EPASGESCMID

While recently approved antibiotics are fairly well characterized regarding suitable dosage regimens, older antibiotics – and these are the vast majority of antibiotics in use – were approved up to 60 years ago. Naturally, these approved dosages were not developed according to current standards of science and continued use of these drugs without further study carries significant downside consequences for individual patients as well as for health care in general. Additionally, some indications that have been approved a long time ago may not be adequate any more.

The current situation:

–       The efficacy of an antibiotic and, therefore, the likelihood of a favorable clinical outcome, especially in critically ill patients depends on an optimized dosing regimen (dosage, dosing interval, treatment duration). Many old antibiotics are registered and used with inadequate dosing regimens.

–       The dosing regimen strongly influences the emergence of resistance. Optimized dosing that minimizes the risk of resistance development during therapy benefits both individual patients and society as less resistant bacteria would circulate in the health care environment. Optimizing dosing regimens help preserve the effectiveness of existing antimicrobials for as long as possible. Many old antibiotics are registered and used with insufficient dosing regimens thus promoting emergence of resistance.

–       For last resort antibiotics with a high toxicity potential, optimized dosing regimens may help to reduce the risk of toxicity. Revived antibiotics such as colistin represent a special challenge.

–       Approval of novel antibiotics requires clinical studies that show non-inferiority (or in specific cases superiority) to existing antibiotics. Comparators administered with an outdated, but approved though less effective dosing regimen, may be distorted in favor of the new antibiotic. For approved antibiotics, industry sponsored clinical studies might show a benefit relative to the insufficient dosing regimen of an old comparator. Therefore, the suboptimal dosing regimens used with comparators might bias the approval and usage of new and future antibiotics.

More information:

• Mouton JW, Ambrose PG, Canton R, Drusano GL, Harbarth S, MacGowan A, et al. Conserving antibiotics for the future: new ways to use old and new drugs from a pharmacokinetic and pharmacodynamic perspective. Drug Resist Updat 2011;14:107–17.
• European Commission. EU research projects: AIDA—preserving old antibiotics for the future. EC: 2012.
• Drusano GL, Lodise TP. Saving lives with optimal antimicrobial chemotherapy. Clin Infect Dis. 2013 Jan;56(2):245-7.
• Tam VH, Nikolaou M. A novel approach to pharmacodynamic assessment of antimicrobial agents: new insights to dosing regimen design. PLoS Comput Biol. 2011 Jan 6;7(1):e1001043.
• Martinez MN, Papich MG, Drusano GL. Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target. Antimicrob Agents Chemother. 2012 Jun;56(6):2795-805.
• U. Theuretzbacher: Pharmacokinetic and pharmacodynamic issues for antimicrobial therapy in patients with cancer. Clin Infect Dis. 2012;54(12):1785-92