pharmacodynamics and alternative antimicrobial dosing...

ADULT IN FEC TIOUS DIS EASE NOTES

Pharmacodynamics andalternative antimicrobial

dosing regimensMANY YEARS HAVE PASSED SINCE THE DIS COV ERY OF PENI CIL -

lin by Fleming in 1929 and, al though many other an ti -mi cro bi als have since been dis cov ered, the de bate re gard ingop ti mal doses and dos ing regi mens con tin ues. An ti mi cro bialther apy is unique in many re spects since the ‘r ece ptors’ towhich the antimicrobial is di rected is a liv ing mi cro or gan ismthat may be found in vir tu ally any lo ca tion in the body. The de -ter mi nants of out come of the in fec tious pro cess have beenwell de scribed and in clude a com plex in ter ac tion among themi cro or gan ism (bug), the an ti mi cro bial (drug) and the in -fected in di vid ual (host). The bug- drug- host in ter ac tion may be de scribed in terms of the phar ma coki net ics of the drug, phar -ma co dy nam ics of the bug- drug in ter ac tion and the host re -sponse. Phar ma coki net ics deals with the dis po si tion of thedrug in the body and the pro vi sion of ac tive drug at the site ofthe in fec tion, whereas phar ma co dy nam ics deals with the time course of drug ac tiv ity and the mecha nisms of ac tion of drugson the mi cro or gan ism. The host re sponse is proba bly themost im por tant vari able in any bug- drug- host in ter ac tionsince it is the abil ity of the host to de stroy or con tain the mi cro -or gan isms that ul ti mately leads to re cov ery.

It is the in ter play of drug phar ma coki net ics, pharmaco dy -nam ics and the host re sponse on which dos ing regi mens ofan ti mi cro bi als are pro posed. The con cept of a thera peu tic levelwith re spect to peni cil lin was dis cussed as early as 1944 (1). Itwas sug gested that con tinu ous ther apy with peni cil lin was nec -es sary to main tain a criti cal level dur ing ther apy. Stud ies con -ducted in the early 1950s us ing a mouse model dem on strated that in ter mit tent ther apy was as ef fec tive as con tinu ous ther -apy (2,3). The suc cess in these early tri als with in ter mit tentdos ing was thought to de pend on the length of the dos age in -ter val and the amount of time dur ing which drug lev els re -mained ef fec tive in the se rum. Based on these early stud iesmost an ti mi cro bi als have been given as in ter mit tent doseswith usual dos age sched ules of three or four times daily. Withbeta- lactam agents it was also thought that some bac te rial re -growth was nec es sary to ob tain bac te ri cidal ac tiv ity.

Dur ing the past dec ade fac tors gov ern ing the phar ma coki -netic pa rame ters of an ti mi cro bi als (dis tri bu tion into tis sues,free ver sus bound an ti mi cro bi als, ef fect of dos age on half- life) have been fur ther clari fied and at ten tion has shifted to wardsnew phar ma co dy namic pa rame ters other than the tra di tional

in vi tro and static mini mal in hibi tory con cen tra tion (MIC). Newdata have ac cu mu lated on the dy namic in ter ac tion of thebug- drug in ter ac tion, in clud ing the rate of bac te rial kill ing, thepostan ti bi otic ef fect (PAE), the in flu ence of sub in hibi tory drugcon cen tra tions, ef fec tive re growth time and postan ti bi otic leu -ko cyte en hance ment (4). The phar ma co dy namic ac tiv ity of aspe cific an ti mi cro bial may vary con sid era bly de pend ing onthe mi cro or gan ism and the set ting in which it is used. The dif -fer ent phar ma co dy namic pa rame ters among classes not un -ex pect edly will have a ma jor im pact on the de ter mi nants ofop ti mal dos ing regi mens. As in for ma tion has ac cu mu latedfrom in vi tro ki netic mod els, ani mal mod els and, to a lesser ex -tent, hu man clini cal tri als, the tra di tional ap proaches to an ti -mi cro bial dos ing are be ing ques tioned, and al ter na tive dos ing regi mens are be ing pro posed and im ple mented in many Ca -na dian hos pi tals.

For ex am ple, both in vi tro mod els and ani mal stud ies havedem on strated that the most re li able pre dic tor of in vi tro ac tiv -ity for beta- lactams is the time dur ing which the an ti mi cro bialse rum con cen tra tion ex ceeds the MIC of the of fend ing patho -gen (5-11). The very high ini tial se rum con cen tra tions ob -tained af ter par enteral ad mini stra tion do not ap pear tocon trib ute to the ef fi cacy of these agents. The bac te ri cidal ac -tiv ity of the peni cil lins and cepha lo sporins does not in creasewith in creas ing se rum con cen tra tions, pro vided the MICs ofthe mi cro or gan ism are ex ceeded. The PAE (sup pres sion ofbac te rial growth that per sists af ter brief ex po sure of or gan -isms to an ti mi cro bi als) for beta- lactams has been ob servedsince the ini tial dis cov ery of an ti mi cro bi als (12). Most beta- lactams have in vi tro PAEs of 1.5 to 3 h against most Gram- positive mi cro or gan isms but rela tively short or no PAE (lessthan 0.5 h) against Gram- negative mi cro or gan isms (4). Thecar bape nems (imipe nem) are an ex cep tion to this gen eralrule for Gram- negatives, ex hib it ing a PAE of more than 1 h (4).Fur ther more, it must be em pha sized that in vivo PAEs aremore pro longed than in vi tro PAEs (13), likely due to the pres -ence of neu tro phils and se rum fac tors (14). Since the timedur ing which drug con cen tra tions ex ceed the MIC ap pears tobe a ma jor de ter mi nant of ef fi cacy of beta- lactams, con tinu -ous in fu sion of agents with very short half- lives but mod estan ti bac te rial ac tiv ity or in ter mit tent in fu sion of agents withlonger half- lives but with very high an ti bac te rial ac tiv ity may

CAN J INFECT DIS VOL 6 NO 1 JANU ARY/FEB RU ARY 1995 9

be the pre ferred routes of de liv ery. An other im por tant ob ser -va tion is that, with the ex cep tion of en do car di tis and per hapsmen in gi tis, no ad di tional bene fits are seen with ex tremelyhigh con cen tra tions of beta- lactams. The rele vant im pact ofthese find ings to the prac tis ing cli ni cian is that the large mul ti -gram dos ages of the newer ex tended spec trum peni cil linsand the sec ond- and third- generation cepha lo sporins com -monly used dur ing the 1980s are no longer gen er ally nec es -sary. Spe cific ex am ples in clude the use of piper acil lin every 6to 8 h, cef tri ax one 1 to 2 g every 24 h, ce fo taxime 1 to 2 gevery 12 h and cef tazidime 1 to 2 g every 12 h (15- 20). Thesedos ing regi mens take ad van tage of the ex cel lent an ti bac te rial ac tiv ity (ex tremely low MICs) and ex tended half- lives of thepar ent com pound or of an ac tive me tabo lite as in the case ofce fo taxime.

The ami no gly cosides, qui nolones and met roni da zole areex am ples of an ti mi cro bi als that ex hibit ma jor concentration- dependent kill ing and that pro duce pro longed PAEs. Theseagents have a kill rate that is great est at high con cen tra tions(4,21). Sev eral ani mal mod els and clini cal data have cor re -lated peak ami no gly co side se rum con cen tra tions with out -come (22- 26). It has been sug gested that peak lev els eight- to 10- fold higher than the MIC are ca pa ble of pre vent ing any re -growth of re sis tant or gan isms (27). The in vi tro PAEs for ami -no gly cosides against most Gram- positive and Gram- negative or gan isms are at least 2 to 3 h, and the in vivo PAEs have been re corded to be as high as 12 h (13). Simi larly, qui noloneshave in vi tro PAEs from 1.5 to 3 h for Gram- negative ba cilli,whereas met roni da zole has a pro longed PAE (greater than 3h) ver sus an aero bic bac te ria (4). The rele vant im pact for thecli ni cian has been the ad vent of once- daily dos ing of ami no -gly cosides at a dose of 5 to 7 mg/kg (28,29) for gen ta mi cinand to bra my cin and twice- daily dos ing of met roni da zole incon ven tional doses, which has been adopted by many hos pi -tals.

In the fu ture, it is likely that fur ther re fine ments to an ti mi -cro bial dos ing will oc cur not only for spe cific agents but alsofor spe cific pa tient popu la tions. Tri als are un der way with con -tinu ous low dose in fu sions of beta- lactams, and the first largeran dom ized pro spec tive trial of once- ver sus multiple- dailyami no gly co side dos ing in feb rile neu tro penic pa tients hasbeen com pleted (30). Not only are we likely to see fur ther new de vel op ments in the dos ing and de liv ery of es tab lished an ti -mi cro bi als, but char ac teri za tion of the op ti mal dos ing pa rame -ters for newer agents will likely also oc cur dur ing theirpre mar ket ing evalua tion. We hope that all of these de vel op -ments will con tinue to move to wards im proved clini cal out -comes and re duced tox ic ity in the pa tient popu la tions that weserve.

REF ER ENCES1. Fillett WS, Cambier MJ, McCormick JE. The treatment of lobar

pneumonia and pneumococcal empyema with penicillin. Bull NY Acad Med 1994;20:140-3.

2. Eagle H, Fleischman R, Musselman AD. Effect of schedules ofadministration on the therapeutic effect of penicillin. Am J Med1950;9:280-99.

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therapy with penicillin. The effect of the interval betweeninjections on therapeutic efficacy. N Engl J Med1953;248:481-8.

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6. Blaser J, Stone BB, Groner MC, et al. Comparative study withenoxacin and netilmicin in a pharmacodynamic model todetermine importance of ratio of antibiotic peak concentration toMIC for bacterial activity and emergency of resistance.Antimicrob Agents Chemother 1987;31:1054-70.

7. Zinner ZH, Dudley MN, Gilbert D, et al. Effect of dose andschedule on cefoperazone pharmacodynamics in an in vitromodel of infection in a neutropenic host. Am J Med1988;85(Suppl 1A):56-8.

8. Gerber AU, Craig WA, Brugger HP, et al. Impact of dosingintervals on activity of gentamicin and ticarcillin againstPseudomonas aeruginosa in granulocytopenic mice. J Infect Dis 1983;147:910-7.

9. Roosendaal R, Bakker-Woudenberg IA, van den Berg JC, et al.Therapeutic efficacy of continuous versus intermittentadministration of ceftazidime in an experimental Klebsiellapneumoniae. J Infect Dis 1985;152:373-8.

10. Roosendaal R, Bakker-Woudenberg IA, Berghe-Van Raffe M, etal. Continuous versus intermittent administration of ceftazidimein experimental Klebsiella pneumoniae pneumonia in normaland leukopenic rats. Antimicrob Agents Chemother1986;30:403-8.

11. Vogelman B, Gudmundsson S, Leggett J, et al. Correlation ofantimicrobial pharmacokinetic parameters with therapeuticefficacy in an animal model. J Infect Dis 1988;158:831-47.

12. Eagle H, Musselman AD. The slow recovery of bacteria from thetoxic effects of penicillin. J Bacteriol 1949;58:475-90.

13. Craig WA. Post-antibiotic effects in experimental infectionmodels: relationship to in vitro phenomena and to treatment ofinfections in man. J Antimicrob Chemother 1993;31(SupplD):149-58.

14. Long MH, Shapland CE, Leonard LA, Rowland H. Antibiotics and human defence mechanisms: the effects of ampicillin andcefotaxime on intra- and extracellular killing of Salmonellaenteritidis. J Antimicrob Chemother 1984;14(Suppl B):81-9.

15. Boughton BJ, Harris RI, Brown RM, et al. Gentamicin and lowdose piperacillin in febrile neutropenic patients. J Antimicrob Chemother 1989;24:45-51.

16. Cade JF, Presnell J, Keighby C, Sinickas V. Efficacy of a lowdose of cefotaxime in serious chest infections. Chest1992;101:1393-8.

17. Trenholme GM, Schmitt BA, Nelson JA, Gvazdinskas LC,Harrison BB, Parkhurst GW. Comparative study of threedifferent dosing regimens of cefotaxime for treatment ofGram-negative bacteraemia. Diagn Mcrobiol Infect Dis1989;12:107-11.

18. Paradis D, Valee F, Allard S, et al. Comparative study ofpharmacokinetics and bactericidal activities of cefpirome,ceftazidime, ceftriaxone, imipenem, and ciprofloxacin.Antimicrob Agents Chemother 1992;36:2085-92.

19. Low DE, Mandell L. A prospective open-label multicentre trial onthe use of 1 g, once daily ceftriaxone in lower respiratory tractinfections. Can J Infect Dis 1994;5(Suppl C):3C-8C.

20. Jonsson M, Wadder M. Pharmacokinetics of ceftazidime inacutely ill hospitalized elderly patients. Eur J Clin MicrobiolInfect Dis 1992;11:15-21.

21. Smith JT. Awakening the slumbering potential of the 4-quinoloneantibacterials. Pharmacol J 1984;233:299-305.

22. Gerber AU, Feller-Segessenmann C. In vitro assessment of invitro killing patterns of Pseudomonas aeruginosa. J Antimicrob Chemother 1985;15(Suppl A):201-6.

23. Gerber AU, Vastola AP, Brandel J, Craig WA. Selection ofaminoglycoside-resistant variants of Pseudomonas aeruginosain an in vivo model. J Infect Dis 1982;146:691-7.

In fec tious dis ease notes

10 CAN J INFECT DIS VOL 6 NO 1 JANU ARY/FEB RU ARY 1995

24. Powell SH, Thompson WL, Luthe MA, et al. Once-daily vscontinuous aminoglycoside dosing: efficacy and toxicity inanimal and clinical studies of gentamicin, netilmicin, andtobramycin. J Infect Dis 1983;14:918-32.

25. Moore RD, Lietman PS, Smith CR. Clinical response toaminoglycoside therapy: importance of the ratio of peakconcentration to minimal inhibitory concentration. J Infect Dis 1987;155:93-9.

26. Moore RD, Smith CR, Lietman PS. The association ofaminoglycoside plasma levels with mortality in patients withGram-negative bacteraemia. J Infect Dis 1984;149:443-8.

27. Craig WA. Once-daily dosing of aminoglycosides. Can J InfectDis 1994;5(Suppl C):28C-33C.

28. Gilbert DN. Once-daily aminoglycoside therapy. AntimicrobAgents Chemother 1991;35:399-405.

29. Nicolau D, Quintiliani R, Nightingale CH. Once-dailyaminoglycosides. Conn Med 1992;56:561-3.

30. EORTC. Efficacy and toxicity of single daily doses of amikacinand ceftriaxone versus multiple daily doses of amikacin andceftazidime for infection in patients with cancer andgranulocytopenia. Ann Intern Med 1993;119:584-93.

JM Conly MD FRCPC

To ronto, On tarioSD Sha fran MD FRCPC

Ed mon ton, Al berta

In fec tious dis ease notes

CAN J INFECT DIS VOL 6 NO 1 JANU ARY/FEB RU ARY 1995 11

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