Septic patients in the intensive care unit (ICU) represent some of the sickest patients in the hospital, and optimal initial antibiotic selection is paramount to their survival. In this patient population, the key is to select an empiric regimen that maximizes antibiotic effect but also limits the development of resistance. Within each antibiotic class are drugs that may have a high or low resistance potential. The precise mechanism by which the difference arises is unknown. “Low resistance potential” antibiotics are antimicrobials that rarely induce resistance among bacteria, even when used frequently and for extended periods of time. In addition to selecting antibiotics that have a low resistance potential, consideration should be given toward selecting an agent with favorable pharmacokinetics (PK) and pharmacodynamics (PD). Essentially, septic patients should be treated urgently with the highest tolerable/nontoxic antimicrobial dose of a drug with low resistance potential to maximize microbial killing while minimizing the risk of selecting out drug-resistant mutants.
Antibiotic Pharmacokinetic and Pharmacodynamic Considerations to Minimize Resistance and Optimize Effectiveness
PK define the fate of an antibiotic within the body (i.e., absorption, volume of distribution, blood and tissue levels, hepatic metabolism/excretion, and renal excretion). Antibiotic PK describe the effects of the antibiotic on both the host and the infecting microorganism. Both parameters are essential to consider in choosing an antimicrobial regimen for critically ill patients with serious infections. The inhibitory/cidal effect of antibiotics on bacteria can be categorized as demonstrating concentration-dependent killing, time-dependent killing, or a combination of both and depends on the antibiotic and the targeted pathogen. Concentration-dependent killing kinetics describe the increased bacterial killing that occurs as antibiotic concentrations increase above the minimal inhibitory concentration (MIC) and are expressed as the maximum serum antibiotic concentration (C max ) to the MIC ratio (C max /MIC). The fluoroquinolones—aminoglycosides, metronidazole, and daptomycin—all exhibit concentration-dependent killing. When selecting these antibiotics, the dose must be maximized for optimal effect. The higher the dose used, the more potent the antibiotic killing. Achieving a high concentration is particularly important when selecting an antibiotic with a relatively wide toxic-to-therapeutic ratio (i.e., aminoglycosides), making once daily dosing highly desirable. There are two benefits to this dosing strategy. Giving a high dose of the antibiotic only once per day generates a very high, but rapidly cleared, peak serum concentration, providing optimal and rapid bacterial killing. As the drug concentration subsequently falls, tissue levels rapidly diminish, preventing accumulation and decreasing the risk of toxicity. Adding to the optimized killing provided by the single daily peak level is the prolonged postantibiotic effect (PAE) characteristic of aminoglycosides. The PAE extends antimicrobial capacity well after the serum concentrations have fallen below the MIC for the pathogenic microorganism (up to 8 to 12 hours).
Antibiotics that display time-dependent killing kinetics include the β-lactams, carbapenems, macrolides, and linezolid. In these compounds, an increase in the serum concentration above 4–5× MIC does not increase killing. Thus the key to antimicrobial activity lies in keeping the blood level close to this point for as long as possible—the time of drug concentration above the MIC for the dosing period (T > MIC). Therefore, even when antibiotics that demonstrate time-dependent killing are used, there is little downside with high doses of the drug, particularly in critically ill patients with infection. The killing kinetics of other antimicrobials may have more complex PD that better fit an integration of the time over MIC, expressed as the area under the concentration curve over the MIC (AUC 0-24 :MIC).
Some antimicrobials, such as doxycycline or vancomycin, exhibit kinetics that are dependent on time and concentration, reflecting the MIC of the pathogen. When gram-positive cocci with an MIC of less than 1 μg/mL are exposed to vancomycin, the drug functions with time-dependent killing kinetics. However, when the MIC is greater than 1 μg/mL, the kinetics are dependent on concentration. The aminoglycosides and quinolones also demonstrate this duality with some pathogens (i.e., concentration-dependent kinetics [C max /MIC ratio]) as well as AUC 0-24 /MIC ratio ( Table 17-1 ).
| Antibiotic PK/PD Parameters | Optimal Dosing Strategies |
|---|---|
| Concentration-Dependent Antibiotics (C max :MIC) | |
| Use highest effective dose (without toxicity) |
| Time-Dependent Antibiotics (T > MIC) | |
| |
| Use high doses (which increase serum concentrations and increase T > MIC for more of the dosing interval) |
| Other Antibiotics (C max :MIC/T > MIC and/or AUC 0-24 /MIC) | |
| Quinolones | |
| >125 (effective) | |
| >250 (more effective) | Use highest effective dose (without toxicity) |
PK principles dictate the concentration and distribution of each antibiotic in serum and body fluids over time. The overall concentrations of drug in the serum are affected by the antibiotic’s peak serum concentrations, volume of distribution, serum half-life (t 1/2 ), protein binding, and renal or hepatic function. Peak serum concentration, protein binding, and volume of distribution (V d ) will directly determine the tissue concentrations of an antibiotic in the tissue where the pathogen resides ( Table 17-2 ).
| Antibiotic PK Parameters | Sepsis ↑ with Capillary Permeability ∗ (Intravascular → Interstitial Fluid Shifts) | Suggested Dosing Recommendations |
|---|---|---|
| Water-Soluble Antibiotics (Low V d Water Soluble) | ||
|
|
|
| Lipid-Soluble Antibiotics (High V d → Lipid Soluble) | ||
|
| |
∗ Also with mechanical ventilation, burns, and hypoalbuminemia.
For the most part, antibiotics that exhibit time-dependent killing are bacteriostatic whereas those with concentration-dependent kinetics are bactericidal. Exceptions to this are the penicillins, carbapenems, and monobactams, which are bactericidal despite relying on time-dependent kinetics ( Tables 17-3 and 17-4 ). In addition, certain antibiotics may exhibit both types of killing kinetics depending on how they are used; for example, doxycycline, which uses time-dependent kinetics and is usually bacteriostatic, is bactericidal at high concentrations, a characteristic usually reserved for concentration-dependent antibiotics. In addition to these factors, antibiotics that exhibit concentration-dependent kinetics tend to have prolonged PAE, but there are some antibiotics that are dependent on time (e.g., doxycycline) that also have a PAE.
| High Resistance Potential Antibiotics | Usual Resistant Organisms for Each Antibiotic | Preferred Low Resistance Potential Antibiotic Alternatives |
|---|---|---|
| Aminoglycosides | ||
| Gentamicin/tobramycin | P. aeruginosa | Amikacin |
| Cephalosporins | ||
| Ceftazidime | P. aeruginosa | Cefepime |
| Tetracyclines | ||
| Tetracycline | S. pneumoniae S. aureus | Doxycycline or Minocycline |
| Quinolones | ||
| Ciprofloxacin Ciprofloxacin | S. pneumoniae P. aeruginosa | Levofloxacin or Moxifloxacin Levofloxacin |
| Glycopeptides | ||
| Vancomycin | MSSA MRSA | Linezolid or Daptomycin or Minocycline |
| Carbapenems | ||
| Imipenem | P. aeruginosa | Meropenem or Doripenem |
| Macrolides | ||
| Azithromycin | S. pneumoniae | No other macrolide Alternatives include doxycycline, levofloxacin, or moxifloxacin |
| Dihydrofolate Reductase Inhibitors | ||
| TMP-SMX | S. pneumoniae | Doxycycline |
| Infection Type/Site | Usual Pathogen at Site | Usual Nonpathogens at Site | Preferred Empiric Therapy with Low Resistance Potential Antibiotics | Penicillin Allergy | ||
|---|---|---|---|---|---|---|
| CVC-Associated Bacteremia ∗ | ||||||
| MSSA MRSA CoNS GNBs (aerobic) VSE | B. fragilis Non-Group D streptococci | Meropenem plus either vancomycin (if MRSA likely) or linezolid (if VRE likely) | Meropenem plus either vancomycin (if MRSA likely) or linezolid (if VRE likely) | |||
| Intra-abdominal Sepsis | ||||||
| Cholecystitis/cholangitis | E. coli K. pneumoniae VSE | B. fragilis | Levofloxacin or moxifloxacin | Levofloxacin or moxifloxacin | ||
| Peritonitis/colon perforation | B. fragilis GNBs (aerobic) | Non-Group D streptococci | Ertapenem or piperacillin/tazobactam or moxifloxacin or tigecycline | Ertapenem or moxifloxacin or tigecycline | ||
| VAP/NP | P. aeruginosa GNBs (aerobic) | B. fragilis MSSA/MRSA VSE/VRE Burkholderia cepacia A. baumannii S. maltophilia | Meropenem or doripenem or levofloxacin (750 mg) or cefepime | Meropenem or doripenem or levofloxacin (750 mg) | ||
| Urosepsis | ||||||
| Community acquired | GNBs (aerobic) VSE | B. fragilis MSSA/MRSA | Piperacillin/tazobactam or meropenem | Meropenem | ||
| Nosocomial | P. aeruginosa GNBs (aerobic) | B. fragilis MSSA/MRSA | Piperacillin/tazobactam or meropenem | Meropenem | ||
| Skin and Soft Tissue Infections | ||||||
| Cellulitis | Group A, B, C, G streptococci | MSSA/MRSA | Ceftriaxone or cefazolin | Vancomycin or clindamycin | ||
| Abscess | MSSA/MRSA | Group A, B, C, G streptococci | Ceftaroline or minocycline or Vancomycin or linezolid | Vancomycin or linezolid or minocycline | ||
Antibiotic Susceptibility Testing and Resistance
A discussion on maximizing the dosing of antimicrobials would not be complete without consideration of antibiotic resistance. Resistant organisms are becoming more prevalent worldwide and pose a significant problem for clinicians and ICUs. Despite this fact, there is no international agreement on the definitions of the terms “resistant” or “susceptible.” The breakpoints used in susceptibility testing are based on achievable serum concentrations using the recommended doses of antibiotics for bloodstream infections. Interpretation of susceptibility reports on nonbloodstream isolates must be carefully performed. Infections are difficult to treat when the chosen antibiotic does not adequately penetrate the target tissues (e.g., the prostate or the central nervous system). The clinician must extrapolate likely tissue concentrations at the infection site from achievable serum concentration. Failure to consider this issue may result in clinical failure to eradicate infection despite laboratory reports indicating that the organism in question is susceptible. It is critical to remember that with certain organisms (e.g., methicillin-resistant Staphylococcus aureus [MRSA]), in vitro susceptibility testing does not predict in vivo clinical effectiveness. The source of discordance may lie in patient physiology that differs from in vitro conditions (e.g., the media used for testing). Local acidosis and hypoxia may also decrease the activity of some antibiotics.
Even without these confounding factors, inherent differences between in vitro susceptibility and in vivo efficacy must be taken into account. As an example, treating MRSA with trimethoprim-sulfamethoxyzole (TMP-SMX), doxycycline, or clindamycin, which are often reported as effective on in vitro testing, may not be successful. Instead, anti-MRSA antibiotics such as minocycline, linezolid, daptomycin, or vancomycin, with proven clinical effectiveness against MRSA, provide a greater chance of eradicating the infection. Listeria monocytogenes appears susceptible to cephalosporins, but clinical experience indicates that this β-lactam class of antibiotics does not work in vivo for meningitis, for example ( Table 17-5 ).
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