 74 (1991) 249-257 5. Zhanel, G. G. and R. E. Ariano: Once-daily aminoglycoside dosing: Maintained efficacy with reduced nephrotoxicity. Ren. Fail. 14 (1992) 1-9 6. Zhanel, G. G. and W. A. Craig: Pharmacokinetic contributions to postantibiotic effects (PAE): Focus on aminoglycosides Clin. Pharmacokinet. 1993 (submitted) 7. Zhanel, G. G., D. J. Hoban, and G. K. M. Harding: The postantibiotic effect (PAE): A review of in-vitro and in-vivo data. Ann. Pharmacother. 25 (1991) 478--484 8. Zhanel, G. G., D. J. Hoban, and G. K. M. Harding: Subinhibitory antimicrobial concentrations: A review of in-vitro and in-vivo data. Can. J. Infect. Dis. 3 (1992) 193-201 9. Zhanel, G. G., J. A. Karlowsky, R. J. Davidson, and D. J. Hoban: Antimicrobial activity of subinhibitory concentrations of aminoglycosides against Pseudomonas aeruginosa as determined by the killing curve method and the postantibiotic effect (PAE). Int. J. Exp. Clin. Chemother. 37 (1991) 141-151 10. Zhanel, G. G., J. A. Karlowsky, R. J. Davidson, and D. J. Hoban: Effect of human cerebrospinal fluid (CSF) on the post antibiotic effect (PAE) of cefotaxime, ciprofloxacin and gentamicin against Escherichia coli. Antimicrob. Agents. Chemother. 36 (1992) 1136-1139 Dr. G. G. Zhanel, MS-6 Microbiology, Health Science Centre, 820 Sherbrooke Street, Winnipeg, Manitoba,Canada, R3A 1R9