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Current challenges in the management of the infected patient

Nicolau, David P

Current Opinion in Infectious Diseases: February 2011 - Volume 24 - Issue - p S1–S10
doi: 10.1097/01.qco.0000393483.10270.ff
Supplement Articles

Purpose of review Management of hospital-associated infections (HAIs) has been made more challenging by the increasing proportion of immunocompromised or otherwise severely ill patients and increasing prevalence of antibiotic-resistant pathogens in this environment. This review examines strategies to optimize clinical outcomes and lower healthcare costs for patients with HAIs by focusing on patient-related, pathogen-related, and drug-related factors.

Recent findings Factors have converged to increase the risk of infection with antibiotic-resistant pathogens in the current hospital environment, including the increasing prevalence of resistant species and number of hospitalized patients with conditions increasingly susceptible to infection with drug-resistant bacteria. Although the list of bacterial pathogens associated with HAIs has been fairly constant over time, the prevalence and resistance profile of these individual species continues to evolve. Periodic antibiograms should be utilized to access local patterns of resistance within the different hospital wards. Outcomes for patients with HAIs are optimized with early empiric treatment with an appropriate regimen, selected on the basis of patient characteristics and local resistance patterns. Dosing strategies should be utilized to ensure that the efficacy of an appropriate antibiotic is optimized, by achieving the pharmacodynamic target predictive of its efficacy. Using these strategies improves quality of care and is associated with lower overall healthcare costs.

Summary Bacterial resistance is an increasing problem in the hospital environment, and has been associated with poorer clinical outcomes and elevated healthcare costs. By using patient characteristics, local antibiograms, and dosing strategies to achieve an optimal pharmacodynamic profile, early appropriate empiric therapy can be utilized to improve clinical outcomes, minimize the development of resistance, and reduce healthcare costs.

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA

Correspondence to David P. Nicolau, Director, Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06074, USA Tel: +1 860 545 3941; e-mail:

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Management of bacterial infections has become increasingly complex, as the general severity of illness or immune status of hospitalized patients has worsened, antibiotic resistance has increased, and the pipeline for new agents is diminishing. Infected patients are treated in a variety of institutional settings, from community hospitals to large academic medical centers, but a common principle of effective treatment is the rapid recognition of infection and the initiation of appropriate therapy, defined as an antimicrobial with laboratory-based susceptibility to the infecting pathogen. This strategy has been shown to reduce infection-related morbidity and mortality; however, the indiscriminate use of therapeutic entities may lead to the emergence of resistance in target pathogens or the development of superinfections (i.e., Clostridium difficile). Hence, when using antibiotics, it is prudent for the practicing clinician to be mindful of these benefits as well as the potential risks. This will not only improve the clinical outcomes of the infected patient, but will also reduce societal and healthcare costs associated with therapeutic failure.

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Optimizing outcomes

Optimizing infection-related outcomes requires a focus on three interrelated factors. In simple terms, attention needs to be directed towards the competency of the patient, the etiologic pathogen and its susceptibility profile, and the choice of drug. This review examines each of these factors, providing a general overview of the current state of affairs and guidelines on optimal patient management and antibiotic use.

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Patient (host) factors

As mentioned, the current hospitalized population is characterized by an increased number of patients with multiple comorbidities, chronic or severe disease, and/or who are otherwise immunocompromised [1]. There has also been a general aging of the US population, and advanced age is associated with greater risk of comorbidity, chronic and/or severe disease, polypharmacy, and immunodeficiency. Furthermore, many patients admitted to a hospital have received prior surgical or medical interventions (i.e., blood products, oncologic, or rheumatologic medications) that alter patient immunity. Moreover, consideration should be given to the prior use of antibiotic therapy and thus the increased risk of infection with an antibiotic-resistant pathogen. In addition, the more severe the illness for which the patient is hospitalized, the more likely the patient will have an extended hospital stay, frequently with use of intubation, parenteral nutrition, or other medical devices (i.e., central venous or urinary catheters), all of which increase the risk of a hospital-acquired infection (HAI) with a drug-resistant pathogen.

Infection with an antibiotic-resistant versus antibiotic-susceptible pathogen has been associated with greater risk of mortality, increased length of hospital stay, and higher healthcare and societal costs [2–4]. Risk of infection with a resistant pathogen increases with advancing age, immunodeficiency, multiple comorbidities, and prior antibiotic use. Inappropriate antibiotic therapy is more likely to occur in patients infected with resistant bacteria, and the risk of mortality is particularly elevated in immunocompromised patients or those with severe disease who also experience a delay in the initiation of appropriate antibiotic therapy [5,6].

Hence, patient characteristics by themselves and through interactions with bacterial pathogens and antibiotic therapy have a major impact on clinical outcomes and costs. These patient characteristics, including advanced age; presence of comorbidities (e.g., malnutrition; diabetes mellitus; alcoholism; cancer; or chronic heart, lung, renal, or hepatic disease); immunosuppressive conditions or use of immunosuppressant drugs; malnutrition; recent intubation; parenteral nutrition; recent or prolonged hospitalization (≥5 days); and prior antibiotic use, are important considerations when determining treatment for a given patient, and are commonly incorporated in treatment guidelines for both community-acquired or hospital-acquired infections [7–9].

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Pathogen factors

Hospitalized patients with a suspected bacterial infection typically receive empiric therapy before diagnostic test results are known. With empiric treatment, clinicians need to consider the most likely causative pathogen(s) when prescribing initial therapy. Patient characteristics and local susceptibility trends, determined through periodic antibiograms, provide important clues as to the likelihood of infection with an antibiotic-resistant species. Institutional antibiograms are important and should be performed for different institutional departments or units, because the incidence and susceptibility of pathogenic bacteria can vary widely for different institutions within the same geographic area and for different departments within a given institution [10–12].

When considering nosocomial or HAI-related infections, the following organisms are commonly identified: Gram-negative (e.g., Escherichia coli, Klebsiella pneumoniae, Enterobacter species, Pseudomonas aeruginosa, and certain Acinetobacter species) and Gram-positive (e.g., Staphylococcus aureus, Enterococci, and coagulase-negative staphylococci) bacterium [13,14]. Although the bacterial pathogens commonly associated with these infections have not changed much over recent times, variation in their prevalence and resistance profiles have been noted by patient type, institution, institutional department, and infection site. In addition, Clostridium difficile infections are becoming more common and troublesome than in the past [15,16]. Table 1 presents the results from a surveillance of bacterial isolates associated with HAI in the ICU for 1986–2003, illustrating the most commonly isolated pathogens and their variation by infection site [17]. Although these data provide insight into our national epidemiologic trends during the study period, it should be recognized that considerable differences may be observed over time, both within and among individual ICUs, as well as across international borders.

Table 1

Table 1

Although the organisms causing HAIs have not changed, their resistance to common antibiotics has. Antibiotic resistance has become an increasing problem in the United States and worldwide, and involves both Gram-negative and Gram-positive bacteria [18–22]. Moreover, there is now evidence of increasing numbers of strains that are resistant to multiple antibiotic drugs or drug classes, so-called multiple-drug resistant (MDR) organisms. Because of this, the selection of empiric and directed treatment after pathogen identification has become more difficult in both nosocomial and community-acquired settings.

Resistance is a complex problem affected by various mechanisms that are expanding and, increasingly, that are occurring together. Overuse or misuse of antibiotic agents is a key factor creating selective pressure for the emergence and amplification of resistant bacteria. Key mechanisms of antibiotic resistance include production of β-lactamases that inactivate β-lactam drugs, production of other enzymes that inactivate nonβ-lactam antibiotics, alteration in drug-binding targets, expression of efflux pumps (preventing drug access to the intracellular target), and downregulation or modification of membrane pores required for drug entry into the cell [18,21,23].

β-Lactamase production is the most important mechanism of resistance among Gram-negative bacilli; the number of types of these enzymes with broadened activity has increased, including extended-spectrum β-lactamases (ESBLs), AmpC-β lactamases, metallo-β-lactamases, and carbapenemases. This means clinicians frequently need to treat patients who have been infected with Gram-negative bacilli resistant to multiple β-lactam antibiotic subclasses. Other Gram-negative bacteria exhibit MDR that involves multiple overlapping mechanisms of resistance, especially P. aeruginosa and Acinetobacter baumannii [24]. It is now a relatively common occurrence in today's hospital environment to encounter patients who have been infected with strains of P. aeruginosa and A. baumannii that are resistant to three or more antibiotic classes.

The most significant Gram-positive bacterium exhibiting MDR is S. aureus, and specifically methicillin-resistant S. aureus (MRSA). Nearly 60% of S. aureus isolates from hospitalized patients located throughout the United States are methicillin-resistant, with high rates in both inpatients and outpatients and somewhat higher rates in ICUs than in other hospital units [25]. MRSA used to be confined to nosocomial infections, but increasing numbers of patients treated as outpatients in emergency departments or in the community are infected with MRSA. Surveillance data from the Minnesota Department of Health indicated a significant increase in the proportion of MRSA cases classified as community-associated from 11% in 2000 to 33% in 2005 (P < .01) [26]. In a study by Styers et al. [25], MRSA rates were 59, 55, and 48% for strains from non-ICU inpatients, ICU, and outpatients, respectively. Moreover, these authors report MRSA rates in outpatient specimens from the lower respiratory tract, skin and skin tissue, and blood were 43, 38, and 41%, respectively, compared with rates of 56, 49, and 49% for inpatient specimens from the same sources [25].

Community-associated MRSA is a common cause of skin and soft-tissue infections (SSTIs). Moran et al. [27] reported that S. aureus was isolated from 76% of individuals seen in university-affiliated emergency departments for SSTIs in August 2004, and 59% of these isolates were resistant to methicillin and various other antibiotics, even though none of the individuals had established risk factors for MRSA. This is significant because it means clinicians treating patients in emergency departments or the community can no longer assume that oral β-lactam drugs or macrolides will suffice as treatment. As a result of the increased prevalence of community-acquired MRSA, empiric coverage should be directed at this pathogen.

The increasing number of MDR bacterial pathogens is a challenge, not only for patient care but also in the context of new drug development. There is a clear need for new drugs with novel mechanisms of action that can be used to combat the increasing number of bacteria that are resistant to multiple classes of currently available agents. Unfortunately, forces have converged to cause pharmaceutical companies to invest fewer and fewer resources towards the development of these new agents [22]. As such, there is an increasing focus on better use (i.e., pharmacodynamic dose optimization, de-escalation of broad-spectrum empiric therapy) of currently available agents to lengthen their clinical lifetime and slow the emergence of further resistance. Other improvements in infection control are also critical in our attempts to slow the emergence and spread of antibiotic-resistant pathogens within the hospital environment or long-term care facilities [28–31].

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Drug-related factors

The patient population at large is increasingly compromised, and antibiotic resistance is increasing at the same time that the development and the subsequent introduction of new agents is slowing [22,32,33]. In other words, the host is increasingly challenged, the organisms are more difficult, and the treatment armamentarium is not expanding to meet the enhanced medical need. Of the triad impacting outcomes – host, pathogen, and drug-related factors – the latter is the only one that is modifiable. Healthcare professionals make treatment decisions, and the choices they make affect outcomes, both in terms of the immediate patient and reducing emergence of resistant strains that can subsequently impact other patients as well. Therefore, it is exceedingly important that clinicians understand the antibacterial drug armamentarium, from a microbiology, pharmacology, toxicity, and ecologic perspective.

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Early, appropriate therapy

For patients with serious bacterial infections [e.g., patients in the ICU with ventilator-associated pneumonia (VAP) or sepsis], failure to administer an appropriate antibiotic therapy in a timely manner is associated with worse hospital-related and infection-related mortality, infection-related morbidity, length of hospital stay, days of antibiotic therapy, and healthcare costs, compared with early appropriate therapy [34–43]. When considering the reasons for inappropriate therapy, the most common is unanticipated antibiotic resistance to the selected therapy [34–36,41,42]. For example, Harbarth et al. [34] reported that infection with a MDR pathogen was one characteristic associated with inappropriate treatment in patients with severe sepsis. Kollef et al. [36] identified infection with an antibiotic-resistant bacteria as the primary reason for inadequate antibiotic therapy in their study of critically ill hospital patients. In a study of patients transferred from long-term care facilities, 49% of patients infected with an antibiotic-resistant bacteria received inappropriate initial antibiotic therapy, compared with only 4% of patients infected with an antibiotic-susceptible strain [42].

It is important that the therapeutic regimen is timely as well as appropriate, and the window of opportunity may be very small for some patient populations, for example, as early as within the first hour in the context of sepsis or septic shock. In a study of patients in the ICU with VAP, the mortality rate was higher for those who received delayed appropriate treatment [i.e., after performing bronchoscopy or obtaining bronchoalveolar lavage (BAL) results] than for those receiving early adequate treatment [38]. Moreover, mortality results were similar for patients who were switched from inadequate to adequate therapy after bronchoscopy and those who continued to receive inadequate therapy, further demonstrating the importance of early adequate or appropriate therapy and the inability to fully rectify an initial error by a later switch in therapy. Similar results have been reported in other studies [44]. Similar benefits of appropriate therapy have also recently been recognized in non-VAP infections in ICU patients and non-ICU patients [45,46].

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Balancing effective therapy with resistance concerns

Although early, appropriate treatment clearly optimizes outcomes, there is a danger of overtreatment and promotion of antibiotic resistance when a broad-spectrum antibiotic or antibiotic regimen is utilized beyond what is required for empiric or directed therapy based on infection resolution. Clinicians continuously have to ask the question: when does the need to treat empirically with a broad-spectrum agent(s) outweigh the need to wait for culture results. The decision usually hinges on patient factors that have been associated with increased risk of infection with a resistant species, together with institutional antibiograms (if available) indicating the likelihood of resistant species in different units of the hospital. Some of these patient factors include critical illness with fever, prior antibiotic use, prolonged mechanical ventilation, recent surgery, and prolonged hospital stay.

Clinicians are responding to the challenge of treating patients in an era of increased numbers of MDR pathogens, as illustrated by the increased use of broad-spectrum antibiotics, such as carbapenems. As shown in Fig. 1 [47], carbapenem usage has increased in the United States by nearly 90% from 2003 to 2008. This is presumably because of broad-based coverage of resistant pathogens provided by this class of agents, including activity against MDR Pseudomonas, MDR Acinetobacter species, and ESBL-producing bacteria [48,49]. However, given the diminishing number of new drugs entering the market, clinicians need to be careful that these are not overused or misused, leading to the emergence of resistance.

Figure 1

Figure 1

As previously stated, although the utilization of broad-spectrum therapy has been shown to reduce infection-related morbidity and mortality in a variety of patient populations, the indiscriminate use and/or the unnecessary prolonged exposure may lead to the emergence of resistance in target pathogens, the destabilization of gut flora, and the subsequent development of superinfection at this or anatomic sites.

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Antimicrobial stewardship

Antimicrobial stewardship is an increasingly important topic in today's hospital environment, and recent guidelines by the Infectious Diseases Society of America and Society for Healthcare Epidemiology of America provide recommendations for programs to enhance such stewardship [50]. As outlined in the guidelines, the primary goal of antimicrobial stewardship is ‘to optimize clinical outcomes while minimizing unintended consequences of pathogenic organisms (such as C. difficile) and the emergence of resistance’ [50]. A secondary goal is to reduce healthcare costs, without adversely affecting patient quality of care. The guidelines note that effective comprehensive antimicrobial stewardship programs have been shown to decrease antimicrobial use by 22–36%, with associated annual savings of US$ 200 000–900 000. These benefits have been observed in both larger academic hospitals and smaller community hospitals. However, as discussed more fully in the study by Dr Goff in this supplement, the potential financial benefits go beyond simply reduction in drug acquisition or usage costs. Again, the primary focus should be on improving clinical outcomes, which will typically have additional benefits in terms of reducing the emergence of resistance and minimizing length of hospital stay, the primary driver of increased healthcare costs as discussed more fully below.

It is important to understand that stewardship is not a one-time event. Rolling out the program is only the first step – a successful stewardship program is a continuous process, and part of that process is not only bringing clinicians new tools but also providing opportunities for multidisciplinary education. This educational process can be very challenging in today's healthcare environment due to the ever-changing prescriber base, high patient caseloads, and reduced protected time for educational updates. These educational efforts should include information regarding both the successes and shortcomings of one's institutional efforts in addition to future opportunities for improvement.

Another critical component of an effective program is the development of clinical guidelines and/or pathways for optimal antibiotic use. A 2001 study by Ibrahim et al. [51] reported that application of a clinical guideline for VAP treatment increased the initial administration of adequate antibiotic therapy and decreased the overall duration of antibiotic therapy. More recently, we have also reported the successful implementation of a VAP pathway that improved clinical and microbiologic outcomes in the face of emerging pathogen resistance in the ICU setting [52]. In addition, another study also showed that high adherence to an institutional pathway for antibiotic treatment in ICU patients with VAP (>70% compliance) was associated with a shorter duration of treatment for first pneumonia episode (6 vs. 10 days, P = .001), a shorter duration of mechanical ventilation (178 vs. 318 h, P = .017), and a shorter ICU stay (10 vs. 24 days, P = .001) compared with low adherence [53]. In other words, failure to utilize clinical guidelines or pathways lessens the potential for good microbiologic and clinical outcomes.

Establishing good institutional guidelines should, in part, be based on local susceptibility patterns within the hospital and the different units, as determined by periodic antibiograms. As discussed, inadequate antibiotic therapy is more likely if antibiotic resistance is present. A review of the literature indicates that the bacterial pathogens most commonly associated with inadequate antibiotic therapy of VAP are P. aeruginosa (>35%), S. aureus (>20%), and Acinetobacter species (approximately 20%) [54].

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Poor outcomes despite appropriate therapy: treatment timing and dosing issues

The outcome of a bacterial infection may be poor despite selection of an appropriate antibiotic agent. For example, as depicted in Fig. 2, a number of studies of patients with serious infections have reported mortality rates of 15–40%, even though patients were administered appropriate antimicrobial therapy [38,44,55–58]. Three explanations for continued mortality in the face of appropriate antimicrobial therapy are continuation of a terminal process, treatment delay, or inadequate dosing, leading to inadequate drug exposure.

Figure 2

Figure 2

In the context of sepsis and septic shock, treatment may eliminate the instigating pathogen from the bloodstream, but the sepsis process (i.e., the host response to the insult) can continue and eventually lead to patient's death. In addition, as previously mentioned, the timing of treatment can be an important variable, and a delay in treatment might contribute to a less-than-optimal outcome despite the use of an appropriate regimen. In earlier times, clinicians would often initiate empiric treatment with a relatively narrow-spectrum antibiotic and then modify treatment as needed when the culture results became available 3 or 4 days later that revealed a resistant species. However, we now understand that early appropriate therapy is paramount for optimal outcomes, for both Gram-negative and Gram-positive organisms. For example, in the case of sepsis or septic shock, the window of opportunity is the first hour after the process has been identified – a huge challenge [59]. For S. aureus infections, data support the importance of appropriate antibiotic therapy within 48 h of infection onset [60]. As antimicrobial susceptibility results are typically not available this quickly using traditional diagnostic tools, data such as these highlight the importance of understanding local resistance patterns and other factors that increase risk of infection with a resistant species, and making an appropriate choice for initial empiric therapy.

Lastly, poor outcomes may be observed despite the use of an appropriate (as defined by laboratory-based susceptibility criteria) antibiotic because the dosing regimen is insufficient to achieve the necessary level of drug exposure to ensure antibacterial effects. Tam et al. [61] studied the treatment of bacteremia due to P. aeruginosa with piperacillin-tazobactam or other appropriate empirical (control) therapy within 24 h of positive culture results. The results showed piperacillin-tazobactam was associated with a similar 30-day mortality rate as control treatment when P. aeruginosa with high susceptibility to piperacillin-tazobactam [minimum inhibitory concentration (MIC) ≤16 mg/l] was involved (30 vs. 21%, P = .673). However, piperacillin-tazobactam therapy was associated with increased mortality (>80 vs. ∼20%, P = .004) when species with reduced piperacillin-tazobactam susceptibility (MIC ≤32 or 64 mg/l) were involved. This illustrates that with organisms closer to the susceptibility breakpoint for a given antibiotic, although they might still be distinguished as susceptible according to clinical laboratory standards, conventional doses of the antibiotic agent may be insufficient to optimize outcomes.

This is true not only for piperacillin-tazobactam but also for other agents, including other β-lactams, fluoroquinolones, and other antibiotic classes [62,63]. We are beginning to see MRSA with reduced susceptibility to vancomycin, and one of the ways to approach this is to push the vancomycin doses higher [64]. However, some studies have shown that aggressively increasing the vancomycin dose (through concentrations >15 μg/ml) does not necessarily improve clinical outcomes in patients with MRSA infections compared with traditional dose targets (5–15 μg/ml) [65]. Increasing antibiotic doses also raises the concern about escalating toxicity profiles.

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Supplemental strategies to improve outcomes

It is clear that effective antimicrobial stewardship means more than simply choosing the correct antimicrobial agent. It also means de-escalating an initial broad-spectrum antimicrobial regimen once culture results demonstrate a resistant species is not involved [66], as well as using various approaches to optimize the pharmacodynamic properties of currently available agents in an attempt to improve efficacy and minimize the development of resistance [67,68]. Switching from intravenous to oral administration or decreasing the treatment duration after infection resolution are other strategies that can be used to decrease healthcare-related costs without compromising outcomes.

Antibiotics can be classified by their pharmacodynamic profile. The three general pharmacokinetic/pharmacodynamic parameters most predictive of antibiotic efficacy are duration of time a drug concentration remains above the MIC (T > MIC), ratio of the maximal drug concentration to the MIC (C max: MIC), or ratio of the area under the drug concentration time curve at 24 h to the MIC (AUC0–24: MIC) [67–69]. Agents whose efficacy is best predicted by T > MIC are called time-dependent agents, whereas those whose efficacy is best predicted by C max: MIC or AUC: MIC are concentration-dependent drugs. Optimal drug exposure and clinical outcomes, including minimization of drug resistance, can best be achieved by understanding the pharmacodynamic parameter best correlating with efficacy for a given drug, and then dosing to achieve that measure.

β-Lactams are among the most frequently administered antimicrobials in hospitals, cephalosporins and penicillins for more general usage and, increasingly, carbapenems to satisfy the need for appropriate empiric therapy in the setting of growing resistance. β-Lactams are time-dependent agents whose efficacy is best predicted by T > MIC [68]. The optimal T > MIC varies by β-lactam class: 60–70% for cephalosporins and 40% for carbapenems. Optimal efficacy for a carbapenem is best achieved by dosing in a manner that ensures that the concentration of the drug at the target site remains above that of the MIC for at least 40% of the dosing interval, typically defined as a 24-h period. Strategies to increase the T > MIC include increasing the dose, increasing the dosing frequency (without a subsequent increase in the dose), or extending the infusion time of intravenous agents. Dose-escalation techniques (increasing the dose or dosing interval) are relatively ineffective strategies to increase T > MIC and β-lactam efficacy [68,70]. Although some increase in T > MIC or exposure may be achieved, it is usually nonproportional, small, and insufficient to achieve optimal T > MIC or drug exposure. For example, doubling the drug dose typically does not mean a doubling of the T > MIC, and hence does not lead to a meaningful improvement in efficacy, but it does double the cost and potential toxicity associated with a given therapy. To improve drug exposure, one can use a once-daily compound with sufficient potency that optimizes the pharmacodynamic profile, or for the shorter half-life β-lactams, a strategy to increase the T > MIC is to increase the infusion duration of intravenous agents. By lengthening the infusion time, the T > MIC can be increased, while using the same dose and dosing interval. By playing with these parameters, an optimal T > MIC can be achieved in a reproducible manner that does not increase drug costs. Moreover, because of the inherent safety of β-lactams in the clinical setting, the strategy of prolonged infusion can be combined with higher β-lactam doses when desiring better coverage of pathogens with reduced susceptibility. This is a potentially exciting opportunity allowing clinicians to best avail themselves of the existing drug armamentarium to optimize clinical outcomes and minimize resistance in the context of a diminishing drug pipeline.

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Bacterial resistance and increasing healthcare costs

Infections caused by resistant versus susceptible bacterial species are associated with higher mortality, longer hospital stays, and increased healthcare costs [3]. A recent study by Evans et al. [71] compared cost and hospital length of stay data for 604 surgical admissions treated for at least one Gram-negative rod infection caused by susceptible species (n = 467) or a species resistant to at least one major antibiotic class (n = 137). Infection with a resistant versus susceptible Gram-negative rod was associated with longer median hospital length of stay (29 vs. 13 days, P < .0001) and longer median ICU length of stay (13 vs. 1 day, P < .0001), and higher median hospital costs (US$ 80 500 vs. 29 604, P < .0001) and higher median antibiotic costs (US$ 2607 vs. 758, P < .0001). Hence, infection with a resistant species increased the total cost of hospital care by more than 2.5-fold.

As noted earlier, part of the reason for the increased costs associated with resistant pathogens is due to initial inadequate antibiotic therapy. This has led to a general strategy in many institutions to ‘hit hard and fast’ with a broad-spectrum agent(s) when a resistant species is likely to be involved [72], with step-down or modification of therapy if and when culture data prove otherwise. Various components of care contribute to overall costs, but drug acquisition and usage costs are only a small contributor. Although a reduction in antimicrobial costs is the most common justification for implementing an antimicrobial stewardship program [73], a number of studies have demonstrated that drug acquisition costs are a relatively small and often insignificant portion of total healthcare costs, in the range of about 5% (Fig. 3) [74–78]. In terms of both patient outcomes and healthcare costs, it is typically more important to treat as early as possible with an appropriate regimen, even if more expensive, than to begin with inadequate therapy that leads to longer hospital stay and poorer patient outcomes – as well as increasing the risk of resistance.

Figure 3

Figure 3

These points are illustrated in a recent 2010 study reported by our center that looked at hospital costs associated with the use of a clinical pathway implemented in ICUs to optimize antibiotic regimen selection for patients with VAP [79]. VAP-related length of stay, hospitalization costs, and antibiotic costs were compared between patients treated using the pathway and a historical control group treated according to prescriber preference. Results showed patients in the clinical pathway group were more frequently aggressively dosed with more costly antibiotics as empiric therapy, including more frequent use of combination therapy targeting P. aeruginosa (93 vs. 12%, P < .001) and triple-drug therapy targeting both MRSA and P. aeruginosa (79 vs. 4%, P < .001). Despite this, VAP hospitalization cost was lower for the clinical pathway versus control group (US$ 47 033 vs. 90 585, P < .001). These data showed hospital costs were similar for the two groups over the first week of VAP (US$ 24 501 vs. 28 106), but were significantly lower for the clinical pathway group during week 2 (US$ 12 231 vs. 20 947, P < .001). Patients treated with the clinical pathway also had shorter lengths of ICU stay after VAP, shorter total hospital lengths of stay after VAP, and a lower infection-related mortality rate (9 vs. 21%). Costs for VAP-associated antibiotics accounted for 1.49% of total hospital costs for patients in the clinical pathway group and 0.64% in the control group. There was no significant difference in mean antibiotic drug costs between the treatment groups (US$ 766 vs. 934, P = .45).

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Optimal outcomes for bacterial infections are best achieved by early empiric therapy with an appropriate regimen, making modifications as necessary after the availability of culture results. Selection of the initial empiric therapy should be based on patient characteristics and data from local antibiograms combined with pharmacodynamic dosing strategies to optimize antibiotic exposures. In terms of financial costs, the costs saved by avoiding treatment failure are generally much greater than the costs spent on antibiotic therapy. As illustrated by our economic study of VAP management, drug-acquisition cost is an important but often small component of overall healthcare costs for patients with serious bacterial infections. In addition, we demonstrated that the utilization of more potent antimicrobial regimens combined with a de-escalation strategy in our VAP population resulted in improved clinical and microbiologic outcomes. As shown in our publication, clinicians can use less-expensive, less-potent antimicrobial therapies for longer periods and get inferior outcomes, or one could administer optimally designed regimens that improve the quality of care and lower healthcare costs. Lastly, although strong infection control programs should be advocated to enhance awareness and minimize the spread of resistant pathogens, the only modifiable factor in the context of the host–bug–drug triad is the choice of the antibiotic, dose, and duration. In the era of increasing resistance, an aging/compromised patient population, and a dwindling pipeline of novel agents, the implementation of antibiotic stewardship practices is paramount if good clinical outcomes are to be sustained.

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This supplement was supported through an educational grant from Merck & Co., Inc.

The author declares no conflicts of interest.

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antibiotic resistance; antibiotic stewardship; pharmacodynamic; pharmacokinetic

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