Chapter 48: Antimicrobial Therapies in the ICU

The clinical and radiographic presentation is consistent with late-onset ventilator-associated pneumonia. The goals of therapy include eradication of the causative organism and symptom resolution. Initiation of appropriate antibiotic therapy is essential in achieving these goals for all infections including ventilator-associated pneumonia. Prior to antibiotic initiation, samples for culture should be drawn from any suspected sources. It is important to obtain cultures prior to antibiotic therapy, as failure to do so has been shown to decrease the yield of the causative organism.¹ Current guidelines by the Infectious Diseases Society of America recommend that at least two sets of blood cultures and a lower respiratory tract sample be obtained to aid in the diagnosis of pneumonia.² Cultures are critical in helping to identify the causative organism(s), which will dictate the choice of antibiotics as well as the duration of therapy. Culture data also help to determine the duration of therapy as certain bacterial species have been shown to respond better to shorter durations of antibiotics than have other species.³ Negative lower respiratory tract samples at 72 hours in the absence of antibiotic changes can be used to discontinue antibiotic therapy, limiting unnecessary drug exposure.² If the samples are positive, they help in the identification of the causative organism and its in vitro susceptibility profile. This information is essential for antibiotic de-escalation and tailoring of antibiotic therapy to ensure appropriate treatment while minimizing the risk for the development of resistance.

While culture data are extremely important in the delivery of an optimal antibiotic regimen, it is imperative that the collection of cultures not delay the initiation of the empiric antibiotic regimen. If cultures cannot be obtained in a timely manner, then antibiotics should not be withheld simply to increase the yield of cultures. The time to initiation of appropriate empiric therapy is vital in patients with suspected infection. This has been demonstrated in multiple types of infections including sepsis, pneumonia, and meningitis. A recent study assessing time from onset of hypotension to the delivery of appropriate antibiotics demonstrated an increase in mortality rate of 7% per hour for every hour in delay of antibiotic administration.⁴ This was not an isolated finding, as several studies of sepsis due to varying infections have shown similar results.^{5, 6, 7} These findings have led to consensus guidelines for sepsis to recommend antibiotic administration within 1 hour of onset of severe sepsis or septic shock.⁸ Similar recommendations are made regarding timing of antibiotic administration in other guideline statements based on these or similar data.^{2, 9, 10}

The important thing to remember with these data is that the key is delivery of appropriate antibiotics. An antibiotic regimen with poor or no in vitro activity against the causative organism is termed inadequate or inappropriate empiric antibiotic therapy (IEAT). The administration of IEAT has been shown to be an independent risk factor for mortality in critically ill patients with various infections, including bacteremia and pneumonia.^{11, 12} When deciding on an empiric regimen that will minimize IEAT and the associated mortality, there are multiple drug-, hospital-, infection-, and patient-specific factors that must be taken into account (Figure 48-1). These factors are highly dependent on one another and must all be addressed in order to select the most appropriate empiric antibiotic regimen.

When providing an optimal antibiotic regimen, one must consider the drug's pharmacokinetic and pharmacodynamic parameters in order to maximize bactericidal or bacteriostatic activity and prevent antimicrobial resistance. Pharmacokinetics includes the processes of absorption, distribution, metabolism, and elimination of a given drug. A list of pharmacokinetic parameters and their definitions is given in Table 48-1. These factors along with the dose and administration frequency determine the amount of drug in the serum or body tissue and the duration of the drug's availability in those areas. Critical illness adds another level of complexity as critically ill patients undergo a number of physiologic changes that affect these pharmacokinetic parameters.

Absorption and Distribution

Some common changes in critical illness include decreases in gastrointestinal perfusion and motility, intestinal atrophy, and physical incompatibilities with enteral nutrition or other medications. These parameters are important to consider as they can significantly decrease the bioavailability of oral antibiotics, thereby limiting their role during critical illness. Changes in bioavailability can then affect the following pharmacokinetic parameters: maximum concentration (C_max) achieved in serum, steady-state or plateau serum concentration (C_ss), area under the curve (AUC), and time to peak concentration (T_max) seen after drug administration. Because of the aforementioned limitations, it is recommended to avoid the use of oral antibiotics in favor of intravenous antibiotics, particularly if there is a question of gastrointestinal function and/or motility. Drug distribution to tissues is also significantly affected in critical illness. Factors such as pH, fluid shifts, and hypoalbuminemia may have a significant effect on volume of distribution changes (V_d), resulting in varying concentrations at the site of infection. Physiochemical characteristics such as hydrophilicity and lipophilicity also play a role in determining a drug's volume of distribution and clearance.¹² Blood levels achieved by hydrophilic antibiotics such as aminoglycosides, β-lactams, colistin, and linezolid are largely affected by increased volumes of distribution as commonly seen in critically ill patients. Lipophilic antibiotics such as fluoroquinolones, lincosamides, macrolides, and tigecycline distribute well into fat tissue and therefore have a largely unchanged V_d. All of these factors need to be taken into consideration when deciding on an antibiotic dosing regimen to ensure efficacy and avoid drug toxicity.

Metabolism and Excretion

In the critically ill, alterations in hepatic blood intrinsic clearance and protein binding can significantly affect the metabolism of antibiotics, possibly resulting in the need for dosage modifications.

The clearance of antibiotics is often unpredictable and can either be increased or decreased depending on the renal function. Renal clearance is the most common elimination pathway for antibiotics; therefore, renal dysfunction or failure encountered with critical illness can have a significant impact on a patient's elimination half-life (t_1/2).¹³

Pharmacodynamics

Pharmacodynamics demonstrates the relationship between the pharmacologic effect and drug concentrations and has been used to determine microbiologic and/or clinical outcomes. Pharmacodynamics predicts the ability of antibiotics to exert their bactericidal (ie, kill the bacteria) or bacteriostatic (ie, inhibit the growth of the bacteria) effects. The minimum inhibitory concentration (MIC) is the minimum concentration of an antimicrobial that will inhibit the growth of bacteria and is a good predictor of the efficacy of an antibiotic against a given pathogen. However, it does not take into account the duration or extent of antimicrobial activity. The time course of antimicrobial activity varies greatly from class to class and correlates with different pharmacodynamic parameters. A list of the commonly encountered antibiotic classes and the optimal pharmacodynamic parameters that correlate with efficacy is given in Table 48-2. A graphical representation of the interaction between pharmacokinetic and pharmacodynamic parameters is depicted in Figure 48-2.

In order to maximize efficacy and minimize toxicity, antibiotics will exert their action in one of two killing methods: time-dependent killing or concentration-dependent killing. In antibiotics that possess time-dependent kill, namely, β-lactams, maximal killing relies on the time antibiotic serum concentrations remain consistently above the MIC (T > MIC). It is important to note that time-dependent antibiotics do not rely on the peak concentration achieved in serum but, instead, on how long these concentrations remain above the MIC. Once the serum concentration drops below the MIC for time-dependent antibiotics, bacterial regrowth will occur, potentially resulting in therapeutic failure. Therefore, the goal with these agents should be to maximize the time of exposure. Among the time-dependent antibiotics, the goals to achieve maximum antimicrobial activity can vary greatly. For example, to maximize their antimicrobial effects, cephalosporins, penicillins, and carbapenems must spend 60% to 70%, 50%, and 40% of the dosing interval above the MIC, respectively.¹⁴

There are several drug classes that exhibit concentration-dependent or time-independent killing effects. For these antibiotics, maximal bactericidal activity is achieved when optimal concentrations are above the MIC. It is not dependent on how long they remain above the MIC; instead, it is dependent on the concentration achieved after a single dose. Aminoglycosides and fluoroquinolones are examples of two drug classes whose effects are concentration dependent. The peak/MIC and AUC/MIC ratios are the pharmacodynamic parameters that correlate with the efficacy of aminoglycosides and fluoroquinolones, respectively. Aminoglycosides must achieve a maximum concentration of greater than 10 times the MIC, while fluoroquinolones must achieve an AUC/MIC ratio of greater than 125.^{14, 15}

Ideally, all antibiotic dosing should be determined by routine measurement of drug concentrations at the site of infection in order to ensure that the aforementioned pharmacodynamic parameters are met. Unfortunately, this is not routinely performed with all antibiotics. Serum levels are routinely monitored when aminoglycosides and glycopeptides are administered. However, there is a lack of data and experiences addressing measurable drug concentrations at all potential sites of infection. This dearth of information limits the degree to which pharmacodynamic parameters (AUC/MIC, T > MIC, C_max/MIC) can be calculated at the site of infection.

In addition to pharmacodynamic properties of a given antibiotic, the antibiotic spectrum of activity is extremely important. A basic understanding of a given antibiotics spectrum of activity is crucial to select an antibiotic that will cover the most likely causative pathogens from a suspected source. Failure to consider spectrum of activity can lead to an increased risk for administering IEAT, potentially increasing patient mortality rate.

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.

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.

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 V_d, 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 V_d 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 V_d 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

In addition to underlying disease states and organ dysfunction, the site of infection plays a significant role in selection of an antibiotic regimen. For antimicrobials to be effective they must be able to reach the site of infection at concentrations high enough to exert their bacteriostatic or bactericidal effects. Antibiotic penetration into tissues is determined by passive diffusion, active transport, lipid solubility, molecular weight, and protein binding. These factors are of particular importance when selecting an antibiotic regimen for the treatment of meningitis, osteomyelitis, and pneumonia in particular.

In the treatment of meningitis, the degree of lipid solubility of the antibiotic must be taken into consideration. Lipid solubility is a major factor in determining an antibiotic's ability to cross the blood-brain barrier. Drugs that are lipophilic and nonpolar penetrate the cerebrospinal fluid (CSF) most readily and include fluoroquinolones, rifampin, and metronidazole.⁴⁷ β-Lactams are the antibiotic class used most frequently in the treatment of CSF infections despite the fact that they are hydrophilic and highly polarized. They are used frequently because of their wide therapeutic index and the ability of patients to tolerate large systemic doses. However, their use may be largely limited by their inability to achieve significant concentrations at the site of infection when treating infections caused by organisms with high MICs. Aminoglycosides are often also used in the treatment of CSF infections. However, intravenous therapy is discouraged due to inadequate penetration into the site of infection. In these cases, direct or local instillation into the CSF via intraventricular or intrathecal administration ensures drug delivery to the site of infection.

The treatment of osteomyelitis poses a challenge as clinical evidence is lacking and differs between the stages (acute versus chronic) and location of the infection. Data from drug penetration studies into bone matrix are evolving.^{48, 49, 50} For these reasons, the treatment of osteomyelitis often requires larger than normal doses and a longer duration of treatment—often a minimum of 6 to 8 weeks. Generally antibiotics that possess a moderate to large V_d may be used to treat such invasive infections. Commonly used antibiotics include β-lactams, trimethoprim-sulfamethoxazole, clindamycin, rifamycins, and vancomycin. There is a growing body of evidence in the use of local instillation of antibiotic-impregnated cement beads with drugs such as aminoglycosides for the treatment of chronic osteomyelitis.^{51, 52, 53}

Hospital-acquired pneumonia accounts for approximately 25% of all ICU-acquired infections in the United States.² Inadequate antimicrobial therapy has been identified as the most significant predictor of patient mortality. It is imperative that the antimicrobial treatment chosen possesses adequate lung penetration ability in order to ensure treatment success while decreasing the potential for future antibiotic resistance. Antibiotics such as β-lactams, macrolides, fluoroquinolones, linezolid, rifamycins, and trimethoprim-sulfamethoxazole penetrate well into the lungs, especially in the setting of inflammation. Drugs such as intravenous vancomycin and aminoglycosides have low to moderate penetration into the lungs and are dependent on the level of inflammation. It is therefore important to maximize the doses of these agents to avoid potential therapeutic failure and antimicrobial resistance. While daptomycin possesses a large volume of distribution, the parent compound is inactivated by lung surfactant and should not be used for the treatment of pneumonia. Optimization of these antimicrobial regimens must consider the pharmacokinetic/pharmacodynamic parameters of each antibiotic (time- versus concentration-dependent killing). Broad-spectrum agents should be administered as empiric treatment in order to prevent IEAT in a patient with MDR organisms. Culture results are usually finalized within the first 48 to 72 hours, at which time the antibiotic regimen should be de-escalated. De-escalation or narrowing the spectrum of activity and/or decreasing the number of antibiotics should be individualized and culture/pathogen guided. For recommendations on empiric and pathogen-guided therapy as well as antibiotic dosage recommendations, please refer to the guidelines published by the Infectious Diseases Society of America and the American Thoracic Society.²

The most important factors to take into consideration when prescribing an empiric antibiotic regimen are the patient and hospital microbiologic flora as well as local and institutional resistance patterns. This information is typically available in a hospital setting in the form of a hospital antibiogram. An antibiogram is simply a report of the antimicrobial susceptibility profile of an organism or bacterial species to a group of antimicrobial agents. Table 48-4 shows an example of a hospital antibiogram. While patient-specific cultures are pending, the antibiogram can be used to guide empirical antibiotic therapy based on the likely pathogens and the susceptibilities to anti-infectives available at a given institution. Antibiograms report data as a percent of susceptibilities and are usually updated annually to evaluate resistance trends. A common mistake encountered when interpreting the hospital antibiogram is the assumption that if two different antibiotics possess activity against 90% of Pseudomonas aeruginosa isolates, then the combination of both antibiotics will possess activity against 100% of these isolates. This is an incorrect assumption and the selection of the appropriate antibiotic therapy should be carefully considered. For example, looking at the antibiogram in Table 48-4, the selection of cefepime would cover 94% of P aeruginosa isolates and amikacin would cover 93% of these isolates. However, if given as combination therapy you can only assume that you will cover 94% of isolates as the 6% of isolates that are resistant to cefepime may also be resistant to amikacin. When used correctly to determine a patient's empiric regimen, antibiograms can be extremely helpful in minimizing inadequate empiric antibiotic therapy, but they are not without their limitations.

Later in the day the susceptibilities for the P. aeruginosa species isolated on BAL are available and are reported as follows (where S, sensitive; R, resistant; I, intermediate):

An antibiotic susceptibility panel is a report provided by the microbiology laboratory. A susceptibility panel will commonly include a selection of antibiotics, the MIC against the isolated organism, and susceptibility to that antibiotic. Once a causative organism is identified, it is imperative that the patient receive an antibiotic regimen to which the organism is sensitive. This may require modification of the initial empiric regimen. Often times you must wait for susceptibilities to be finalized by the laboratory before adjusting your empiric regimen. The susceptibilities are determined by comparing the concentrations to the established MIC breakpoints set by the US Food and Drug Administration and Clinical Labs Standards Institute. These susceptibilities are then reported as sensitive, intermediate, or resistant. If an organism is resistant to a listed antibiotic, the use of it will result in therapeutic failure and should be avoided. If an organism is reported to be intermediate, successful eradication of the infection will be largely dependent on the location of the infection and the ability to achieve that concentration at the site. In general, antibiotics that are reported as having intermediate activity should be avoided.

When an organism is reported as being susceptible to an antibiotic, the MIC should be evaluated. Treatment success is dependent on whether the chosen antibiotic can achieve concentrations above the MIC at the site of infection. However, one cannot simply compare the MICs between antibiotics and choose the one with the lowest MIC. For example, in the above susceptibility panel example, both imipenem/cilastatin and amikacin were tested for susceptibility against P aeruginosa and the reported MICs were 4 μg/mL and 16 μg/mL, respectively. One cannot assume imipenem/cilastatin is the better option simply because the MIC is lower. Each organism has a different MIC breakpoint and therefore a different threshold for resistance to tested antibiotics. Instead, one should compare the MICs of the isolated organism to the known MIC breakpoints for an antibiotic. This information is typically found along with the antibiogram. An example of MIC breakpoints can be found in Table 48-5. Rather than directly comparing the concentrations, a better method would be to compare how many dilutions the MIC is from its respective breakpoint. The closer the MIC is to its breakpoint, the less favorable the antibiotic option.

Once susceptibilities have been reported, the next step is to evaluate the appropriateness of the antibiotic therapy. It is at this point that the decision should be made to either broaden or narrow therapy as indicated. There are many situations in which broad-spectrum antibiotics should be continued—particularly when the source of the infection is not identified or controlled. However, it is important to consider that one of the leading causes of antimicrobial resistance is the inappropriate continuation of broad-spectrum antibiotics and failure to narrow therapy when a susceptibility panel is available. Narrowing of therapy, also referred to as de-escalation, is often defined as switching to a regimen with a narrower spectrum of activity or decreasing the total number of antibiotics. This approach to antibiotic therapy can also help in decreasing the development of future infection with MDR organisms.^{54, 55}

In the above patient case, P aeruginosa was isolated, which was sensitive to only amikacin and imipenem/cilastatin. When comparing the MICs of the isolated organism to the known breakpoints for those drugs, the isolate had an MIC to amikacin of 16, which is 1 dilution from being intermediate (32), while the MIC to imipenem was 4, which is also 1 dilution from being intermediate (8). To ensure treatment success and decrease the development of antimicrobial resistance, antibiotic concentrations must reach at least the MIC, but preferentially four to five times the MIC, at the site of infection. These concentrations are not only difficult to quantify but they will also be difficult to achieve as high concentrations increase the risk for drug-related toxicities. The choice between imipenem/cilastatin and amikacin should be made based on patient-specific factors such as drug allergies, intolerances, drug interactions, and organ dysfunction and the ability of the chosen agent to adequately penetrate the site of infection.

Inadequate dosing and inappropriate and/or untimely administration of antibiotics are known risk factors for the increase in mortality rate observed in critically ill patients.^{11, 56} Increasing antibiotic resistance in recent years has led to a renewed interest in ways to maximize the pharmacodynamic parameters of antibiotics.^{17, 57, 58, 59} Areas of interest and research have included once-daily dosing of aminoglycosides, prolonged and continuous infusions of time-dependent antibiotics, and aerosolized antibiotics. Pharmacodynamics is influencing the mode of administration for both time- and concentration-dependent antibiotics. For time-dependent antibiotics, several studies have demonstrated continuous (total daily dose administered over 24 hours) or extended infusion (intermittent dose administered over 3-4 hours) as alternative dosing schemes for β-lactams.^{60, 61, 62, 63, 64} These dosing schemes recommend an initial loading dose prior to the continuous or extended-interval infusion. The initial loading dose is given to increase the probability of attaining the pharmacodynamic target sooner. Population studies of pharmacokinetics and distribution of MIC values have demonstrated a higher probability of achieving the goal percentage of time above the MIC with continuous or extended infusions when compared to the conventional 30- or 60-minute intermittent infusions at similar daily doses. Attaining consistent concentrations above the MIC has been shown to correlate to better clinical cure rates as demonstrated by several retrospective reviews conducted by Lorente et al. These studies suggested that continuous infusions of meropenem, ceftazidime, and piperacillin/tazobactam resulted in higher clinical cure rates in patients with ventilator-associated pneumonia due to gram-negative bacilli compared to when these same agents were given intermittently (30-minute infusions).^{65, 66} Limitations to the continuous or extended-interval administration include drug-drug compatibility, intravenous access, and drug stability at room temperature.

For concentration-dependent antibiotics, namely, aminoglycosides, once-daily administration of these agents is also guided by pharmacodynamic concepts.^{67, 68} Maximal concentration achieved above the MIC (C_max > MIC) or the AUC/MIC ratio ensures optimal bactericidal activity when these antibiotics are administered once daily (eg, tobramycin 5-7 mg/kg daily) compared to the conventional thrice-daily dosing (eg, tobramycin 2 mg/kg q8h). Once-daily administration of aminoglycosides does not pose a greater risk for toxicities, specifically nephrotoxicity and ototoxicity, compared to the conventional dosing scheme. The clinical efficacy of once-daily aminoglycosides has been demonstrated in a variety of different patient populations including those with intra-abdominal infections, pneumonia, and bacteremia. However, patient populations such as those with significant and/or unpredictable alterations in pharmacokinetic parameters of volume of distribution and drug clearance have not been adequately studied. These populations include patients receiving renal replacement therapy; patients with renal failure, ascites, or burns; pregnant women; and neonatal/pediatric patients.^{67, 68}

These modes of administration allow for optimization of microbiologic coverage, and thus the practical and cost advantages of their applications are important for treating complex infections (eg, severe nosocomial pneumonia) involving difficult-to-treat organisms with higher MIC values (eg, P aeruginosa, Acinetobacter species).^{69, 70}

Local instillation of antibiotics, namely via aerosolization, plays a unique role in the treatment of MDR organisms. Aerosolized antibiotics (eg, aminoglycosides, colistin) distribute almost exclusively into the lungs with minimal systemic exposure. Most of the literature on the clinical utility of aerosolized antibiotics exists in patients with cystic fibrosis. However, there is a growing body of evidence in their utility for the adjunctive treatment of ventilator-associated pneumonia. The current Infectious Diseases Society of America and American Thoracic Society pneumonia guidelines recommend considering adjunctive aerosolized antibiotic therapy when treating MDR pathogens, most commonly P aeruginosa and A baumannii.² A recent retrospective study of aerosolized aminoglycosides and colistin, in addition to intravenous therapy, had a notable clinical response (73%) in critically ill trauma patients with MDR ventilator-associated pneumonia.⁷¹ In addition, several other case series of aerosolized antibiotics have reported high levels of clinical success with difficult-to-treat infections.^{72, 73, 74}

Because of the highly resistant strain of P aeruginosa that was isolated in the patient case, the ability to maximize your pharmacodynamic target for imipenem (T > MIC) with traditional dosing would be difficult, if not impossible. If traditional dosing were chosen for this patient, it would not be unreasonable to select the highest dose of imipenem/cilastatin approved per the package insert (1000 mg IV q6h) in an attempt to maximize the T > MIC. Another option in this patient would be to give imipenem as a 1-g loading dose followed by either a continuous infusion of 2 g over 24 hours or intermittent prolonged infusions of 1 g over 3 to 4 hours given every 8 hours. In general, aminoglycosides should never be used as monotherapy for gram-negative infections. However, due to the high MIC to amikacin and the relatively poor penetration of aminoglycosides into the lung, IV amikacin would likely be of little benefit owing to an inability to maximize the pharmacodynamic goal (C_max/MIC).

As previously discussed, the practice of administering an empiric antibiotic regimen containing more than one antibiotic with activity against a given organism to minimize the risk of IEAT is a widely utilized practice. Empiric double coverage is of particular benefit when infections due to P aeruginosa or other nosocomial pathogens are suspected. However, once the susceptibility profile is available, the use of more than one antibiotic with activity against the causative organism is a topic of much debate. The argument for the use of combination therapy is based on two potential benefits: synergy against the causative organism and prevention of the development of resistance. However, these arguments are based primarily on in vitro results, which cannot be assumed to also occur in vivo. Potential disadvantages of the continued use of combination therapy include the possibility for antagonism, increased cost, and adverse effects, as well as potential for selection of MDR bacteria.

Numerous studies have compared monotherapy to combination therapy with varied results. In an effort to control for the differences between these studies, several meta-analyses have been conducted. The largest of these meta-analyses included 64 studies comparing β-lactam monotherapy with β-lactam/aminoglycoside combination therapy in the treatment of sepsis. The authors demonstrated no differences in mortality outcomes between the treatment groups. However, monotherapy resulted in significantly less nephrotoxicity.⁷⁵ A meta-analysis evaluating the same question in ventilator-associated pneumonia demonstrated similar results with no mortality rate differences between monotherapy and combination therapy.⁷⁶ Despite these meta-analyses, some practitioners will continue to treat specific organisms (P aeruginosa) and infections (endocarditis) with combination therapy. Various guideline recommendations actually make differing recommendations on continued combination therapy after organism identification based on site and causative organism. Therefore, current guideline recommendations should be referenced when deciding on monotherapy or combination therapy at this stage in treatment.^{2, 8, 9, 10, 77} In general, once a causative organism is identified, monotherapy based on the susceptibility profile is adequate for most patients and most infections. Patients who would be the most likely to benefit from continued combination therapy are patients with MDR infections or those with infections due to high MIC organisms where the susceptible antibiotics have limited penetration into the site of infection. However, there are few available data to support this practice.

In the patient case discussed above, the causative organism for the ventilator-associated pneumonia was an MDR P aeruginosa susceptible to only amikacin and imipenem/cilastatin. In this patient it would be reasonable to consider combination intravenous therapy because both drugs have limited penetration into the lung parenchyma and the MIC for the organism is relatively high. This limited penetration could potentially result in an increased risk for clinical failure with antibiotic monotherapy. To overcome this limited penetration you would likely need to give very high doses of IV amikacin, potentially increasing the risk of nephrotoxicity and ototoxicity associated with this drug. Adjunctive therapy with aerosolized amikacin at a dose of 1000 mg inhaled every 12 hours would provide not only local delivery of drug to the site of infection but also double coverage while potentially limiting the risk of systemic adverse effects.

The optimal duration of antibiotic treatment is highly variable based on the site of infection, the causative organism, concomitant disease states, and the patient's clinical response to therapy. Guideline-recommended treatment durations range from as little as 3 days in asymptomatic catheter-associated urinary tract infections to as many as 8 weeks for some etiologies of endocarditis.^{77, 78} Traditionally the majority of these recommendations for optimal duration are based on expert opinions rather than data supporting one duration over another. For example, the traditional duration of therapy for pneumonia was 14 to 21 days. However, recent data demonstrated that as few as 8 days of therapy results in therapeutic resolution without any differences in mortality rate, ventilator-free days, or recurrent infections compared to 15 days of therapy. In addition, patients who received 15 days of therapy had higher rates of recurrent infections due to more resistant organisms. Similar data are available for selected forms of endocarditis as well. It is important to realize that these durations are simply starting points and that each individual patient may respond differently and require shorter or longer durations of therapy.