Patient-specific factors that need to be taken into account include drug allergies and/or intolerances, risk for resistant organisms, and concomitant disease states. Allergies to antibiotics are commonly reported in hospitalized patients. Of these reported allergies, immunoglobulin E (IgE)–mediated allergic reactions are of the most concern. Signs and symptoms of IgE-mediated reactions may include but are not limited to anaphylaxis, urticarial rash, pruritus, angioedema, hyperperistalsis, broncho spasm, hypotension, and arrhythimas.21 Patients reporting these types of allergies to a given antibiotic or antibiotic class should receive alternative therapy with another antibiotic class that does not possess cross-reactivity. However, in circumstances where a patient has limited options and must receive a drug to which he or she is allergic, antibiotic desensitization should be conducted. Desensitization is the process of administering small amounts of drug in doubling amounts every 10 to 15 minutes until a therapeutic dose can be administered.22 This is a time-consuming process that requires several hours before being able to administer the first full dose of an antibiotic. As was discussed previously, current data demonstrate that delays in antibiotic administration of greater than 1 hour increase mortality rates by about 7% compared to the previous hour.4 Therefore, an alternative antibiotic class should be considered before undergoing the timely process of desensitization. Patients with a history of a non–IgE-mediated reaction to a drug should be challenged with that drug if it is the drug of choice for the given infection.
Antimicrobial resistance has become a significant problem in critically ill patients. Multiple patient-specific parameters may increase a patient's risk for developing a multidrug-resistant (MDR) infection. Infections caused by Pseudomonas aeruginosa, Acinetobacter baumannii, extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae species, vancomycin-resistant Enterococcus species (VRE), and methicillin-resistant Staphylococcus aureus (MRSA) are of particular concern. A general list of factors that increase the risk for infection with resistant organisms is included in Table 48-3. Of note, a growing body of evidence reports that previous exposure to various antibiotics is related to the rise in infections caused by ESBL-producing Enterobacteriaceae species, VRE, and MRSA.23, 24 Initial assessment of a patient should include identification of these risk factors and consideration when selecting an empiric antibiotic regimen. Of note, antibiotics that have been administered within the past 2 weeks should be avoided in the empiric regimen as the causative organisms may have developed resistance.2 Failure to identify patients with these risk factors increases the likelihood of providing inadequate empiric antibiotic therapy, potentially increasing the risk of mortality.
Table 48-3.Risk Factors for Multidrug-Resistant (MDR) Infections ||Download (.pdf) Table 48-3. Risk Factors for Multidrug-Resistant (MDR) Infections
Antimicrobial therapy in the preceding 90 d
Current hospitalization of ≥ 5 d
High prevalence of resistance in community
Hospitalization of ≥ 2 d in the last 90 d
Residence in long-term care facility
Home wound care
Exposure to others with MDR organisms
Immunosuppression (drug or disease related)
Structural lung diseases
Concomitant disease states are an extremely important factor when selecting and dosing an empiric antibiotic regimen. Figure 48-3 lists disease states commonly encountered in critically ill patients and the impact on pharmacodynamic parameters and drug dosing requirements. Critical illness typically encompasses one or more of these disease states.
Common ICU disease states, effects on pharmacokinetic parameters, and antibiotic classes affected. Cl, clearance; Vd, volume of distribution changes.
The most common reason antibiotics are adjusted in the critically ill is because many currently available antibiotics are renally eliminated. Common causes of reduced renal clearance include age and acute or chronic renal failure. Failure to adjust doses of renally eliminated antibiotics can result in accumulation to supra-therapeutic levels, thereby increasing the risk of concentration-dependent adverse effects. Examples of these adverse effects include seizures secondary to use of β-lactams, carbapenems, and fluoroquinolones, and further renal insult after aminoglycoside use.25, 26 Depending on the agent chosen, a reduction in dose for concentration-dependent or in dosing interval for time-dependent antibiotics may be the optimal adjustment. Another complicating factor is the initiation of hemodialysis in patients with acute or chronic renal failure. Different modes of dialysis remove varying amounts of drug, and therefore specific references regarding dosage adjustments should be sought out for patients in renal failure receiving hemodialysis.27, 28 It is important to assess the need for antimicrobial dosage adjustment in any patient with unstable renal function, renal dysfunction, or failure.
Much like the kidneys, the liver also plays an important role in the absorption, distribution, and elimination of many drugs. Hepatic impairment and subsequent alterations in hepatic drug clearance are much more difficult to quantify than changes in drug clearance observed with renal disease. The pharmacokinetic alterations seen in hepatic impairment are not consistent or are not well defined, making it difficult to assess the need for drug dosage adjustment. The semiquantitative Child-Pugh score can be used to assess the degree of liver dysfunction, but this only offers minimal guidance for drug adjustment as it does not take into account the ability to metabolize drugs.29 In drugs eliminated through both renal and hepatic routes, a decrease in hepatic clearance may be partially compensated for by increases in renal clearance. Owing to large variations in pharmacokinetics in liver disease, specific dosage recommendations are generally lacking, particularly in severe liver disease. Most sources simply recommend reducing the dose without giving specific dosing recommendations, or avoiding the drug in severe hepatic disease.30, 31, 32
Obesity is extremely prevalent in our society today and may impact as many as one in four patients in the intensive care unit (ICU).33 Unfortunately, there is a paucity of data regarding antibiotic dosing in patients who are obese, and even less in those who are critically ill. Obesity is most likely to affect an antibiotic's Vd, and therefore dosage adjustments may be necessary. Further complicating matters is that estimation of creatinine clearance (CrCl) is difficult in these patients as many of the calculations used for this purpose include weight. In fact, these calculations have been shown to overestimate CrCl when using total body weight (TBW) and underestimate CrCl when using ideal body weight (IBW). As a result, it is difficult to determine an appropriate antibiotic dosing regimen in obese patients.34, 35 More recent data suggest that the use of lean body weight or fat-free weight may better predict CrCl in morbidly obese patients.36 Aminoglycoside antibiotics have the most data in regards to dosing in obesity, partially because of their narrow therapeutic index. The Vd of aminoglycosides in obese patients is increased. However, the degree of increase seen varies based on the study.37 Dosing based on TBW tends to overshoot the desired concentration, while dosing based on IBW tends to underdose obese patients. Therefore, an adjusted body weight (ABW) calculation [ABW = IBW + 0.4 (TBW − IBW)] is typically used for dosing with close therapeutic drug monitoring. Vancomycin dosing appears to correlate best with TBW and should be dosed using this weight with careful therapeutic drug monitoring.38 Despite β-lactams being the largest class of antibiotics, there are relatively few data for dosing in the obese patient population. Available data suggest that increased doses may be warranted for cephalosporins and penicillins.37 The data for carbapenems are minimal, and therefore it is difficult to make dosing recommendations.37 The data on fluoroquinolones are variable, but higher doses may be required because of their concentration-dependent activity.37 Current data for linezolid suggest that no dosage adjustments are necessary.39, 40 Data for daptomycin suggest that it should be dosed on TBW.41, 42 While these provide us some direction on dosage requirements in obese patients, there are few data in critically ill obese patients. This makes it difficult to determine the most appropriate doses for these patients. These patients will likely require higher doses than patients of normal body weight, but to what degree is unknown.
Patients who have experienced thermal injury undergo significant changes in pharmacokinetics, resulting in dramatic increases in Vd and clearance for most antibiotics. These patients tend to have an acute phase, lasting for approximately 48 hours following injury, which is marked by increased capillary permeability and hypovolemia. These patients then enter the hyperdynamic phase of their injury with increased cardiac output, protein loss, and fluid shifts. This hyperdynamic phase varies based on the extent of injury but typically persists for 7 to 10 days.43 For nearly all antibiotics studied, increases in dose and frequency of administration are required in patients with thermal injury.43, 44, 45, 46 Patients with traumatic injuries are often thought to be most similar to patients with thermal injuries in that they tend to be younger and hypermetabolic. However, there are very few studies evaluating the effects of traumatic injury on dosage requirements. The available data are highly variable, showing increased, decreased, and no change in clearances for various drugs.13