Marin H. Kollef
Scott T. Micek
Lee P. Skrupky
Antimicrobial resistance has emerged as an important variable influencing patient mortality and overall resource use in the hospital setting (1). Intensive care units (ICUs) worldwide are faced with increasingly rapid emergence and spread of antibiotic-resistant bacteria. Both antibiotic-resistant Gram-negative and Gram-positive bacteria are reported as important causes of hospital-acquired infections. In many circumstances, particularly with methicillin-resistant Staphylococcus aureus and Enterococcus faecium and Gram-negative bacteria producing extended-spectrum β-lactamases with resistance to multiple other antibiotics, few antimicrobial agents remain for the effective treatment of seriously ill patients (1,2). Within hospitals, ICUs are an important area for the emergence of antimicrobial resistance due to the following (1,2,3,4,5,6):
· The frequent use of broad spectrum agents
· The physical crowding of patients with high-acuity diseases within relatively small specialized areas
· Reductions in nursing and other support staff due to economic pressures, which increase the likelihood of person-to-person transmission of micro-organisms
· The presence of more chronically and acutely ill patients who require prolonged hospitalizations and often harbor antibiotic-resistant bacteria.
For the reasons listed above, hospitals—and particularly ICUs—are at the center of the problem of escalating bacterial resistance. The antibiotic treatment strategies described in this chapter attempt to balance the need to provide appropriate initial antimicrobial treatment to patients with serious infections while minimizing further development of antibiotic resistance. Many of these strategies—developed in the ICU setting—also have application in non-ICU areas of the hospital. The strategies described in this review adhere to the Centers for Disease Control and Prevention 12-step program for the prevention of antimicrobial resistance (http://www.cdc.gov/drugresistance/healthcare/). One of the key elements in this strategy is to consult experts in the field of antimicrobial resistance (e.g., infectious disease experts, infection control practitioners, microbiologists) when designing interventions aimed at optimizing the treatment of infected patients and minimizing the emergence of antimicrobial resistance.
The primary treatment strategy described in this chapter will be the approach of antibiotic de-escalation (7). De-escalation is a treatment strategy that attempts to provide appropriate initial antimicrobial therapy to optimize patient outcomes while avoiding the consequences of excessive or unnecessary antibiotic administration (Figs. 104.1 and 104.2).
Key Points
1. Efforts should be made to rapidly identify the source and site of infection and to obtain specimens for culture, antimicrobial susceptibility testing, and rapid diagnostic tests. Obtaining these specimens should not delay initial empiric therapy in a critically ill patient.
2. Initial treatment with an appropriate antibiotic regimen is one of the most important factors influencing the outcome of critically ill patients with infection.
3. Infection with antibiotic-resistant micro-organisms increases the likelihood that inappropriate initial antibiotic therapy will be prescribed to critically ill patients.
4. Host factors influence the likelihood that a patient will be infected with antibiotic-resistant pathogens (e.g., prior hospitalization or antibiotic treatment, admission from a nursing home or other high-risk environment).
5. Avoidance of unnecessary antibiotic exposure in the ICU setting is important to reduce the emergence of and subsequent infection with antibiotic-resistant micro-organisms.
Essential Diagnostic Tests And Procedures
1. For patients with septic shock, establish adequate intravenous access and assess intravascular volume status (e.g., measure central venous pressure).
2. Perform a directed medical history and physical examination to identify potential sources and sites of infection.
3. Obtain specimens for microbiologic testing including blood, urine, and lower respiratory tract secretions. Other specimens should be directed by the initial history/physical examination (e.g., ascites, pleural fluid, cerebral spinal fluid).
4. Perform radiographic evaluation to identify infection sites requiring expeditious surgical or percutaneous drainage (intra-abdominal abscess, thoracic empyema, necrotizing skin, or visceral infection).
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Figure 104.1. Antimicrobial de-escalation promotes initial administration of broad-spectrum antibiotics to patients at risk for infection with multidrug-resistant pathogens, followed by the reduction of the number of antimicrobials used and/or their spectrum of activity based on subsequent pathogen identification and antimicrobial susceptibility testing. |
Initial Therapy
1. Administer intravenous fluids to the patient with septic shock to achieve predetermined goals (e.g., central venous pressure >8 mm Hg, oxygen saturation of central venous blood [SsvcO2] >70%).
2. An initial appropriate antibiotic regimen should be prescribed with adequate activity against all pathogens likely to be responsible for the infection.
3. Initial antibiotic dosing and interval of administration should be pharmacokinetically based to ensure that drug concentrations at the site of infection are adequate to achieve therapeutic drug levels.
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Figure 104.2. Clinical algorithm for the de-escalation approach to antibiotic treatment of serious infections in patients with risk factors for multidrug-resistant pathogens. Optimally, de-escalation of antimicrobial treatment would always occur once the pathogen causing infection and its antimicrobial susceptibility are known. |
4. Drainage of amenable infection sites should occur once the patient has received adequate intravascular fluid replacement and appropriate initial antibiotic therapy.
5. Antibiotic treatment should be reassessed as soon as microbiologic test results become available.
6. Failure of initial antimicrobial therapy should prompt a thorough re-evaluation to identify the reason for failure (e.g., inadequate fluid resuscitation, inappropriate initial antimicrobial therapy, unidentified collection of infected fluid needing drainage).
Antimicrobial Resistance: Risk Factors and Influence on Outcome
Antimicrobial use is the key driver for the emergence of antibiotic resistance. Therefore, antibiotic treatment strategies in the ICU need to take this into account to optimize clinical outcomes, both efficacy and the prevention of subsequent resistance to these drugs. Several investigators have demonstrated a close association between the prior use of antibiotics and the emergence of subsequent antibiotic resistance in both Gram-negative and Gram-positive bacteria (6,8,9). Other factors promoting antimicrobial resistance include prolonged hospitalization, the presence of invasive devices such as endotracheal tubes and intravascular catheters (possibly due to the formation of biofilms on the surfaces of these devices), residence in long-term treatment facilities, and inadequate infection control practices (6). The emergence of new strains of existing pathogens within the community setting has created additional stressors favoring the entry of resistant micro-organisms into the hospital setting. This has most recently been demonstrated by the identification and spread of community-associated, methicillin-resistant Staphylococcus aureus (MRSA) (10). However, the prolonged administration of antimicrobial regimens appears to be the most important factor promoting the emergence of antibiotic resistance that is potentially amenable to intervention (9,11,12).
Many clinical investigations have shown that antimicrobial regimens that lack action against identified micro-organisms that cause serious infections (i.e., inappropriate initial antimicrobial therapy) are associated with greater hospital mortality (13,14,15,16,17,18). Unfortunately, changing antibiotic therapy to an appropriate regimen after antimicrobial susceptibility data become available has not been demonstrated to improve clinical outcomes (19). These studies suggest that the increasing prevalence of antimicrobial resistance has led to greater overall hospital mortality, in part, through the administration of less effective antibiotic agents. The recent Infectious Disease Society of America/American Thoracic Society (IDSA/ATS) guidelines for the treatment of nosocomial pneumonia emphasize the importance of inappropriate initial antimicrobial therapy as a determinant of hospital mortality (20). This guideline also stresses the importance of maintaining local, frequently updated antibiograms within individual hospitals and ICUs to ensure the appropriateness of antibiotic coverage and the use of proper drug doses to optimize tissue concentrations of antibiotics. In addition to increased hospital mortality, antimicrobial resistance is associated with excess costs. Most of this cost is simply associated with the acquisition of a nosocomial infection, much of which is due to potentially antibiotic-resistant bacteria (9,21). However, the presence of antibiotic resistance may also confer added morbidity and costs (22).
Clinical Factors that Affect Initial Antimicrobial Selection
To provide an empirical antimicrobial regimen with an appropriate spectrum of activity, one must appreciate (a) the likely pathogens causing various infections, (b) local pathogen distribution and resistance patterns, and (c) patient-specific risk factors for resistance. Ideally, administration of appropriately broad-spectrum empiric antimicrobial therapy is based on consideration of all of these factors, and each will be examined in the following section.
Data from the National Nosocomial Infections Surveillance (NNIS) outlines the most frequent infections in participating acute care general hospitals in the United States. This surveillance network was established in 1970 and initially reported only hospital-wide infection rates; however, since 1986, the network has reported ICU infection rates as well. In the 2000 report, device-related infection predominated; 83% of nosocomial pneumonia episodes were associated with mechanical ventilation, 97% of urinary tract infections occurred in catheterized patients, and 87% of primary bloodstream infections occurred in patients with a central catheter (23). A more recent publication of the NNIS data reported pathogen distribution by site of infection and compared data from 1975 and 2003 as demonstrated in Table 104.1 (24). In general, the occurrence of hospital-acquired infections attributed to potentially antibiotic-resistant bacteria (e.g., Staphylococcus aureus, Pseudomonas aeruginosa) is increasing (23,24).
The NNIS data outline the changing spectrum of bacterial infection among patients with hospital-acquired pneumonia where Gram-negative aerobes remain the most frequently reported pathogen associated with pneumonia (65.9%); however Staphylococcus aureus (27.8%) was the most frequently reported single species (23,24). In patients with primary bloodstream infections, coagulase-negative staphylococci (42.9%) has remained the most common pathogen reported and Staphylococcus aureus (14.3%) was reported as frequently as enterococci (14.5%). In patients with urinary tract infections, Escherichia coli (26%) was the most frequently reported isolate; however, Pseudomonas aeruginosa constituted 16.3% of reported isolates, increasing from 10.6% in the 1989 to 1998 data. In surgical site infections, the proportion of isolates that were Gram-negative decreased significantly during the past two decades. Gram-positive pathogens are now more commonly associated with both bloodstream infections and skin and skin structure infections, whereas Gram-negative aerobes predominate in pneumonia and urinary tract infections (23,24,25).
One of the most concerning trends reported in the NNIS data is the increasing isolation of Acinetobacter species in urinary tract infections, pneumonia, and surgical site infections (23,24,25). Although overall numbers of isolates of Acinetobacter are still relatively small (approximately 2.0%), the percentage increase is significant. Even more concerning is the recent report of community-acquired pneumonia now attributed to Acinetobacter species, suggesting that this pathogen is extending its area of influence outside of the health care setting (26).
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Table 104.1 Relative percentage by Site of Infection of pathogens associated with nosocomial infection |
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Also disconcerting is the observation made by the NNIS report that for each of the antibiotic-pathogen combinations tested, there was a significant increase in resistance between study periods. Most impressive were trends in carbapenem- and cephalosporin-resistant Pseudomonas aeruginosa and Acinetobacter species (23,24). Rates of imipenem- and amikacin-resistant Acinetobacter isolates are approaching 20% and have been steadily increasing since 1990. The intrinsically multidrug-resistant (MDR) nature of this organism makes these trends particularly worrisome, as many isolates lack effective treatment options and represent a serious public health concern. Last, 2003 rates of third-generation cephalosporin-resistance in Escherichia coli (6.4%) and Klebsiella pneumoniae (14.2%) provide estimates of the presence of extended-spectrum β-lactamase (ESBL) producing often MDR bacteria, again with very limited treatment options in hospitals in the United States (24,27).
The prevalence of MDR pathogens varies by patient population, hospital, and type of floor or unit in which the patient resides, which underscores the need for local surveillance data. MDR pathogens are more commonly isolated from patients with severe, chronic underlying disease—for example, those with risk factors for health care–associated infection (Table 104.2) and patients with late-onset hospital-acquired infections. The importance of these risk factors was demonstrated by Trouillet et al. (9) for potentially antibiotic-resistant ventilator-associated pneumonia (VAP) in 135 mechanically ventilated patients. The duration of ventilation before the onset of VAP and prior antibiotic use (within 15 days prior to developing VAP) were both significant risk factors associated with VAP caused by antibiotic-resistant pathogens. Late-onset VAP (≥5 days), in patients who had previously received antibiotics was generally caused by MDR pathogens such as Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia, or MRSA. The authors concluded that this study provided evidence for the need of a more rational approach to selecting initial empiric antibiotic therapy before culture results were available in patients with VAP to provide an appropriate initial regimen.
A study by Namias et al. (28) examined how variable MDR pathogen distribution can occur among ICUs even from a single hospital. These investigators found highly variable rates of susceptibility to several problem pathogens in their trauma, surgical, and medical ICUs and found that while Acinetobacter susceptibility rates to imipenem were low in the surgical ICU, susceptibility was very good in the trauma ICU. Similar variations in infection rates with MDR pathogens have been reported between different cities and countries (29,30). These data suggest that consensus guidelines for antimicrobial therapy will need to be modified at the local level (for example, according to county, city, hospital, and ICU) to take into account local patterns of antimicrobial resistance. In addition, it is helpful for clinicians to appreciate local specific resistance rates of certain Gram-negative pathogens such as ESBL-producing Klebsiella pneumonia or Escherichia coli, fluoroquinolone-resistant Pseudomonas aeruginosa, or carbapenem-resistant Acinetobacter baumannii. When risk of these pathogens is identified, empirical therapy must be tailored accordingly.
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Table 104.2 Definitions of Infection Categories (with focus on bacterial pathogens) |
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In addition to local or regional variance, numerous patient-specific factors affect the risk of isolation of a resistant pathogen. Therefore, the choice of empirical antibiotic agents should be based on local patterns of antimicrobial susceptibility and must also take into account patient-specific characteristics that may influence the risk of infection with a resistant pathogen. Patients of particular concern are those at risk for hospital-acquired infections caused by Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter species due to the high frequency with which they cause infection, their resistance to numerous antibiotics, and their associated high mortality rates. Infections with these potentially antibiotic-resistant bacteria have occurred primarily among hospitalized patients and/or among patients with an extensive hospitalization history and other predisposing risk factors like indwelling catheters, past antimicrobial use, decubitus ulcers, postoperative surgical wound infections, or treatment with enteral feedings or dialysis.
Differentiating Health Care–Associated Infections from Community-Acquired Infections
Health care–associated bacteremia (HCAB) and health care–associated pneumonia (HCAP) have recently been described as infections developing in patients admitted to the hospital from high-risk environments (20,31,32,33). These high-risk environments include nursing homes and extended care facilities, or patients' homes if they are receiving chronic dialysis, home infusion therapy, or home wound therapy, or have had a recent hospitalization (Table 104.2) (34). These risk factors increase the likelihood of infection with MDR bacteria that are more commonly seen in nosocomial infections as compared with community-acquired infections.
Health care services, such as dialysis, chemotherapy, and same-day surgery, are increasingly provided in the outpatient environment (34). At present, pneumonia and bloodstream infections related to these health care–associated interventions often are classified as community-acquired infections and are initially treated as such. However, given the frequent transfer of patients and health care workers between these facilities and hospitals, an outpatient facility is likely to be distinct from the true community setting and may more closely resemble the nosocomial setting in terms of the pathogens it might house. For example, MRSA strains isolated from patients infected in health care–associated settings are distinct from those that are truly community-acquired and have different susceptibility to antibiotics (10).
In addition to the complexity introduced by evolving health care practices, the causative pathogens associated with community-acquired infections have also changed in prevalence in recent years. Although Streptococcus pneumoniae remains the most common causative pathogen for community-acquired pneumonia, other potential pathogens (e.g., Chlamydia pneumoniae, Mycoplasma pneumoniae, Acinetobacter species, MRSA, and Legionella spp) exist and their prevalence changes over time and varies by geographic location (26,35). Furthermore, the emerging antimicrobial resistance of community-acquired pathogens has complicated the management of these infections. These changes necessitate an evolving treatment strategy based on the most recent findings regarding microbiology and epidemiology (10,20,35).
A De-Escalation Approach for the Antibiotic Treatment of Serious Infection in the Hospitalized Patient
Above all, it is imperative to provide an initial antibiotic regimen that is active against the pathogen(s) causing the underlying infection in a seriously ill patient to optimize clinical outcomes (36). Additionally, the prescribed antibiotics must be dosed adequately according to their pharmacodynamic characteristics, given at the proper interval, and monitored for toxicities to achieve tissue levels that will kill the pathogens (6). After an initial appropriately broad-spectrum antibiotic regimen is prescribed, modification of the regimen using a de-escalation strategy should occur based on the results of the patient's clinical response and microbiologic testing (Fig. 104.2). Based on the de-escalation strategy, modification of the initial antibiotic regimen should include decreasing the number and/or spectrum of antibiotics, if possible based on culture and sensitivity results, shortening the duration of therapy in patients with uncomplicated infections who are demonstrating signs of clinical improvement, or discontinuing antibiotics altogether in patients who have a noninfectious cause identified accounting for the patient's signs and symptoms. The following sections describe individual antibiotic classes as well as methods for implementing a de-escalation approach at the local hospital level. These methods should be used, in combination, according to local preferences to achieve the desired balance between prescribing appropriate initial antibiotic treatment to patients with a serious infection and minimizing the emergence of antimicrobial resistance.
Antibiotics, Their Mode of Action, Clinical Indications for their use, and Associated Toxicities
Most antimicrobial agents used for the treatment of infections may be categorized according to their principal mechanism of action. For antibacterial agents, the major modes of action include the following (37):
1. Interference with cell wall synthesis
2. Disruption of the bacterial cell membrane
3. Inhibition of protein synthesis
4. Interference with nucleic acid synthesis
5. Inhibition of a metabolic pathway
Tables 104.3, 104.4, and 104.5 review the major pathogens, the antimicrobials of choice by pathogen, and the major toxicities of specific agents, respectively.
Cell Wall Active Antibiotics
Antibacterial drugs that work by inhibiting bacterial cell wall synthesis include the β-lactams—such as the penicillins, cephalosporins, carbapenems, and monobactams—and the glycopeptides, including vancomycin and teicoplanin. β-Lactam agents inhibit the synthesis of the bacterial cell wall by interfering with the enzymes required for the synthesis of the peptidoglycan layer. Vancomycin and teicoplanin also interfere with cell wall synthesis by preventing the cross-linking steps required for stable cell wall synthesis.
Disruption of Bacterial Cell Membrane
Disruption of the bacterial membrane is a less well characterized mechanism of action. Polymyxin antibiotics appear to exert their inhibitory effects by increasing bacterial membrane permeability, causing leakage of bacterial contents. The cyclic lipopeptide, daptomycin, appears to insert its lipid tail into the bacterial cell membrane, causing membrane depolarization and eventual death of the bacterium.
Inhibition of Bacterial Protein Synthesis
Macrolides, aminoglycosides, tetracyclines, chloramphenicol, streptogramins, and oxazolidinones produce their antibacterial effects by inhibiting protein synthesis. Bacterial ribosomes differ in structure from their counterparts in eukaryotic cells. Antibacterial agents take advantage of these differences to selectively inhibit bacterial growth. Macrolides, aminoglycosides, and tetracyclines bind to the 30S subunit of the ribosome, whereas chloramphenicol binds to the 50S subunit. Linezolid is a Gram-positive antibacterial oxazolidinone that binds to the 50S subunit of the ribosome on a site that has not been shown to interact with other classes of antibiotics.
Inhibition of Nucleic Acid Synthesis
Fluoroquinolones exert their antibacterial effects by disrupting DNA synthesis and causing lethal double-strand DNA breaks during DNA replication.
Inhibition of a Metabolic Pathway
Sulfonamides and trimethoprim block the pathway for folic acid synthesis, which ultimately inhibits DNA synthesis. The common antibacterial drug combination of trimethoprim, a folic acid analogue, plus sulfamethoxazole (a sulfonamide) inhibits two steps in the enzymatic pathway for bacterial folate synthesis.
Mechanisms of Resistance to Antibacterial Agents
Most antimicrobial agents exert their effect by influencing a single step in bacterial reproduction or bacterial cell function. Therefore, resistance can emerge with a single point mutation aimed at bypassing or eliminating the action of the antibiotic. Some species of bacteria are innately resistant to at least one class of antimicrobial agents, with resulting resistance to all the members of those antibacterial classes. However, the emergence and spread of acquired resistance due to the selective pressure to use specific antimicrobial agents is of greater concern due to the spread of such resistance. Several mechanisms of antimicrobial resistance are readily transferred to various bacteria. First, the organism may acquire genes encoding enzymes, such as β-lactamases, that destroy the antibacterial agent before it can have an effect. Second, bacteria may acquire efflux pumps that extrude the antibacterial agent from the cell before it can reach its target site and exert its effect. Third, bacteria may acquire several genes for a metabolic pathway that ultimately produces altered bacterial cell walls that no longer contain the binding site of the antimicrobial agent, or bacteria may acquire mutations that limit access of antimicrobial agents to the intracellular target site via down-regulation of porin genes. Susceptible bacteria can also acquire resistance to an antimicrobial agent via new mutations such as are noted above.
Strategies that Optimize the Efficacy of Antibiotics While Minimizing Antibiotic Resistance
Formal Protocols and Guidelines
Antibiotic practice guidelines or protocols have emerged as a potentially effective means of both avoiding unnecessary antibiotic administration and increasing the effectiveness of prescribed antibiotics. Automated antimicrobial utilization guidelines have been successfully used to identify and minimize the occurrence of adverse drug effects due to antibiotic administration and to improve antibiotic selection (6). Their use has also been associated with stable antibiotic susceptibility patterns for both Gram-positive and Gram-negative bacteria, possibly as a result of promoting antimicrobial heterogeneity and specific end points for antibiotic discontinuation. Automated and nonautomated antimicrobial guidelines have also been employed to reduce the overall use of antibiotics and limit the use of inappropriate antimicrobial treatment, both of which could affect the development of antibiotic resistance (38). One way these guidelines limit the unnecessary use of antimicrobial agents is by recommending that therapy be modified when initial empiric broad-spectrum antibiotics are prescribed and the culture results reveal that narrow-spectrum antibiotics can be used.
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Table 104.3 Most Common Pathogens Associated with Sites of Serious Infection Commonly Seen in the Adult Intensive Care Unit Setting |
Hospital Formulary Restrictions
Restricted use of specific antibiotics or antibiotic classes from the hospital formulary has been used as a strategy to reduce the occurrence of antibiotic resistance and antimicrobial costs. Such an approach has been shown to achieve reductions in pharmacy expenses and adverse drug reactions from the restricted drugs. However, not all experiences have been uniformly successful, and the homogenous use of a single or limited number of drug classes may actually promote the emergence of resistance (6). Restricted use of specific antibiotics has generally been applied to those drugs with a broad spectrum of action (e.g., carbapenems), rapid emergence of antibiotic resistance (e.g., cephalosporins), and readily identified toxicity (e.g., aminoglycosides). To date, it has been difficult to demonstrate that restricted hospital formularies are effective in curbing the overall emergence of antibiotic resistance among bacterial species. This may be due in large part to methodologic problems. However, their use has been successful in specific outbreaks of infection with antibiotic-resistant bacteria, particularly in conjunction with infection control practices and antibiotic educational activities.
Use of Narrow-Spectrum Antibiotics
Another proposed strategy to curtail the development of antimicrobial resistance, in addition to the judicious overall use of antibiotics, is to use drugs with a narrow antimicrobial spectrum. Several investigations have suggested that infections such as community-acquired pneumonia can usually be successfully treated with narrow spectrum antibiotic agents, especially if the infections are not life threatening. Similarly, the avoidance of broad-spectrum antibiotics, especially those associated with rapid emergence of resistance (cephalosporins, quinolones), and the reintroduction of narrow-spectrum agents (penicillin, trimethoprim, gentamicin), along with infection control practices have been successful in reducing the occurrence of specific infections in the hospital setting (6). Unfortunately, ICU patients often have already received prior antimicrobial treatment, making it more likely that they will be infected with an antibiotic-resistant pathogen (9). Therefore, initial empiric treatment with broad-spectrum agents is often initially necessary for hospitalized patients to avoid inappropriate treatment until culture results become available and de-escalation can occur (Fig. 104.2) (14).
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Table 104.4 Drugs of Choice in Serious Infectionsa |
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Quantitative Cultures and Assessment of Infection Risk
Pneumonia is the most common hospital-acquired infection among mechanically ventilated patients. A recent meta-analysis of four randomized trials demonstrated that the use of quantitative bacterial cultures obtained from the lower respiratory tract may, in theory, facilitate de-escalation of empiric broad-spectrum antibiotics and reduce drug-specific antibiotic days of treatment (39). Another recent study found that patients with a clinical suspicion for VAP and culture-negative bronchoalveolar lavage (BAL) results for a major pathogen could have antimicrobial therapy safely discontinued within 72 hours (40). Interestingly, the mean modified clinical pulmonary infection scores of these patients was approximately six, suggesting that this quantitative clinical assessment of the risk for VAP could have been used to discontinue antibiotics as previously suggested (41). Regardless of whether quantitative culture methods are used, the results of microbiologic testing should be used to routinely modify or discontinue antibiotic treatment in the appropriate clinical setting.
Combination Antibiotic Therapy
Several recent meta-analyses recommend the use of monotherapy with a β-lactam antibiotic, as opposed to combination therapy including an aminoglycoside, for the definitive treatment of severe sepsis once antimicrobial susceptibilities are known (42,43). Additionally, there is no definitive evidence that the emergence of antibiotic resistance is reduced by the use of combination antimicrobial therapy. However, empiric combination therapy directed against high-risk pathogens such as Pseudomonas aeruginosa should be encouraged until the results of antimicrobial susceptibility become available. Such an approach to empiric treatment can increase the likelihood of providing appropriate initial antimicrobial therapy with improved outcomes (15).
Antibiotic Cycling and Scheduled Antibiotic Changes
The concept of antibiotic class cycling has been suggested as a potential strategy for reducing the emergence of antimicrobial resistance (6). In theory, a class of antibiotics or a specific antibiotic drug is withdrawn from use for a defined time period and reintroduced at a later time in an attempt to limit bacterial resistance to the cycled antimicrobial agents. Unfortunately, mathematical modeling suggests that the use of antibiotic cycling will be inferior to “mixing” of antibiotics as a strategy to reduce the emergence of antimicrobial resistance (44). Nevertheless, several earlier studies of antimicrobial cycling have found beneficial outcomes in terms of antibiotic resistance, with benefits extending outside of the ICU setting. More recent rigorous studies of antimicrobial cycling have failed to confirm these findings (45,46). Although antimicrobial heterogeneity or mixing seems to be a logical policy, simple cycling of antibiotics combined with prolonged treatment exposures seems to be a strategy that will only promote further antibiotic resistance.
Antimicrobial Decolonization Strategies
The prophylactic administration of parenteral antibiotics has been shown to reduce the occurrence of nosocomial infections in specific high-risk patient populations requiring intensive care (47). Similarly, topical antibiotic administration (i.e., selective digestive decontamination), with or without concomitant parenteral antibiotics, has also been shown to be effective at reducing nosocomial infections (48). However, the routine use of selective digestive decontamination has also been linked to the emergence of antimicrobial resistance. Additionally, the mixed results of recent negative trials for VAP prevention using iseganan and chlorhexidine, an antimicrobial peptide and antiseptic, respectively, to decontaminate the oropharynx in mechanically ventilated patients sheds doubt on the overall utility of this practice (49,50,51). Based on these studies, antimicrobial and nonantimicrobial agents should be considered for oral decontamination only in appropriate high-risk ICU patients or to assist in the containment of outbreaks of MDR bacterial infections in conjunction with established infection control practices.
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Table 104.5 Toxicities Associated with Antimicrobials |
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Shorter Courses of Antibiotic Treatment
Prolonged administration of antibiotics to hospitalized patients has been shown to be an important risk factor for the emergence of colonization and infection with antibiotic-resistant bacteria (9,12). Therefore, recent attempts have been made to reduce the duration of antibiotic treatment for specific bacterial infections. Several clinical trials have found that 7 to 8 days of antibiotic treatment is acceptable for most nonbacteremic patients with VAP (11,41). Similarly, shorter courses of antibiotic treatment have been successfully used in patients at low risk for VAP (38,40,41) with pyelonephritis (52) and for community-acquired pneumonia (53). In general, the shorter-course treatment regimens have been associated with a significantly lower risk for the emergence of antimicrobial resistance compared to more traditional durations of antibiotic treatment ranging from 14 to 21 days. In the future, more specific markers for the presence of bacterial infection (e.g., procalcitonin, soluble triggering receptor on myeloid cells [sTREM1]) may allow shorter courses of empiric antibiotic administration in patients without identified bacterial infection. Several recently published guidelines for the antibiotic management of nosocomial pneumonia and severe sepsis currently recommend the discontinuation of empiric antibiotic therapy after 48 to 72 hours if cultures are negative or the signs of infection have resolved (2,20).
Optimizing Pharmacokinetic/Pharmacodynamic (Pk/Pd) Principles
Antibiotic concentrations that are sublethal can promote the emergence of resistant pathogens. Optimization of antibiotic regimens on the basis of pharmacokinetic/pharmacodynamic principles could play a role in the reduction of antibiotic resistance (8). The duration of time the serum drug concentration remains above the minimum inhibitory concentration of the antibiotic (T > MIC) enhances bacterial eradication with β-lactams, carbapenems, monobactams, glycopeptides, and oxazolidinones (Fig. 104.3). Frequent dosing, prolonged infusion times, or continuous infusions can increase the T > MIC and improve clinical and microbiologic cure rates. To maximize the bactericidal effects of aminoglycosides, clinicians must optimize the maximum drug concentration (Cmax)-to-MIC ratio. A Cmax:MIC ratio of ≥10:1 using once-daily aminoglycoside dosing (5–7 mg/kg) has been associated with preventing the emergence of resistant organisms, improving clinical response to treatment, and avoiding toxicity. The 24-hour area under the antibiotic concentration curve-to-MIC ratio (AUIC) is correlated with fluoroquinolone efficacy and prevention of resistance development. An AUIC value of >100 has been associated with a significant reduction in the risk of resistance development while on therapy. As a general rule, clinicians should use the maximum approved dose of an antibiotic for a potentially life-threatening infection to optimize tissue concentrations of the drug and killing of pathogens.
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Figure 104.3. Pharmacodynamic parameters found to be important for the efficacy of antimicrobial agents. AUC, area under the concentration–time curve; Cmax, maximum concentration; MIC, minimum inhibitory concentration; T, time. |
New Antimicrobial Agents
Most new antibiotics have been developed for the treatment of Gram-positive bacteria. Given the increasing prevalence of resistance in Gram-negative bacteria, new agents for these pathogens are urgently needed as well. Until recently, the glycopeptides, vancomycin and teicoplanin, were the only antibacterial compounds available to which MRSA strains remained uniformly susceptible. In 1996, the first clinical isolate of Staphylococcus aureus with reduced susceptibility to vancomycin (vancomycin-intermediate Staphylococcus aureus, or VISA) was reported in Japan and, since then, similar cases have been reported around the world. Only a few years later, clinical isolates of Staphylococcus aureus that were fully resistant to vancomycin were reported in South Africa and Michigan, USA. The emergence of MRSA strains with reduced vancomycin susceptibility has limited the treatment options and increased the incidence of treatment failure (54); infection with one of these strains may be an independent predictor of mortality (55). More concerning are the observations that upward drift in the minimum inhibitory concentrations for vancomycin in MRSA are associated with an increased risk of clinical treatment failures (56). As a result of this upsurge in MRSA resistance, most of the recent advances in the development of new antibiotic agents have predominantly occurred for Gram-positive bacteria. Unfortunately, Gram-negative antibiotic development has lagged behind.
Linezolid
Linezolid is the first licensed member of a new class of antibiotics, the oxazolidinones, that binds to the ribosome and inhibits microbial protein synthesis. This novel mechanism of action provides an antimicrobial activity that is independent of the resistance status toward other antibiotics. Some studies suggest that linezolid may be associated with improved survival and clinical cure rates compared to vancomycin in patients with nosocomial pneumonia. Linezolid is a suitable alternative to vancomycin in nosocomial infections caused by MRSA, particularly in pneumonia. Although a general agreement on the superiority of linezolid to vancomycin and teicoplanin is lacking, it does not require adjustment for renal function at a dosage of 600 mg every 12 hours. Close monitoring of the blood cell count should be done in case of pre-existing myelosuppression and during prolonged treatment.
Daptomycin
Daptomycin is a cyclic lipopeptide active only against Gram-positive organisms, and has been recently approved for the treatment of complicated skin and soft tissue infections, with activity against resistant and susceptible isolates of Staphylococcus aureus. Its once-daily dosing (4 mg/kg IV) and safety profile (except for some concerns for rhabdomyolysis) make daptomycin an attractive option for the treatment of staphylococcal infections. Unfortunately, daptomycin may not be a useful agent for deep-seated tissue infections. A recent trial of 740 patients with pneumonia had to be terminated early due to a lower level of efficacy compared to ceftriaxone. This may be related to the molecular size of this drug, its protein-binding characteristics, and inhibition by pulmonary surfactant. Therefore, the current use of daptomycin should be limited to skin infections and bacteremia and/or endocarditis.
Quinupristin-Dalfopristin
Quinupristin-dalfopristin is a semisynthetic, parenteral streptogramin with activity against most of the Gram-positive pathogens. A multicenter study compared quinupristin-dalfopristin and vancomycin in the treatment of nosocomial pneumonia by Gram-positive pathogens. Similar clinical success rates were observed, including in the MRSA subgroup, although very low rates were seen (30.9% in the quinupristin-dalfopristin group versus 44.4% in the vancomycin group) in the bacteriologically evaluable population. These data suggest that quinupristin-dalfopristin is probably not a better option than vancomycin, with both agents seemingly having limited activity against MRSA pneumonia in this study. Although antimicrobial resistance has not been an overriding concern, the side effect profile of quinupristin-dalfopristin (myalgia, arthralgia, and thrombophlebitis) and its lack of proven efficacy over vancomycin have limited its overall use.
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Figure 104.4. A step-by-step approach to the antibiotic management of serious or life-threatening health care–associated infections. ICU, intensive care unit. |
Tigecycline
Tigecycline is the first glycylcycline to be launched and is one of the very few antimicrobials with activity against Gram-negative bacteria and MRSA. In contrast to classic tetracyclines, tigecycline can be administered only parenterally, and its major side effect appears to be dose-related nausea and emesis. The dosing regimen for tigecycline has been validated in clinical trials that involved a 100-mg loading dose, followed by 50 mg twice daily in patients with complicated infections of the skin and skin structure, as well as intra-abdominal infections. It evades acquired efflux and target-mediated resistance to classical tetracyclines but not chromosomal efflux. The Cmax is low, but tissue penetration is excellent and, in clinical trials, the compound has shown equivalence to imipenem/cilastatin in intra-abdominal infection and to vancomycin plus aztreonam in skin and skin structure infection. Tigecycline may prove particularly useful for the treatment of surgical wound infections, where both Gram-negative bacteria and MRSA are likely pathogens. Tigecycline may also have a role in the treatment of infections due to multiresistant pathogens, including Acinetobacter species and extended-spectrum β-lactamase producing Gram-negatives. Future studies are needed to differentiate the role of tigecycline from other newly available agents including new glycopeptides, linezolid, daptomycin, and ceftobiprole.
Ceftobiprole
Ceftobiprole (BAL5788) is the water-soluble prodrug of BAL9141, a novel broad-spectrum cephalosporin with potent bactericidal activities against MRSA and penicillin-resistant Streptococcus pneumoniae. Until recently, efforts to develop β-lactam antibiotics active against MRSA have largely been unsuccessful. One exception is BAL9141, a novel pyrrolidinone-3-ylidenemethyl cephalosporin specifically designed to have strong affinity for penicillin-binding protein (PBP) 2a known to confer resistance in staphylococci and pneumococci. BAL9141 also binds strongly to the relevant PBPs of most Gram-positive and Gram-negative pathogens and is resistant to many β-lactamases. Ceftobiprole is currently being investigated in patients with pneumonia and complicated skin infections.
Dalbavancin
Dalbavancin is a lipoglycopeptide antimicrobial that has been studied in phase two trials for complicated skin and skin structure infections and catheter-related bloodstream infection. Dalbavancin is a bactericidal agent whose long terminal plasma half-life (9–12 days) allows for the unique dosing of 1,000 mg given on day 1 and 500 mg given on day 8. The long half-life may turn out to be the strength of the drug, allowing for more convenient treatment options in patients requiring prolonged antibiotic therapy (e.g., right-sided infective endocarditis or osteomyelitis). However, the impact of this prolonged half-life on adverse reactions also needs further evaluation.
Telavancin
Telavancin is another lipoglycopeptide in development. Telavancin exerts concentration-dependent bactericidal activity against Gram-positive bacteria, including MRSA. This agent's rapid bactericidal activity arises from two mechanisms: inhibition of peptidoglycan synthesis and interaction with the bacterial membrane. In a recent double-blind randomized control trial, it proved effective for the treatment of complicated skin and skin structure infections given as a once-daily dosing. Telavancin's once daily dosing is appealing, and perhaps the dual mechanism of action will eventually slow the development of resistance to this agent. Additional studies are ongoing to determine the efficacy of this agent in other infections including pneumonia.
Doripenem
Doripenem is a novel broad-spectrum parenteral carbapenem antimicrobial. The chemical formula for doripenem confers ß-lactamase stability and resistance to inactivation by renal dehydropeptidases. Information from presented in vitro studies indicates that doripenem has a spectrum and potency against Gram-positive cocci most similar to imipenem or ertapenem and a Gram-negative activity most like meropenem (twofold or fourfold superiority to imipenem).
Summary
Antimicrobial resistance is a common variable influencing antibiotic prescription decisions and clinical outcomes. Increasingly, clinicians must be able to balance the need to provide appropriate antimicrobial treatment to patients while minimizing the further development of resistance. The practice of antimicrobial de-escalation (Figs. 104.1 and 104.2) should be used to accomplish this difficult but important balance. Moreover, for patients with serious or life-threatening infections, treatment algorithms should be used to ensure that early appropriate therapy is administered to all patients (Fig. 104.4).
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