Chapter 21: Antimicrobials

INTRODUCTION

It has been reported that for every 1-hour delay of effective antimicrobial therapy in patients with septic shock, there is a 7.6% decrease in survival.^1,2 Inadequate empiric therapy has also been associated with increased length of hospital stay.^3,4 In addition to timing and choice of antimicrobials, understanding the pharmacokinetics is vital to providing adequate coverage while minimizing resistance.⁵

PHARMACOKINETICS

Antibiotics can interfere with protein synthesis or common metabolic pathways of the target cells and/or compromise the integrity of the cell wall. They can be classified as either bacteriostatic—ie, inhibiting the growth and replication of bacteria—or bactericidal. Bacteriostatic antibiotics rely on the host’s immune system in order to effectively clear the ­bacteria, whereas agents that are bactericidal are able to kill bacteria independent of the immune response.^6,7 These terms, however, are general categories and may not always apply for a given agent. For example, ampicillin and daptomycin, which are both regarded as bactericidal agents, are bacteriostatic against Enterococcus.⁸ Azithromycin, a member of the traditionally bacteriostatic macrolide class, is bactericidal against Legionella.⁹

The minimum inhibitory concentration (MIC) is conventionally used to describe the susceptibility of the microorganism to an antimicrobial agent and is set by the Clinical and Laboratory Standard Institute (CLSI) using microbiologic, pharmacodynamic/kinetic, and clinical data.¹⁰ It should be noted that MIC values are unique to the antibiotic with respect to an organism and cannot be compared across different agents. For example, levofloxacin with an MIC of less than 2 µg/mL is not less effective against Pseudomonas aeruginosa than piperacillin/tazobactam with an MIC of 4 µg/mL. In fact, in this scenario, levofloxacin would actually be categorized as “resistant,” since the MIC breakpoint for P aeruginosa is 1 µg/mL or less.¹¹ Although MICs are useful in identifying potentially effective antibiotics, these values must be interpreted cautiously, as they do not reflect variable in vivo processes such as penetration of the antibiotic into the site of infection.^10,12

Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) properties of antibiotics can potentially optimize drug therapy and increase clinical effectiveness. By combining relative MICs with the PK/PD parameters of the drugs, antibiotics can be categorized as time-dependent or concentration-dependent. Figure 21-1 and Table 21-1 illustrate the pharmacokinetic and pharmacodynamics indices and associated antibiotics. Antibiotics that are considered to be concentration-dependent, such as fluoroquinolones or aminoglycosides, require a high concentration above the MIC in order to ensure maximal bactericidal activity. For time-dependent antibiotics, activity against microorganisms correlates best with the duration of time the concentration remains above the MIC (T > MIC).¹² In order to reach optimal bactericidal activity against Gram-negative bacteria, the free drug concentration needs to exceed the MIC for 60% to 70% of the dosing interval for penicillins, 70% to 80% for cephalosporins, and 40% to 50% for carbapenems.^13,14...