Share this article on:

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:

Back to Top | Article Outline


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.

Back to Top | Article Outline

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.

Back to Top | Article Outline

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].

Back to Top | Article Outline

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.

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].

Back to Top | Article Outline

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.

Back to Top | Article Outline

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].

Back to Top | Article Outline

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.

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.

Back to Top | Article Outline

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].

Back to Top | Article Outline

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.

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.

Back to Top | Article Outline

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 (Cmax: 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 Cmax: 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.

Back to Top | Article Outline

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.

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).

Back to Top | Article Outline


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.

Back to Top | Article Outline


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

The author declares no conflicts of interest.

Back to Top | Article Outline


1 Weber DJ. Collateral damage and what the future might hold: the need to balance prudent antibiotic utilization and stewardship with effective patient management. Int J Infect Dis 2006; 10:S17–S24.
2 Cosgrove SE. The relationship between antimicrobial resistance and patient outcomes: mortality, length of hospital stay, and healthcare costs. Clin Infect Dis 2006; 42(Suppl 2):S82–S89.
3 Maragakis LL, Perencevich EN, Cosgrove SE. Clinical and economic burden of antimicrobial resistance. Expert Rev Anti Infect Ther 2008; 6:751–763.
4 Roberts RR, Hota B, Ahmad I, et al. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin Infect Dis 2009; 49:1175–1184.
5 Clec'h C, Timsit JF, De Lassence A, et al. Efficacy of adequate early antibiotic therapy in ventilator-associated pneumonia: influence of disease severity. Intensive Care Med 2004; 30:1327–1333.
6 Kollef MH, Ward S. The influence of mini-BAL cultures on patient outcomes: implications for the antibiotic management of ventilator-associated pneumonia. Chest 1998; 113:412–420.
7 Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171:388–416.
8 Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44(Suppl 2):S27–S72.
9 Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis 2010; 50:133–164.
10 Livermore DM, Pearson A. Antibiotic resistance: location, location, location. Clin Microbiol Infect 2007; 13(Suppl 2):7–16.
11 Namias N, Samiian L, Nino D, et al. Incidence and susceptibility of pathogenic bacteria vary between intensive care units within a single hospital: implications for empiric antibiotic strategies. J Trauma 2000; 49:638–645, discussion 645–636.
12 Rello J, Sa-Borges M, Correa H, et al. Variations in etiology of ventilator-associated pneumonia across four treatment sites: implications for antimicrobial prescribing practices. Am J Respir Crit Care Med 1999; 160:608–613.
13 Peterson LR. Bad bugs, no drugs: no ESCAPE revisited. Clin Infect Dis 2009; 49:992–993.
14 Rice LB. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J Infect Dis 2008; 197:1079–1081.
15 Leclair MA, Allard C, Lesur O, Pepin J. Clostridium difficile infection in the intensive care unit. J Intensive Care Med 2010; 25:23–30.
16 Riddle DJ, Dubberke ER. Clostridium difficile infection in the intensive care unit. Infect Dis Clin North Am 2009; 23:727–743.
17 Gaynes R, Edwards JR. Overview of nosocomial infections caused by gram-negative bacilli. Clin Infect Dis 2005; 41:848–854.
18 Hawkey PM, Jones AM. The changing epidemiology of resistance. J Antimicrob Chemother 2009; 64(Suppl 1):i3–i10.
19 Isturiz R. Global resistance trends and the potential impact on empirical therapy. Int J Antimicrob Agents 2008; 32(Suppl 4):S201–S206.
20 Moellering RC Jr, Graybill JR, McGowan JE Jr, Corey L. Antimicrobial resistance prevention initiative: an update – proceedings of an expert panel on resistance. Am J Med 2007; 120:S4–S25, quiz S26–S28.
21 Rahal JJ. Antimicrobial resistance among and therapeutic options against gram-negative pathogens. Clin Infect Dis 2009; 49(Suppl 1):S4–S10.
22 Talbot GH, Bradley J, Edwards JE Jr, et al. Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. Clin Infect Dis 2006; 42:657–668.
23 Tenover FC. Mechanisms of antimicrobial resistance in bacteria. Am J Med 2006; 119:S3–S10, discussion S62–S70.
24 McGowan JE Jr. Resistance in nonfermenting gram-negative bacteria: multidrug resistance to the maximum. Am J Med 2006; 119:S29–S36, discussion S62–S70.
25 Styers D, Sheehan DJ, Hogan P, Sahm DF. Laboratory-based surveillance of current antimicrobial resistance patterns and trends among Staphylococcus aureus: 2005 status in the United States. Ann Clin Microbiol Antimicrob 2006; 5:2.
26 Como-Sabetti K, Harriman KH, Buck JM, et al. Community-associated methicillin-resistant Staphylococcus aureus: trends in case and isolate characteristics from six years of prospective surveillance. Public Health Rep 2009; 124:427–435.
27 Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med 2006; 355:666–674.
28 Henderson DK. Managing methicillin-resistant staphylococci: a paradigm for preventing nosocomial transmission of resistant organisms. Am J Med 2006; 119:S45–S52, discussion S62–S70.
29 Muto CA, Jernigan JA, Ostrowsky BE, et al. SHEA guideline for preventing nosocomial transmission of multidrug-resistant strains of Staphylococcus aureus and enterococcus. Infect Control Hosp Epidemiol 2003; 24:362–386.
30 Shlaes DM, Gerding DN, John JF Jr, et al. Society for Healthcare Epidemiology of America and Infectious Diseases Society of America Joint Committee on the Prevention of Antimicrobial Resistance: guidelines for the prevention of antimicrobial resistance in hospitals. Clin Infect Dis 1997; 25:584–599.
31 Smith PW, Bennett G, Bradley S, et al. SHEA/APIC guideline: infection prevention and control in the long-term care facility, July 2008. Infect Control Hosp Epidemiol 2008; 29:785–814.
32 Bad bugs, no drugs: as antibiotic R&D stagnates, a public health crisis brews. Alexandria, VA: Infectious Diseases Society of America; 2004.
33 Spellberg B, Powers JH, Brass EP, et al. Trends in antimicrobial drug development: implications for the future. Clin Infect Dis 2004; 38:1279–1286.
34 Harbarth S, Garbino J, Pugin J, et al. Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med 2003; 115:529–535.
35 Kang CI, Kim SH, Park WB, et al. Bloodstream infections caused by antibiotic-resistant gram-negative bacilli: risk factors for mortality and impact of inappropriate initial antimicrobial therapy on outcome. Antimicrob Agents Chemother 2005; 49:760–766.
36 Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 1999; 115:462–474.
37 Leibovici L, Shraga I, Drucker M, et al. The benefit of appropriate empirical antibiotic treatment in patients with bloodstream infection. J Intern Med 1998; 244:379–386.
38 Luna CM, Vujacich P, Niederman MS, et al. Impact of BAL data on the therapy and outcome of ventilator-associated pneumonia. Chest 1997; 111:676–685.
39 Micek ST, Lloyd AE, Ritchie DJ, et al. Pseudomonas aeruginosa bloodstream infection: importance of appropriate initial antimicrobial treatment. Antimicrob Agents Chemother 2005; 49:1306–1311.
40 Mueller EW, Hanes SD, Croce MA, et al. Effect from multiple episodes of inadequate empiric antibiotic therapy for ventilator-associated pneumonia on morbidity and mortality among critically ill trauma patients. J Trauma 2005; 58:94–101.
41 Paterson DL, Ko WC, Von Gottberg A, et al. Antibiotic therapy for Klebsiella pneumoniae bacteremia: implications of production of extended-spectrum beta-lactamases. Clin Infect Dis 2004; 39:31–37.
42 Toubes E, Singh K, Yin D, et al. Risk factors for antibiotic-resistant infection and treatment outcomes among hospitalized patients transferred from long-term care facilities: does antimicrobial choice make a difference? Clin Infect Dis 2003; 36:724–730.
43 Vidal F, Mensa J, Almela M, et al. Epidemiology and outcome of Pseudomonas aeruginosa bacteremia, with special emphasis on the influence of antibiotic treatment: analysis of 189 episodes. Arch Intern Med 1996; 156:2121–2126.
44 Rello J, Gallego M, Mariscal D, et al. The value of routine microbial investigation in ventilator-associated pneumonia. Am J Respir Crit Care Med 1997; 156:196–200.
45 Kumar A, Ellis P, Arabi Y, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 2009; 136:1237–1248.
46 Ortega M, Marco F, Soriano A, et al. Analysis of 4758 Escherichia coli bacteraemia episodes: predictive factors for isolation of an antibiotic-resistant strain and their impact on the outcome. J Antimicrob Chemother 2009; 63:568–574.
47 National Sales Perspective (NSP) audit. IMS. December 2008.
48 Baughman RP. The use of carbapenems in the treatment of serious infections. J Intensive Care Med 2009; 24:230–241.
49 Rahal JJ. The role of carbapenems in initial therapy for serious gram-negative infections. Crit Care 2008; 12(Suppl 4):S5.
50 Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 2007; 44:159–177.
51 Ibrahim EH, Ward S, Sherman G, et al. Experience with a clinical guideline for the treatment of ventilator-associated pneumonia. Crit Care Med 2001; 29:1109–1115.
52 Nicasio AM, Eagye KJ, Nicolau DP, et al. Pharmacodynamic-based clinical pathway for empiric antibiotic choice in patients with ventilator-associated pneumonia. J Crit Care 2010; 25:69–77.
53 Nachtigall I, Tamarkin A, Tafelski S, et al. Impact of adherence to standard operating procedures for pneumonia on outcome of intensive care unit patients. Crit Care Med 2009; 37:159–166.
54 Kollef MH. Inadequate antimicrobial treatment: an important determinant of outcome for hospitalized patients. Clin Infect Dis 2000; 31(Suppl 4):S131–S138.
55 Alvarez-Lerma F. Modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit. ICU-Acquired Pneumonia Study Group. Intensive Care Med 1996; 22:387–394.
56 Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A, et al. Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Crit Care Med 2003; 31:2742–2751.
57 Ibrahim EH, Sherman G, Ward S, et al. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest 2000; 118:146–155.
58 Valles J, Rello J, Ochagavia A, et al. Community-acquired bloodstream infection in critically ill adult patients: impact of shock and inappropriate antibiotic therapy on survival. Chest 2003; 123:1615–1624.
59 Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34:1589–1596.
60 Lodise TP, McKinnon PS, Swiderski L, Rybak MJ. Outcomes analysis of delayed antibiotic treatment for hospital-acquired Staphylococcus aureus bacteremia. Clin Infect Dis 2003; 36:1418–1423.
61 Tam VH, Gamez EA, Weston JS, et al. Outcomes of bacteremia due to Pseudomonas aeruginosa with reduced susceptibility to piperacillin-tazobactam: implications on the appropriateness of the resistance breakpoint. Clin Infect Dis 2008; 46:862–867.
62 Bhat SV, Peleg AY, Lodise TP Jr, et al. Failure of current cefepime breakpoints to predict clinical outcomes of bacteremia caused by gram-negative organisms. Antimicrob Agents Chemother 2007; 51:4390–4395.
63 Moise-Broder PA, Sakoulas G, Eliopoulos GM, et al. Accessory gene regulator group II polymorphism in methicillin-resistant Staphylococcus aureus is predictive of failure of vancomycin therapy. Clin Infect Dis 2004; 38:1700–1705.
64 Mohr JF, Murray BE. Point: vancomycin is not obsolete for the treatment of infection caused by methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2007; 44:1536–1542.
65 Jeffres MN, Isakow W, Doherty JA, et al. Predictors of mortality for methicillin-resistant Staphylococcus aureus health-care-associated pneumonia: specific evaluation of vancomycin pharmacokinetic indices. Chest 2006; 130:947–955.
66 Niederman MS. The importance of de-escalating antimicrobial therapy in patients with ventilator-associated pneumonia. Semin Respir Crit Care Med 2006; 27:45–50.
67 Ambrose PG, Bhavnani SM, Rubino CM, et al. Pharmacokinetics–pharmacodynamics of antimicrobial therapy: it's not just for mice anymore. Clin Infect Dis 2007; 44:79–86.
68 Nicolau DP. Containing costs and containing bugs: are they mutually exclusive? J Manag Care Pharm 2009; 15:S12–S17.
69 Mouton JW, Dudley MN, Cars O, et al. Standardization of pharmacokinetic/pharmacodynamic (PK/PD) terminology for antiinfective drugs: an update. J Antimicrob Chemother 2005; 55:601–607.
70 Nicolau DP. Pharmacodynamic optimization of beta-lactams in the patient care setting. Crit Care 2008; 12(Suppl 4):S2.
71 Evans HL, Lefrak SN, Lyman J, et al. Cost of Gram-negative resistance. Crit Care Med 2007; 35:89–95.
72 Slama TG. Gram-negative antibiotic resistance: there is a price to pay. Crit Care 2008; 12(Suppl 4):S4.
73 Drew RH, White R, MacDougall C, et al. Insights from the Society of Infectious Diseases Pharmacists on antimicrobial stewardship guidelines from the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Pharmacotherapy 2009; 29:593–607.
74 Dresser LD, Niederman MS, Paladino JA. Cost-effectiveness of gatifloxacin vs ceftriaxone with a macrolide for the treatment of community-acquired pneumonia. Chest 2001; 119:1439–1448.
75 Friedrich LV, White RL, Kays MB, Burgess DS. Pharmacoeconomic evaluation of treatment of penetrating abdominal trauma. Am J Hosp Pharm 1992; 49:590–594.
76 McKinnon PS, Paladino JA, Grayson ML, et al. Cost-effectiveness of ampicillin/sulbactam versus imipenem/cilastatin in the treatment of limb-threatening foot infections in diabetic patients. Clin Infect Dis 1997; 24:57–63.
77 Nicolau DP, White RL, Friedrich LV, Kays MB. The costs of burn care: an analysis with an emphasis on the use of parenteral antimicrobials. J Burn Care Rehabil 1994; 15:244–250.
78 Paladino JA, Fell RE. Pharmacoeconomic analysis of cefmenoxime dual individualization in the treatment of nosocomial pneumonia. Ann Pharmacother 1994; 28:384–389.
79 Nicasio AM, Eagye KJ, Kuti EL, et al. Length of stay and hospital costs associated with a pharmacodynamic-based clinical pathway for empiric antibiotic choice for ventilator-associated pneumonia. Pharmacotherapy 2010; 30:453–462.

antibiotic resistance; antibiotic stewardship; pharmacodynamic; pharmacokinetic

© 2011 Lippincott Williams & Wilkins, Inc.